DES Årsmøde 2014 - Dansk Endokrinologisk Selskab · Dansk Endokrinologisk Selskabs Årsmøde 2014 Hotel Helnan Marselis, Aarhus Fredag den 17. januar 2014 Registrering ... Gerrit

Årsmøde 2014

Hotel Helnan Marselis - Aarhus/Randers - 17.-18. januar 2014

Medicinsk Endokrinologisk Afdeling MEA Aarhus Universitetshospital

Medicinsk Afdeling Regionshospitalet Randers

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På vegne af Dansk Endokrinologisk Selskab vil årsmødets lokale organisationskomité

gerne takke vore sponsorer og udstillere for godt samarbejde:

Amgen

Astra Zeneca

Axellus

Bayer

BMS

Brahms

Danish Diabetes Academy

Eli Lilly

Ferring

Ipsen

Maribo

Medtronic

MSD

Novartis

Novo Nordisk

Sanofi-Aventis

Takeda Pharma

Viropharma

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Den lokale organisationskomité:

Jens Melgaard Bruun (formand) Regionshospitalet Randers

Troels Krarup Hansen Aarhus Universitetshospital

Morten Møller Poulsen Regionshospitalet Randers

Ulla Kampmann Aarhus Universitetshospital

Esben Søndergaard Aarhus Universitetshospital

Lene Ring Madsen Aarhus Universitetshospital

Christian Kruse (webmaster) Aalborg Universitetshospital

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Program

Dansk Endokrinologisk Selskabs Årsmøde 2014

Hotel Helnan Marselis, Aarhus

Fredag den 17. januar 2014

Registrering Kl. 09.00 – 10.00

Marselissalen Sal 8 Bøgesalen Velkomst Velkomst Velkomst

T1DM 10.00-11.30

Inkretiner 10.00-11.30

Metabolisme 10.00-11.30

Pause Graviditet og endokrinologi 11.45-13.00

Diabetiske komplikationer 11.45-13.00

Bariatri, anorexi og ernæring

11.45-13.00

Frokost Thyroidea

13.45-15.30 Prædiabetes og T2DM

13.45-15.30 Knoglemetabolisme

13.45-15.30 Kaffepause

Kardiovaskulært 16.00-17.30

Blandet endokrinologi 16.00-17.30

Omklædning

Middag Kl. 19.00

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Program

Dansk Endokrinologisk Selskabs Årsmøde 2014

Hotel Helnan Marselis, Aarhus

Lørdag den 18. januar 2014

Marselissalen Uddeling af abstract-priser

Kl. 09.00 - 09.30

Uddeling af Niels Schwartz Sørensen prisen + foredrag Kl. 09.30 – 10.30

Kaffepause

Nyt om de Nationale Behandlingsvejledninger

Kl. 11.00 – 11.30

International Invited speaker: Professor Per-Henrik Groop, Helsinki, Finland

Kl. 11.30 – 12.30 Frokost

Kl. 12.30

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Abstract- og præsentationsoversigt

”T1DM”

Fredag 17. januar 2014, kl. 10.00-11.30

Marselissalen

Abstract 1-9

Chairs: Ulrik Pedersen-Bjergaard og Peter Rossing

1 Genetic risk score modelling for disease progression in new-onset type 1 diabetes patients – Evidence for TNFAIP3 and SKAP2 as modulators of β-cell apoptosis.b Caroline A. Brorsson, Lotte B. Nielsen, Anne M. Traulsen, Marie Louise Andersen, Tina Fløyel, Lukas A. Berchtold, Regine Bergholdt, Lars Hansen, Henrik B. Mortensen, Flemming Pociot and Joachim Størling.

2 Development of Anti-idiotypic Antibodies Against the Monoclonal Autoantibody IC2 in an Attempt to Normalize the Deficient Natural Killer T-cell Activity in Type-1 Diabetes. Jensen KL, Engmose CP, Engkilde K, Lermark Å, Brogren CH

3 Is TRAF3IP2 involved in the pathogenesis of type 1 diabetes and beta-cell apoptosis via induction of NFkB? Ann Bech Thomsen, Lise Wogensen Bach, Joachim Størling, Caroline Brorsson, Flemming Pociot.

4 Effect of insulin analogues on frequency of documented hypoglycaemia in patients with type 1 diabetes and recurrent severe hypoglycaemia Agesen RM, Kristensen PL, Beck-Nielsen H, Nørgaard K, Perrild H, Christiansen JS, Jensen T, Hougaard P, Parving H-H, Thorsteinsson B, Tarnow L, Pedersen-Bjergaard U

5 Glucose-dependent insulinotropic polypeptide augments glucagon responses to hypoglycaemia in type 1 diabetes Mikkel Christensen, Salvatore Calanna, Alexander Hovard Sparre-Ulrich, Peter Lommer Kristensen, Mette Marie Rosenkilde, Francesco Purrello, Gerrit van Hall, Jens Juul Holst, Tina Vilsbøll and Filip Krag Knop

6 Behandlingskvalitet hos patienter med type 1 diabetes i behandling med insulinpumpe Hans Jørgen Gjessing, Ulla Linding Jørgensen, Charlotte Chrois Møller, Jette Pedersen, Ellen Grodum, Karoline Schousboe

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7 Short-term effects of NPH insulin, insulin detemir and insulin glargine on the IGF-IGFBP-GH axis in patients with type 1 diabetes Zhulin Ma, Jens Sandahl Christiansen, Torben Laursen, Torsten Lauritzen, Jan Frystyk

8 Targeting intensive versus conventional glycemic control for type 1 diabetes mellitus: systematic review with meta-analyses and trial sequential analyses of randomized clinical trials Pernille Kähler, Berit Grevstad, Thomas Almdal, Christian Gluud, Jørn Wetterslev, Søren Søgaard Lund, Allan Vaag, Bianca Hemmingsen

9 Diabetes udløst af højdosis steroidbehandling hos kræftpatienter Schultz H, Kristensen PL, Engelholm SA, Harder E, Pedersen-Bjergaard U

Ekstra Proteolytic fragmented and chimeric IC2 monoclonal autoantibody against the pancreatic beta-cell surface chemically labeled with the near-infrared fluorochromes for near-infrared noninvasive imaging of the pancreatic beta-cell mass. Brogren CH, Al-Shamary N, Sefeld M, Briat A

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”Inkretiner”

Fredag 17. januar 2014, kl. 10.00-11.30

Sal 8

Abstract 10-18

Chairs: Tina Vilsbøll og Jørgen Rungby

10 Weight reducing effects of liraglutide in mice are dependent on number of daily injections rather than dose Emilie Balk-Møller, Hannelouise Kissow

11 Glucagon-like peptide-1 (GLP-1) reduces mortality and improves lung function in a model of experimental obstructive lung disease in female mice. Niels-Erik Viby, Marie S. Isidor, Katrine B. Buggeskov, Steen S. Poulsen , Jacob B. Hansen and Hannelouise Kissow

12 Luminal glucose stimulates GLP-1 secretion from the isolated perfused rat small intestine by SGLT-1 and GLUT2 mediated uptake and L-type calcium channel activation Rune Ehrenreich Kuhre, Charlotte Rasmussen, Berit Svendsen, Jens Juul Holst

13 Activation of renal GLP-1 receptors located in the afferent arterioles causes an increase in renal blood flow Jensen, E.P., S.S. Poulsen, H.Kissow, C.Deacon, J.J. Holst and C.M. Sorensen

14 Targeting the L-cell – Does G-protein Coupled Receptor 40 Activation Stimulate Glucagon-like-peptide-1 Secretion? Louise Wulff Christensen, Berit Svendsen, Jens Juul Holst

15 Impaired incretin effect and gastrointestinal-mediated glucose disposal in non-diabetic patients with cirrhosis Anders E. Junker, Lise L. Gluud, Jens J. Holst, Filip K. Knop, Tina Vilsbøll

16 The effects of liraglutide and ischemic postconditioning on myocardial salvage after ischemia-reperfusion injury in pigs. Ekström K, Dalsgaard M, Iversen KK, Pedersen-Bjergaard U, Vejlstrup NG, Diemar SS, Idorn M, Thorsteinsson B, Engstrøm T.

17 Liraglutide is associated with a decreased risk of acute myocardial infarction in type 2 diabetes mellitus patients. Søren Gregersen, Jakob Starup-Linde, Jan Scheel-Thomsen, Michael Gejl, Peter Vestergaard.

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18 Near-normalization of glycaemic control with a glucagon-like peptide-1 receptor agonist in combination with physical exercise: a randomized double-blinded placebo-controlled clinical trial Pernille Mensberg, Signe Nyby, Peter G. Jørgensen, Heidi Storgaard, Jacob C. Sivertsen, Magnus T. Jensen, Bente Kiens, Erik A. Richter, Filip K. Knop and Tina Vilsbøll.

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”Metabolisme”

Fredag 17. januar 2014, kl. 10.00-11.30

Bøgesalen

Abstract 19-27

Chairs: Esben Søndergaard og Jens Otto Jørgensen

19 Persistent AS160 and TBC1D1 phosphorylation in human skeletal muscle 30 min after a single bout of exercise Mikkel H. Vendelbo, Andreas B. Møller, Jonas T. Treebak, Lars C Gormsen, Jørgen F. P. Wojtaszewski, Jens Otto L. Jørgensen, Niels Møller, Niels Jessen

20 Regulation of glycogen synthase during exercise and exercise recovery in skeletal muscle of overweight subjects with and without Type 2 diabetes: Effects of insulin. Andreas James Thestrup Pedersen, Janne Rasmus Hingst, Kurt Højlund, Martin Friedrichsen, Jonas Møller Kristensen, Jørgen F.P. Wojtaszewski

21 Molecular mechanisms of exercise-induced autophagy in human skeletal muscle – effect of substrate availability A.B. Møller, M.H. Vendelbo, B. Christensen, B.F. Clasen, J.O. Jørgensen, N. Møller and N. Jessen

22 Growth Hormone (GH)-infusion and fasting both reduce mRNA expression of G0/G1 Switch Gene 2 (G0S2) in human subjects Peter K. Brask-Thomsen, Birgitte Nellemann, Mikkel H. Vendelbo, Thomas S. Nielsen, Ann M. Bak, Steen B. Pedersen, Berthil F. F. Clasen, Niels Møller, Esben T. Vestergaard, Niels Jessen and Jens Otto L. Jørgensen.

23 Regulation of ANGPTL4 in human muscle- and adipose tissue Rikke Viggers, Ann Mosegaard Bak, Niels Møller, Jens Otto Lunde Jørgensen, Niels Jessen

24 Intravenous catheters, causes elevated IL-6 locally. Karen Fjeldborg, Steen Bønløkke Pedersen, Bjørn Richelsen

25 Impaired insulin-mediated VLDL-triglyceride Kinetics in Overweight/Obese men with Non-alcoholic Fatty Liver Disease Poulsen MK , Nellemann B, Pedersen SB, Grønbæk H, Nielsen S

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26 Gastrointestinal-mediated glucose disposal in total pancreatectomised patients Asger Lund, Jonatan I. Bagger, Mikkel Christensen, Magnus Grøndahl, Elisabeth R. Mathiesen, Carsten P. Hansen, Jan Storkholm, Steen Larsen, Jens J. Holst, Tina Vilsbøll and Filip K. Knop

27 Metabolic Effects of an Amino Acid infusion during LPS Exposure mimicking acute Infection in Humans N. Rittig, E. Bosjnak, HH. Thomsen, B. Richelsen, JO. Jørgensen, N. Møller

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”Graviditet og endokrinologi”

Fredag 17. januar 2014, kl. 11.45-13.00

Marselissalen

Abstract 28-34

Chairs: Birte Nygaard og Claus H. Gravholt

28 Adverse pregnancy outcome and mitochondrial dysfunction in women with subclinical hypothyroidism. Anne-Dorthe Feldthusen, Palle Lyngsie Pedersen, Jacob Larsen, Tina Toft Kristensen, Jan Kvetny.

29 Monitoring and evaluation of the Levothyroxin replacement therapy in pregnant women with hypothyroidism. Julia Hubaveshka, Luba Freja Liubov Michaelsson, Birte Nygaard.

30 Antithyroid behandling i tidlig graviditet giver betydende risiko for medfødte misdannelser. Et dansk nationalt studie af 1.820 eksponerede børn. Stine Linding Andersen, Jørn Olsen, Chun Sen Wu og Peter Laurberg

31 Brug af antithyroid medicin bør begrænses i tidlig graviditet og ophøre før 6. graviditetsuge. Peter Laurberg & Stine Linding Andersen

32 Abdominal circumference is higher in children born of women with polycystic ovary syndrome than controls Hanne Mumm, Dorte Glintborg, Jens Aage Sørensen, Lise Lotte Torvin Andersen, Dorte Møller Jensen, Marianne Andersen

33 Lower levels of placental growth hormone in early pregnancy in type 1 diabetic women giving birth to large for gestational age infants Lene Ringholm, Anders Juul, Ulrik Pedersen-Bjergaard, Birger Thorsteinsson, Peter Damm, Elisabeth R. Mathiesen

34 Morbidity and mortality in offspring born to mothers with type 1 diabetes. Sine Knorr, Kirstine Stochholm, Zuzana Vlachova, Birgitte Bytoft, Tine Dalsgaard Clausen, Rikke Beck Jensen, Peter Damm, Henning Beck-Nielsen, Dorte M. Jensen, Claus Højbjerg Gravholt

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”Diabetiske komplikationer”

Fredag 17. januar 2014, kl. 11.45-13.00

Sal 8

Abstract 35-42

Chairs: Lise Tarnow og Dan Hesse

35 Foot protection in bed in patients with diabetic pressure ulcers and serious comorbidity. Anne Rasmussen, Per Holstein, Kirsten Engelhard Nielsen, Martin Ridderstråle.

36 Effects of Leucopatch™, an Autologous, Leucocytes and Platelet Rich Fibrin Patch, in Patients with Hard-to-Heal Diabetic Foot Ulcers. A pilot study. Magnus Löndahl, Lise Tarnow, Tonny Karlsmark, Rasmus Lundquist, Anna Marie Nielsen, Morten Michelsen, Anders Nilsson, Mariusz Zakrzewski, Bo Jörgensen.

37 Magnetic resonance imaging for volumetric evaluation of diabetic polyneuropathy: A methodological pilot study Michael Vaeggemose MSc PhD-stud, Steffen Ringgaard MSc PhD, Knud Yderstraede MD PhD, Niels Ejskjaer MD PhD, Henning Andersen MD PhD Prof

38 Soluble Urokinase Plasminogen Activator Receptor is associated with diabetes and diabetic complications in patients with type 1 diabetes S Theilade, S Lyngbæk, TW Hansen, J Eugen-Olsen, M Fenger, P Rossing and JL Jeppesen

39 Ficolin B in Diabetic Kidney Disease Charlotte Berg Holt, Jakob Appel Østergaard, Steffen Thiel, Troels Krarup Hansen

40 Circulating levels of mid regional pro-adrenomedullin (MR-proADM) are not associated with major cardiovascular events or renal failure in patients with type 1 diabetes Pernille Holmager, Ulrik Pedersen-Bjergaard, Anne-Sophie Sejling, Birger Thorsteinsson, Jens Faber, Caroline Kistorp.

41 Effect of Aldosterone Receptor Blockade on Galectin 3 in Patients with Diabetic Nephropathy Morten Lindhardt, Maria Lajer, Hiddo Jan Lambers Heerspink, Peter Rossing and Rudolf A. de Boer.

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42 Low-density lipoprotein cholesterol is associated with fracture risk in diabetes patients - a nested case-control study Jakob Starup-Linde, Soeren Gregersen, Peter Vestergaard

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”Bariatri, anorexi og ernæring”

Fredag 17. januar 2014, kl. 11.45-13.00

Bøgesalen

Abstract 43-49

Chairs: Filip Knop og Jens Meldgaard Bruun

43 Changes in body weight, hormonal status, and physical activity during cannabinoid treatment in patients with severe, enduring anorexia nervosa: results from a randomised, controlled study Alin Andries, Bibi Gram, Jan Frystyk, Allan Flyvbjerg, René Klinkby Støving

44 Bone status in patients with anorexia nervosa and relationship with biochemical findings and findings at psychiatric interview Stine Aistrup Eriksen Msc, Hanne Prietzel MD, Jenna Rosenqvist Ibsen MD , Marlene Briciet Lauritsen MD DrMedSc, Peter Vestergaard MD PhD DrMedSc, Gry Kjærsdam Telléus Cand. Psych.

45 Whey, Casein, and Post-Prandial Lipaemia; a 12-week, randomized, parallel-controlled, human intervention study Bohl M., Gregersen S., and Hermansen K.

46 First report of cases treated with the EndoBarrier gastrointestinal liner in Denmark Ulrich Rohde, Ebbe Langholz, Peter Vilmann, Steffen U. Friis, Tina Vilsbøll and Filip K. Knop

47 Effect of gut-hormone inhibition on energy intake, glucose tolerance and pulse rate after Roux-en-Y Gastric Bypass surgery Maria Saur Svane, Kirstine Bojsen-Møller, Carsten Dirksen, Nils Bruun Jørgensen, Christoffer Martinussen, Jens Juul Holst, Sten Madsbad

48 Acute and long-term changes in leptin and ghrelin concentrations after Roux-en-Y gastric bypass Nils Bruun Jørgensen, Carsten Dirksen, Kirstine Bojsen-Møller, Siv Hesse Jacobsen, Maria Svane, Jens Juul Holst, Sten Madsbad, Trine Ryberg Clausen

49 Beta-cell function in response to oral and intravenous challenges after Roux-en-Y gastric bypass Kirstine N Bojsen-Møller, Carsten Dirksen, Nils B. Jørgensen, Siv H Jacobsen, Annette K Serup, Peter H Albers, Dorte L Hansen, Dorte Worm, Lars Naver, Viggo B Kristiansen, Jørgen FP Wojtaszewski, Bente Kiens, Jens J Holst, Erik A Richter, Sten Madsbad

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”Thyroidea”

Fredag 17. januar 2014, kl. 13.45-15.30

Marselissalen

Abstract 50-60

Chairs: Jesper Karmisholt og Thomas Brix

50 Autoreactivity and distribution between naïve and memory cell compartments of circulating Th17 cells and type-1 regulatory T cells in autoimmune thyroid disease. Birte Kristensen, Laszlo Hegedüs , Hans Madsen, Terry Smith, and Claus H. Nielsen.

51 Di-ethylhexyl-phthalate (DEHP) is metabolised by human thyroid cells and may influence thyroglobulin secretion Juliana Frohnert Hansen, Marianne Brorson, Marie-Louise Hartoft-Nielsen, Malene Boas Katharina M. Main, Hanne Frederiksen, Jacob Hofman-Bang, Åse Krogh Rasmussen, Ulla Feldt-Rasmussen

52 Pendrin autoantibodies, using a radioligand binding assay, are detected with low frequency in patients with autoimmune thyroid disease and are undetectable in normal controls Brix TH, Hegedüs L, Weetman AP, Kemp EH

53 Psychiatric morbidity before and after the diagnosis of hyperthyroidism: A nationwide register-based study Frans Brandt, Marianne Thvilum, Dorthe Almind, Kaare Christensen, Anders Green, Thomas Heiberg Brix and Laszlo Hegedüs

54 Iodine fortification may influence the age-related change in thyroid volume – a longitudinal population-based study (DanThyr). Anne Krejbjerg, Inge Pedersen, Lena Bjergved, Allan Carlé Torben Jørgensen, Hans Perrild, Lars Ovesen, Lone Rasmussen, Nils Knudsen og Peter Laurberg.

55 Increased psychiatric morbidity before and after the diagnosis of hypothyroidism: A nationwide register study Marianne Thvilum, Frans Brandt, Dorthe Almind, Kaare Christensen, Thomas H Brix, Laszlo Hegedüs

56 Reference change values for the Hospital Anxiety and Depression Scale, SF-36 and hypothyroid score in patients with stable subclinical hypothyroidism Jesper Karmisholt, Stig Andersen and Peter Laurberg

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57 The impact of Graves’ disease and it’s treatment on handwriting characteristics Giampaolo Papi, M.D. Ph.D., Cristina Botti, Salvatore Maria Corsello, M.D. Ph.D., Anna Vittoria Ciardullo, M.D., Alfredo Pontecorvi, M.D. Ph.D., and Laszlo Hegedüs

58 Randomised controlled trial of the effect of long-term selenium supplementation on serum thyrotropin concentrations in euthyroid Danish seniors Kristian Hillert Winther, Steen Bonnema, Frederik Cold, Søren Cold, Mads Nybo, Laszlo Hegedüs

59 The correlation between biochemically assessed thyroid disease and all cause-mortality - The Danish register-based OPENTHYRO study of 239,768 individuals- Anne Sofie Laulund, Mads Nybo, Thomas Heiberg Brix, Bo Abrahamsen, Henrik Løvendahl Jørgensen, Laszlo Hegedüs.

60 Development of autoimmune overt hypothyroidism is highly associated with childbirths and induced abortions – but only in premenopausal women. Allan Carlé, Inge Bülow Pedersen, Nils Knudsen, Hans Perrild, Lars Ovesen, Lone Banke Rasmussen, Torben Jørgensen, and Peter Laurberg.

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”Prædiabetes og T2DM”

Fredag 17. januar 2014, kl. 13.45-15.30

Sal 8

Abstract 61-70

Chairs: Ulla Kampmann og Søren Gregersen

61 Metabolic inflexibity in obese subjects: Unaltered insulin sensitivity after 72 h of fasting with and without acipimox Ann Mosegaard Bak, Mikkel Holm Vendelbo, Rikke Viggers, Jørgen Rungby, Jens Otto Lunde Jørgensen, Niels Jessen, Niels Møller

62 Effect of the primary human bile acid chenodeoxycholic acid and the bile acid sequestrant colesevelam on glucose metabolism in patients with type 2 diabetes and in healthy control subjects Morten Hansen, Matthijs Scheltema, David P. Sonne, Jens J. Holst, Tina Vilsbøll and Filip K. Knop

63 High Intensity Interval Training Improves Insulin Mediated Glucose Clearance in Skeletal Muscle in Patients with Type 2 Diabetes and healthy controls Nielsen MB, Skaaby S, Andersen NB, Petersen HHH, Helge JW, Dela F

64 Incidence of diabetes and diabetes complications among migrants in Denmark Marit Eika Jørgensen, Zaza Kamper-Jørgensen, Bendix Carstensen, Marie Norredam, Ib Christian Bygbjerg, Gregers Stig Andersen

65 Insulintilfælde under behandling med sulfonylurinstof hos patienter med type 2-diabetes i Region Hovedstaden Sascha Pilemann-Lyberg, Birger Thorsteinsson, Ole Snorgaard, Mette Zander, Henrik Vestergaard og Michael E. Røder

66 Prescribing Patterns of Antidiabetic Drugs within the First Year following Diagnosis of Type 2 Diabetes: Results from the DD2 study Anil Mor, Klara Berencsi, Elisabeth Svensson, Jørgen Rungby, Jens Steen Nielsen, Søren Friborg, Ivan Brandslund, Jens Sandahl Christiansen, Allan Vaag, Henning Beck-Nielsen, Henrik Toft Sørensen, Reimar Wernich Thomsen

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67 Family history of diabetes and the association with demographic and anthropometric characteristics among newly diagnosed diabetes type 2 patients: Results from the DD2 study Elisabeth Svensson, Klara Berencsi, Simone Sander, Anil Mor, Jørgen Rungby, Jens Steen Nielsen, Søren Friborg, Ivan Brandslund, Jens Sandahl Christiansen, Allan Vaag, Henning Beck-Nielsen, Henrik Toft Sørensen, Reimar Wernich Thomsen

68 Glucose lowering effects and low risk of hypoglycaemia in maturity onset diabetes of the young patients when treated with a glucagon-like peptide-1 receptor agonist – a double-blind randomised cross-over trial Signe H. Østoft, Jonatan I. Bagger, Torben Hansen, Oluf B. Pedersen, Jens J. Holst, Filip K. Knop and Tina Vilsbøll

69 Pathophysiological phenotypes of clinically diagnosed type 2 diabetes Jacob Volmer Stidsen, Reimar W. Thomsen, Jens Steen Nielsen, Jørgen Rungby, Sinna Pilgaard Ulrichsen, Klara Berensci, Søren Friborg, Ivan Brandslund, Aneta A. Nielsen, Jens Sandahl Christiansen, Henrik Toft Sørensen , Jan Erik Henriksen, Henning Beck-Nielsen

70 Does intensive glycaemic control influence health-related quality of life in patients with type 2 diabetes? A systematic review with meta-analysis of randomised clinical trials Bianca Hemmingsen, Søren S Lund, Christian Gluud, Allan Vaag, Thomas Almdal, Christina Hemmingsen, Jørn Wetterslev

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”Knoglemetabolisme”

Fredag 17. januar 2014, kl. 13.45-15.30

Bøgesalen

Abstract 71-81

Chairs: Bente Langdahl og Bo Abrahamsen

71 aBMD at the hip measured by DXA overestimate cortical vBMD assesed by QCT scans Anne Kristine Amstrup, Tanja Sikjær, Leif Mosekilde, Lars Rejnmark

72 External auditory canal and middle ear diseases in bisphosphonate-treated osteoporosis patients. A Danish National Register Based Cohort Study Anne-Luise Thorsteinsson, Peter Vestergaard, Pia Eiken

73 Osteoporosis in male respiratory patients Rana Bibi, Peter Laurberg, Ulla Weinreich, Eigil Husted Nielsen

74 Frakturer og refrakturer fra et dansk perspektiv Louise Hansen, Stine Aistrup Eriksen, Bente Lomholt Langdahl, Pia A Eiken, Kim Brixen, Bo Abrahamsen, Jens-Erik Beck Jensen, Torben Harsløf og Peter Vestergaard

75 Risiko for infektioner og cancersygdom hos patienter med postoperativ hypoparathyreoidisme Line Underbjerg, Tanja Sikjaer, Leif Mosekilde, Lars Rejnmark Medicinsk-Endokrinologisk Afdeling, MEA, Aarhus Universitetshospital, Tage-Hansens Gade

76 Low thyrotropin levels as a predictor of major osteoporotic fractures – The OPENTHYRO register cohort Abrahamsen Bo, Jørgensen Henrik L, Laulund Anne Sofie, Nybo Mads, Brix Thomas H, Hegedüs L

77 Hyponatremia and Bone Mineral Density: A Cross-Sectional Study Kruse C; Eiken P; Vestergaard P

78 Effekten af per oral mætningsdosis af vitamin D3 på serumkoncentration af vitamin D3 Cand.med. Rasmus Bo Jansen og ovl., klinisk lektor, dr.med. Ole Lander Svendsen

79 Resveratrol increases vBMD at the spine in obese men: A randomized controlled trial MJ Ornstrup, T Harsløf, T Kjær, SK Paulsen, BL Langdahl, SB Pedersen

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80 Vitamin D treatment in primary hyperparathyroidism: a randomized placebo controlled trial Lars Rolighed, Lars Rejnmark, Tanja Sikjaer, Lene Heickendorff, Peter Vestergaard, Leif Mosekilde, and Peer Christiansen.

81 Biochemical markers of bone turnover in diabetes patients- a meta-analysis, and a methodological study on the effects of glucose on bone markers. Peter Vestergaard, Stine Aistrup Eriksen, Simon Lykkeboe, Aase Handberg, Jakob Starup-Linde

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”Kardiovaskulært”

Fredag 17. januar 2014, kl. 16.00-17.30

Marselissalen

Abstract 82-90

Chairs: Caroline Kistorp og Per Løgstrup Poulsen

82 Markedly Elevated 24-hour Ambulatory Blood Pressure in Healthy Male Carriers of Arg82Cys in CD300LG Identifies the Gene as a Possible Novel Regulator of Blood Pressure Julie Støy, Ulla Kampmann, Arne Hørlyck, Lotte Ibsen, Nils Magnusson, Jørgen Rungby, Per Løgstrup Poulsen,Ivan Brandslund, Cramer Christensen, Niels Grarup, Torben Hansen, Oluf Pedersen, Niels Møller

83 Treatment of subclinical hyperthyroidism with radioiodine: MRI-evaluated effect on the heart Peter Dall Mark (stud. med.), Mikkel Andreasen, Claus Leth Petersen, and Jens Faber.

84 Cerebrovascular event rate after radioiodine therapy la Cour JL, Jensen LT, 2, Nygaard B

85 Associations between glycaemic deterioration and central haemodynamics in non-diabetic individuals. The ADDITION-PRO study Nanna B. Johansen, Signe S. Rasmussen, Niels Wiinberg, Dorte Vistisen, Marit E. Jørgensen, Erling B. Pedersen, Torsten Lauritzen, Annelli Sandbæk, Daniel R. Witte

86 Morning blood pressure surge is not associated with pulse wave velocity, cerebral white matter lesions or urinary albumin excretion in patients with newly diagnosed type II diabetes Lyhne J, Laugesen E, Høyem P, Christiansen JS, Knudsen ST, Hansen KW, Hansen TK, Poulsen PL.

87 Ambulant 24 timers besemmelse af pulsbølgehastighed og aorta blodtryk: et pilot projekt Christoffer Krogager, Niklas Rossen, Esben Laugesen, Søren Tang Knudsen, Per Løgstrup Poulsen, Klavs Würgler Hansen

88 Diabetes and stroke: Liraglutide is associated with a decreased risk of stroke in type 2 diabetes mellitus. A nested case-control study Jan Scheel-Thomsen, Jakob Starup-Linde, Michael Gejl, Soeren Gregersen, Peter Vestergaard

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89 Vitamin D and carotid intima media thickness in 416 Danish patients with type 2 diabetes mellitus (T2D) at entry into the CIMT trial K. Winckler , T. W. Boesgaard, L. Tarnow, H. Vestergaard, T. Almdal, L. Lundby-Christensen, A. Vaag, S. Madsbad, C. Gluud,

90 Risk Stratification with Plasma-NT-proBNP and Coronary Calcium Score Predicts All-Cause Mortality in Microalbuminuric Type 2 Diabetic Patients. Bernt Johan Illum von Scholten, Henrik Reinhard, Peter Godsk Jørgensen, Simone Theilade, Peter Riis Hansen, Niels Wiinberg, Andreas Kjær, Claus L Petersen, Kaj Winther, Hans-Henrik Parving, Jan Skov Jensen, Peter K Jacobsen, Peter Rossing

Ekstra Assessment of Central Blood Pressure in Patients with Type 2 Diabetes: A Comparison Between Sphygmocor and Invasively Measured Values E. LAUGESEN, N.B. ROSSEN, C.D. PETERS, M. MÆNG, E. EBBEHØJ, S.T. KNUDSEN, K.W. HANSEN, H.E.BØTKER, P.L. POULSEN

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”Blandet endokrinologi”

Fredag 17. januar 2014, kl. 16.00-17.30

Bøgesalen

Abstract 91-99

Chairs: Kirstine Stochholm og Peter Vestergaard

91 Environmentally-Induced Epigenetic Changes in Gametes – Does Our Lifestyle Affect the Next Generation? Ida Donkin, Soetkin versteyhe, Thais de Castro Barbosa, Kui Quan, Lars Ingerslev, Juleen Zierath, Romain Barrès

92 Glucocorticoid-induced adrenal insufficiency in prednisolone treated patients and how it relates to glucocorticoid dose and the duration of treatment Stina Dinsen, Bo Baslund, Marianne Klose, Åse Krogh Rasmussen, Lennart Friis-Hansec, Linda Hilsted, Henning Locht, Annette Hansen, Ulla Feldt-Rasmussen.

93 Anthropometrics in Klinefelter syndrome and the influence of genetic and hypothalamic-pituitary-gonadal markers Simon Chang, Anne Skakkebæk, Anders Bojesen, Jens Michael Hertz, Arieh Cohen, David Michael Hougaard, Mikkel Wallentin, Anders Degn Pedersen, John Rosendahl Østergaard, Claus Højbjerg Gravholt

94 Copeptin in polycystic ovary syndrome Signe Frøssing, Mubeena Aziz, Sven O. Skouby, Caroline Kistorp, Jens Faber

95 Determinants of non-alcoholic fatty liver disease in women with previous gestational diabetes mellitus Signe Foghsgaard, Louise Vedtofte, Camilla Andersen, Emilie S. Andersen1, Lise L. Gluud, Charlotte Strandberg, Thora Buhl, Elisabeth R. Mathiesen, Peter Damm, Jens Svare, Filip K. Knop and Tina Vilsbøll

96 Prevalence of sleep apnea in Danish Type 1 Diabetes patients Henriette Holst Hansen, Lise Tarnow, Ulrik Pedersen-Bjergaard, Brynjulf Mortensen, Michael Laub og Birger Thorsteinsson

97 Obstruktiv søvnapnø hos diabetes patienter henvist til søvnklinik. Freja Eriksen, Anne Roed Jacobsen, Line Thorup, Lykke Bennedsen, Jonas Peter Yde Holm, Klavs Würgler Hansen

24

98 The metabolic effects of lipopolysaccharide depend on intact pituitary stress hormone responses – studies of glucose, lipid and amino acid metabolism in hypopituitary patients and healthy volunteers Ermina Bach, Andreas B. Møller, Jens O. L. Jørgensen, Mikkel H. Vendelbo, Niels Jessen, Jonas F. Olesen, Steen B. Pedersen, Niels Møller

99 Incidence and late prognosis of Acromegaly in Denmark: Preliminary data Jakob Dal, Ulla Feldt-Rasmussen, Marianne Andersen, Lars Ø. Kristensen, Peter Laurberg, Henrik Toft Sørensen, and Jens Otto L. Jørgensen

25

1. Genetic risk score modelling for disease progression in new-onset type 1 diabetes patients – Evidence

for TNFAIP3 and SKAP2 as modulators of β-cell apoptosis.

Caroline A. Brorsson, Lotte B. Nielsen, Anne M. Traulsen, Marie Louise Andersen, Tina Fløyel, Lukas A.

Berchtold, Regine Bergholdt, Lars Hansen, Henrik B. Mortensen, Flemming Pociot and Joachim Størling.

Herlev Hospital, Herlev, Danmark

Hypotese og formål:

Genome-wide association studies (GWAS) have identified over 40 type 1 diabetes risk loci. The clinical

impact of these loci on β-cell function during disease progression is unknown. We hypothesized that

genetic variation in type 1 diabetes candidate genes that are expressed within the β-cells could be involved

in disease mechanisms by modulating the β-cells sensitivity to immune attack. In the current study we

therefore considered genes expressed and transcriptionally regulated by cytokines in human islets to

perform genetic risk score modelling for prediction of β-cell function in children with newly-diagnosed type

1 diabetes.

Metode:

Expression profiles for candidate genes within associated risk loci were investigated in nine human islet

preparations ± cytokine stimulation (TNF-α, IFN-γ, IL-1β) for 48h. SNPs from the corresponding GWAS loci

were genotyped in 257 children (126 girls and 131 boys) with mean age at clinical onset 9.1 ± 3.7 years, in

an international prospective cohort of newly-diagnosed children followed for one year after diagnosis. A

genetic risk score was constructed based on the cumulative number of risk alleles carried by each child.

Using linear regression the risk score was tested for association with HbA1c and insulin-dose adjusted

HbA1c (IDAA1C; a surrogate marker of β-cell function). Individual SNPs were analysed for effect on

stimulated C-peptide, HbA1c and IDAA1c in linear regression models. The effect on β-cell apoptosis of

selected candidate genes was tested by transcriptional knock-down using specific siRNAs in a rat INS-1E cell

line.

Resultater:

Eleven candidate genes were significantly regulated by cytokines in human islets. The genetic risk score

constructed from these genes was positively associated with HbA1c and IDAA1c levels after three and six

months and throughout the study period, respectively. This suggests poorer glycaemic control and residual

β-cell function with increasing genetic risk score. Individual SNP analysis revealed that rs2327832 of

TNFAIP3 and rs7804356 of SKAP2 predicted glycaemic control as assessed by HbA1c and IDAA1C 12 months

after onset. Functional knock-down of TNFAIP3, SKAP2, or both, in INS-1E cells demonstrated involvement

in cytokine-mediated cell death.

Konklusion:

Our results may help predict disease progression in children at type 1 diabetes onset and provide novel

information about genes involved in regulating β-cell apoptosis.

26

2. Development of Anti-idiotypic Antibodies Against the Monoclonal Autoantibody IC2 in an Attempt to

Normalize the Deficient Natural Killer T-cell Activity in Type-1 Diabetes.

Jensen KL1, Engmose CP1, Engkilde K1, Lermark Å2, Brogren CH1

The Bartholin Institute, Rigshospitalet , Copenhagen N, Denmark, 2University Hospital Malmö, Malmö,

Sweden.


A major objective in diabetes research is to identify factors that can prevent β-cell death. Natural Killer T

cells (NKT cells) receive stimulatory signals from CD1d-lipid complexes, and are part of the regulatory

control of the autoimmune T cells. An inhibition of this regulation is thought to be the reason for the β-cell

destruction in Type 1 Diabetes (T1D). The monoclonal autoantibody IC2 that was raised in the BB rat binds

specifically to functional pancreatic β-cells. The autoantigen on the β-cell to which it binds has only been

partially determined. IC2 has been shown to inhibit the IL-2 secretion of NKT cells, which is why

development of an anti-idiotypic antibody (anti-Id Ab) against the paratope of IC2 is interesting. This anti-Id

Ab could prevent the inhibitory role of IC2, which would lead to maintenance of the normal regulatory

functions of the NKT cells and thereby have preventive effects on T1D. Our aim is therefore to develop an

anti-idiotypic antibody binding the paratope of IC2.

Metode:

A modified functional NKT-hybridoma assay with CD1d lipid complexes was used to measure NKT cell IL-2

secretion on a sandwich enzyme-linked immunosorbent assay (ELISA). A modified direct ELISA coated with

IC2-F(ab’)2 fragments was used to measure presence of Anti-Id Ab against IC2 and hybridoma formation

was used to develop the IC2-specific Anti-Id Ab. Rat hybridomas were raised by PEG mediated fusion of

splenocytes from IC2 immunized diabetes resistant BBDR+/+ rats with the rat HAT-sensitive YB2/0 cell line

as fusion partner.

Resultater:

Successful immunizations of BBDR+/+ rats show the syngenic idiotype immunogenic capabilities of IC2. The

amount of anti-Id in the sera of the immunized rats depends on the amount of IC2 injected during the

immunizations. Initial ELISA screening of fusions showed that supernatants from 201 out of 720 wells were

positive of IC2-anti-Id Ab to more or less degree. Successful subcloning have been made and currently six of

them are ready to be propagated, recloned and further investigated. A majority of the subcloned

hybridoma anti-idiotypic antibodies showed inhibition in IC2 binding assays indicating their potential used

for in vivo treatment in preventive studies using diabetic prone BBDP+/+ rats. Similarly, binding to IC2 VH-

CDR3 synthetic peptide was observed in ELISA with most of the antibodies tested, which also is the

expected location of the IC2 specific idiotype.

Konklusion:

Hereby we conclude that development of anti-Id Ab against IC2 can be done in a syngeneic system by

immunization of rats with IC2 without carrier conjugation. Selected monoclonal Abs from this fusion will be

further investigated for prevention of diabetes of the diabetes prone BBDR-/- rat in vivo.

27

3. Is TRAF3IP2 involved in the pathogenesis of type 1 diabetes and beta-cell apoptosis via induction of

NFkB?

Ann Bech Thomsen, Lise Wogensen Bach, Joachim Størling, Caroline Brorsson, Flemming Pociot.

Herlev Hospital


TRAF3IP2 blev identifieret som et nyt kandidat gen for type 1 diabetes ved kombination af genetiske

genome-wide associations data og protein-protein interakations data. Det blev også vist at ekspressionen

af TRAF3IP2 var reguleret af proinflammatoriske cytokiner i humane pankreatiske øer. Hypotesen er, at

TRAF3IP2 via IL-17/NFkB signalering vil give en øget apoptose i beta-celler som følge af proinflammatoriske

cytokiner, og at TRAF3IP2 dermed bidrager til patogenesen af type 1 diabetes. Projektets formål er at

komme tættere på en udredning af TRAF3IP2’s funktion i beta-celler.

Metode:

Ekspression af TRAF3IP2 vil blive undersøgt ved RT-PCR i INS-1E celle-linjen stimuleret med cytokinerne IL-

17, IL-1β og IFN-γ i forskellige tidsperioder. Protein ekspression af TRAF3IP2 vil blive undersøgt ved Western

blot. Det vil blive undersøgt hvorvidt IL-17 øger nitrit produktionen i INS-1E celler, og om IL-17 er involveret

i øget apoptose hos INS-1E cellerne via induktion af TRAF3IP2. Yderligere vil knock down effekten af

TRAF3IP2 i INS-1E celler blive undersøg med gene-specifike siRNA.

Resultater:

TRAF3IP2 ses opreguleret når INS-1E celle-linjen stimuleres med cytokinerne IL-1β og IFN-γ, men TRAF3IP2

er ikke opreguleret af IL-17. TRAF3IP2 er mest opreguleret efter 4 timers stimulering med cytokiner.

Apoptose forsøg viser at cytokinerne IL-1β og IFN-γ øger apoptosen, men IL-17 ser ikke ud til potentiere

effekten. Knock-down af TRAF3IP2 har indtil videre ikke givet en tilfredsstillende KD-effekt, og derfor har

det endnu ikke været muligt at kigge på hvorvidt KD af TRAF3IP2 vil lede til en mindre apoptose-rate i INS-

1E celle-linjen, når disse stimuleres med cytokiner.

Konklusion:

Det ser ikke ud til, at IL-17 har nogen umiddelbar indvirkning på TRAF3IP2 ekspressionen i INS-1E celle-

linjen. Det ser heller ikke ud til, at IL-17 potentierer nitrit produktionen i celle-linjen eller at den potentierer

apoptose-raten. Forsøg med henblik på at udrede TRAF3IP2’s funktionelle rolle i INS-1E celle-linjen mangler

stadig at blive udført, samt at undersøge om IL-17 signaleringsvejen har en mere markant effekt i humane

beta-celler.

28

4. Effect of insulin analogues on frequency of documented hypoglycaemia in patients with type 1

diabetes and recurrent severe hypoglycaemia

Agesen RM1, Kristensen PL1,2,3, Beck-Nielsen H4,5, Nørgaard K6, Perrild H7, Christiansen JS8,9, Jensen

T10, Hougaard P5, Parving H-H9,10, Thorsteinsson B1,11, Tarnow L2,9,12, Pedersen-Bjergaard U1,11

1Department of Cardiology, Nephrology and Endocrinology, Nordsjællands Hospital Hillerød, 2Steno

Diabetes Center, Gentofte, 3Department of Internal Medicine M, Herlev University Hospital 4Department of

Endocrinology M, Odense University Hospital, 5Faculty of Health Sciences, University of Southern Denmark,

Odense, 6Department of Endocrinology, Hvidovre University Hospital, 7Department of Internal Medicine,

Bispebjerg University Hospital, 8Department of Endocrinology M, Aarhus University Hospital, 9Faculty of

Health Sciences, University of Aarhus, 10Department of Medical Endocrinology, Copenhagen University

Hospital, 11Faculty of Health and Medical Sciences, University of Copenhagen, 12Department of Research

and Innovation, Nordsjællands Hospital Hillerød.


Insulin analogue therapy reduces the incidence of hypoglycaemia compared with human insulin in type 1

diabetic patients at low risk of hypoglycaemia (≤ 1 episode of severe hypoglycaemia (SH) per year).

Whether this also applies to patients with recurrent SH remains unclear. The HypoAna trial investigated

whether insulin analogues compared with human insulin are superior in reducing occurrence of

hypoglycaemia in these high risk patients. Here we report results on documented hypoglycaemia (DH).

Metode:

The study was an investigator-initiated 2-year, controlled, multicentre, prospective, randomized, open-

labelled, blinded endpoint (PROBE) trial including 159 patients with type 1 diabetes and ≥ 2 SH episodes in

the preceding year. Patients were randomized to treatment with basal-bolus therapy with insulin analogues

(aspart/detemir) or human insulin (regular/NPH) in a cross-over design. Patients measured 7-point blood

glucose profiles during daytime twice a week and nocturnal blood glucose at 03 a.m. once every month.

The number of episodes of DH (blood glucose ≤ 3.9 mmol/l ± typical symptoms of hypoglycaemia) was

compared in the last 9 months of each treatment arm.

Resultater:

A total number of 9360 episodes of DH were recorded, 52% in the human insulin arm and 48% in the insulin

analogue arm, corresponding to 1.12 and 1.05 episode per patient-week on average, respectively; 16% of

DH were nocturnal (22-07). The intention-to-treat analysis demonstrated a 6% rate reduction (95% CI: 2-

10%; p = 0.0025) in the total number of episodes of DH in patients being treated with insulin analogues

compared with human insulin. The reduction in DH was solely due to reduction in nocturnal DH (rate

reduction 39%; 95% CI: 32-45%; p < 0.0001), whereas daytime DH was similar in the two treatment arms (p

= 0.48). The per-protocol analysis demonstrated similar results. Baseline glycaemic control (HbA1c: 8.0 ±

1.0% (64 ± 11 mmol/mol) (mean ± SD)) was maintained throughout both treatment arms.

Konklusion:

Insulin aspart/detemir significantly reduces the rate of nocturnal DH in patients with type 1 diabetes and

recurrent severe hypoglycaemia compared with regular/NPH insulin. The reduction appears mainly to be

due to use of the long-acting insulin analogue.

29

5. Glucose-dependent insulinotropic polypeptide augments glucagon responses to hypoglycaemia in type

1 diabetes

Mikkel Christensen 1,2, Salvatore Calanna 1,3, Alexander Hovard Sparre-Ulrich 1,4, Peter Lommer

Kristensen 5, Mette Marie Rosenkilde 4, Francesco Purrello 3, Gerrit van Hall 5, Jens Juul Holst 2, Tina

Vilsbøll 1 and Filip Krag Knop 1,2

1 Diabetes Research Division, Department of Medicine, Gentofte Hospital, Hellerup, Denmark;2 Department

of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark;3

Department of Clinical and Molecular Biomedicine, University of Catania, Catania, Italy;4 Department of

Neuroscience and Pharmacology, Panum Institute, University of Copenhagen, Copenhagen, Denmark;5

Department of Cardiology, Nephrology and Endocrinology, Hillerød Hospital, Hillerød, Denmark; 6 Clinical

Metabolomics Core Facility, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.


We have previously demonstrated glucagon-releasing properties of glucose-dependent insulinotropic

polypeptide (GIP) during insulin-induced hypoglycaemia in healthy individuals. In contrast, glucagon-like

peptide 1 (GLP-1) has inhibitory effects on glucagon secretion, which could potentially reduce the glucagon

counter-regulatory responses to hypoglycaemia. We therefore studied the effects of GIP and GLP-1 on

counter-regulatory glucagon responses in patients with type 1 diabetes.

Metode:

In a randomised, double-blind, cross-over study ten male subjects with type 1 diabetes (C-peptide negative,

age: 26±1 years (mean±SE); BMI: 24±0.5 kg/m2; HbA1c: 7.3±0.2%) were administered a 2-hour iv infusion

of either saline, GIP or GLP-1 on separate days. During the first hour, plasma glucose was lowered by insulin

infusion, thereafter recovery was followed for another hour.

Resultater:

GIP infusions elicited larger glucagon responses during the second hour of the study (1.7±0.3 (GIP) vs.

0.4±0.2 (GLP-1) vs. 0.7±0.1 (saline) min×nmol/l, P<0.0001). Glucagon responses on GLP-1 and saline days

were similar. During GIP infusions, significantly less glucose was needed to keep plasma glucose above 2

mmol/l (156±35 (GIP) vs. 234±41 (GLP-1) vs. 214±56 (saline) mg×kg-1, P<0.05). Glucose infusion rates

between GLP-1 and saline days did not differ. Insulin levels, hypoglycaemic symptoms and cognitive

function during hypoglycaemia were similar on all days.

Konklusion:

Our results suggest that exogenous GLP-1 does not reduce glucagon counter-regulatory responses and that

exogenous GIP increases glucagon responses to hypoglycemia in C-peptide negative patients with type 1

diabetes.

30

6. Behandlingskvalitet hos patienter med type 1 diabetes i behandling med insulinpumpe

Hans Jørgen Gjessing, Ulla Linding Jørgensen, Charlotte Chrois Møller, Jette Pedersen, Ellen Grodum,

Karoline Schousboe

Medicinsk afdeling, Fredericia Sygehus.


Årlig vurdering af glykæmisk kontrol, tilfælde med alvorlig hypoglykæmi, ketoacidose og patienttilfredshed

hos patienter med Type 1 diabetes i behandling med insulinpumpe

Metode:

Behandling med insulinpumpe påbegyndt 2005. Kvalitetsdatabase etableret 2009. Registrering af HbA1C,

alvorlig hypoglykæmi, ketoacidose og patienttilfredshed vurderet ved anvendelse af spørgeskemaerne

Diabetes Treatment Satisfaction Questionaire status (DTSQs) og change (DTSQc) versionerne før og hvert

efterfølgende år på behandling med insulinpumpe. Data opgives som median og spændvidde

Resultater:

Pr. 30. november 2013 indeholder databasen data på156 patienter. Heraf er 16 afsluttet pga. fraflytning

(n=7), dårlig compliance (n=4) og efter patientens eget ønske (n=5) dvs. data på i alt 140 aktive patienter. I

alt 36 patienter er tilflyttere i behandling med insulinpumpe. Alder er 40 (18-73) år. 71 er mænd.

Diabetesvarighed 18 (3-55) år. Pumpebehandlingsvarighed 4,3 (0-27,4) år. HbA1c er faldet fra 8 (5,8-13,7)

% før behandling med insulinpumpe til 7,6 (5,4-11,1) % (p<0,01) det seneste år. Den bedre glykæmiske

kontrol har kunnet fastholdes hvert år til og med >= 5 år efter pumpestart (p<0,01). Før og det seneste år

på pumpebehandling har hhv. 13 % og 26 % en HbA1C-værdi < 7 % og 15 % en HbA1C-værdi > 9 %. Median

alder på patienter med HbA1C > 9 % i behandling med insulinpumpe er 21 (20-57) år (n=19). Det seneste år

har 7 patienter haft 9 tilfælde med alvorlig hypoglykæmi (n=128), hvor 21 patienter har haft 60 tilfælde

med alvorlig hypoglykæmi året inden start på pumpebehandling (n=104). 9 tilfælde med ketoacidose er

registreret. Patienttilfredshed er høj og signifikant bedre på pumpebehandling (p<0,01).

Konklusion:

Insulinpumpebehandling er ledsaget af bedre glykæmisk kontrol, få tilfælde med alvorlig hypoglykæmi og

forbedret patienttilfredshed. Dårlig regulering ses især blandt helt unge pumpebrugere.

31

7. Short-term effects of NPH insulin, insulin detemir and insulin glargine on the IGF-IGFBP-GH axis in

patients with type 1 diabetes

Zhulin Ma 1+2, Jens Sandahl Christiansen 2, Torben Laursen 3, Torsten Lauritzen 4, Jan Frystyk 1+2

1) Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, DK-

8000 Aarhus C, Denmark 2) Department of Endocrinology and Internal Medicine, Aarhus University Hospital,

Nørrebrogade, DK-8000 Aarhus C, Denmark 3) Department of Biomedicine - Pharmacology, Faculty of

Health, Aarhus University, DK-8000 Aarhus C, Denmark 4) Department of Public Health, Section of General

Practice, Faculty of Health, Aarhus University, DK-8000 Aarhus C, Denmark


Insulin regulates the GH-IGF-I axis. Therefore, we found it of interest to compare responses of the

circulating GH-IGF system to NPH insulin, insulin detemir and insulin glargine in patients with type 1

diabetes (T1D).

Metode:

Seventeen patients (seven women) with T1D (aged 41.9 (24-63) yr (mean and range), BMI 24.7 (19.5-28.3)

kg/m2, HbA1c 7.2% (6.3-8.0), TID duration 26.2 (8-45) yr) were studied using a randomized, three-period

crossover design. Patients received subcutaneous injections of equal individual doses of NPH, determir and

glargine at 18:00 h. Plasma glucose, serum total IGF-I, bioactive IGF, IGFBPs and GH were measured hourly

for 14 hours after injections.

Resultater:

As compared to NPH and glargine, detemir resulted in lowest 6-14 hrs AUC (mean and range) of IGFBP-1

(1518 [1280-1800]) vs. 1621 [1367-1922] vs. 1020 [860-1210] μg/l x h) and GH (17.1 [14.1-20.6] vs. 15.4

[12.7-18.6] vs. 10.2 [8.5-12.3] μg/l x h), but highest AUC of bioactive IGF (3.8 [3.5-4.2] vs. 3.7 [3.4-4.0] vs.

4.4 [4.1-4.8] μg/l x h) (all p-values <0.01). Interestingly, these differences were unrelated to plasma glucose.

By contrast, the profiles of total IGF-I, IGFBP-2 and IGFBP-3 were comparable between the insulin

preparations.

Konklusion:

Independent of plasma glucose, a single dose of detemir caused larger suppression in serum IGFBP-1 than

NPH and glargine, whereas levels of bioactive IGF were higher, hereby explaining the lower GH levels. Thus,

detemir appears to be more liver specific than glargine and NPH insulin. The physiological significances of

this observation remains, however, to be determined.

32

8. Targeting intensive versus conventional glycemic control for type 1 diabetes mellitus: systematic

review with meta-analyses and trial sequential analyses of randomized clinical trials

Pernille Kähler, Berit Grevstad, Thomas Almdal, Christian Gluud, Jørn Wetterslev, Søren Søgaard Lund, Allan

Vaag, Bianca Hemmingsen

Copenhagen Trial Unit, Rigshospitalet


To assess the benefits and harms of targeting intensive glycemic control versus conventional glycemic

control in patients with type 1 diabetes mellitus on all cause mortality, cardiovascular mortality, macro- and

microvascular complications, cancer, adverse events, hypoglycemia, and weight.

Metode:

Design: Systematic review with meta-analyses and trial sequential analyses of randomized clinical trials.

Data source: The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded and LILACS to

January 2013; hand search of reference lists and conference proceedings; clinical trial databases, and

contact with authors. Study selection: Randomized clinical trials that prespecified different targets of

glycemic control in participants at any age with type 1 diabetes mellitus. Published and unpublished trials in

all languages were included, irrespective of predefined outcomes. Data extraction: Two authors

independently assessed studies for inclusion and extracted data related to study methods, interventions,

outcomes and risk of bias. Risk ratios with 95% confidence intervals were estimated with fixed- and

random effects models. Data were extracted from the intervention period and to the longest follow-up.

Resultater:

Eighteen clinical trials that randomized 2254 participants with type 1 diabetes mellitus (1110 to intensive

control versus 1144 to conventional control) were included. Seventeen trials had high risks of bias. There

was no statistical significant effect of intensive glycemic control on all cause mortality (risk ratio 0.91, 95%

confidence interval 0.51 to 1.62; 1971 participants, 9 trials) or cardiovascular mortality (0.49, 0.19 to 1.24;

1802 participants, 7 trials). Trial sequential analyses showed that data were very sparse. Intensive glycemic

control may reduce the relative risks for the composite macrovascular outcome (0.63, 0.41 to 0.96; P=0.03;

1577 participants, 3 trials) and nephropathy (0.37, 0.27 to 0.50; P<0.00001; 1635 participants, 5 trials), but

trial sequential analyses showed that data were insufficient. The effect estimates of retinopathy,

ketoacidosis, and retinal photocoagulation were not consistently statistically significant between random-

and fixed effects models. Meta-analysis of body mass index showed a statistical significant reduction with

conventional glycemic control compared to intensive glycemic control (mean difference 1.13 kg/m2, 0.18 to

2.07; P=0.02; 1276 participants, 2 trials). The risk of severe hypoglycemia was significantly increased with

intensive glycemic control (1.40, 1.01 to 1.94; 1983 participants, 11 trials), but this finding was not

confirmed in the trial sequential analysis. Where available, sensitivity analyses including data from the

intervention period only generally showed results in agreement with the overall analysis including the

longest follow-up.

Konklusion:

Conclusion: There was no statistically significant effect towards improved all cause mortality with intensive

glycemic control. However, there may be beneficial effects of intensive glycemic control on the composite

macrovascular outcome and on nephropathy and detrimental effects on severe hypoglycemia and BMI, but

data were inadequate for most outcomes. Notably, the data for retinopathy and ketoacidosis were

inconsistent. There was a severe lack of reporting on patient relevant outcomes and most trials had poor

bias control.

33

9. Diabetes udløst af højdosis steroidbehandling hos kræftpatienter Schultz H1, Kristensen PL1,2, Engelholm SA³, Harder E4, Pedersen-Bjergaard U1

1Endokrinologisk forskningsenhed, Nordsjællands Hospital Hillerød, 2Medicinsk afdeling O, Herlev Hospital, 3Radioterapiklinikken, Rigshospitalet, 4Onkologisk og palliativ afdeling, Nordsjællands Hospital Hillerød Hypotese og formål: Hyperglykæmi er en velkendt bivirkning til steroidbehandling. Kræftpatienter med medullært tværsnitssyndrom får typisk 300 mg prednisolon dagligt i 12-14 dage. Der foreligger ikke data vedrørende risikoen for udvikling af diabetes ved steroidbehandling i dette dosisniveau, og der findes ikke retningslinjer for screening hos disse patienter. Formålet med undersøgelsen er - prospektivt - at opgøre incidensen af steroid-induceret diabetes hos

kræftpatienter i højdosis prednisolon-behandling og at identificere risikofaktorer herfor.

Metode:

Kræftpatienter med medullært tværsnitssyndrom, i behandling med tablet prednisolon 300 mg dagligt

under stråleterapi i Radioterapiklinikken (12-14 dage), blev inkluderet. Patienter med kendt diabetes blev

ekskluderet. Baggrundsoplysninger blev hentet fra patienternes journaler. Ved indgang i studiet måltes p-

glukose, HbA1c, C-peptid m.v. Patienterne blev herefter fulgt med daglige p-glukosemålinger, indtil

behandlingen med højdosis prednisolon blev afsluttet. Ambulante patienter blev fulgt med ét dagligt p-

glukose (random) i forbindelse med stråleterapien, og patienter, som var indlagt under behandlingen, fik

målt p-glukose 4 gange dagligt (fastende, random, før aftensmad og før sengetid).

Undersøgelsens primære endepunkt er udvikling af diabetes (WHO kriterier), dvs. 2 uafhængige

blodsukkermålinger ≥ 11,1 mmol/L. Sekundært endepunkt er behandlingskrævende diabetes, dvs. opstart

af insulin- eller anden behandling efter lokale retningslinjer.

Resultater:

42 patienter er foreløbigt inkluderet, heraf to med ikke tidligere erkendt diabetes, dvs. med HbA1c >48

mmol/mol ved baseline. Diabetes diagnosticeredes hos 43 % (95%CI 28-58%; n=18). Blandt patienterne

med nykonstateret diabetes havde 33% (n=6) behandlingskrævende diabetes. Patienter, der udviklede

behandlingskrævende diabetes, var ældre (74 vs. 67 år, p=0.05), havde højere baseline HbA1c (46 vs. 39

mmol/mol, p=0.007) og fik større prednisolondosis (300 vs. 262 mg dgl., p=0.03) end patienter, der ikke

udviklede diabetes (t-tests). Graden af hyperinsulinæmi vurderet ved C-peptid ved baseline var ikke

relateret til udvikling af diabetes.

Konklusion:

Under behandling med højdosis prednisolon udviklede 43% af kræftpatienter med medullært

tværsnitssyndrom steroidinduceret diabetes, og 1/3 af disse måtte insulinbehandles. Dette understreger

vigtigheden af systematisk screening for steroid-induceret diabetes hos denne patientgruppe.

34

Proteolytic fragmented and chimeric IC2 monoclonal autoantibody against the pancreatic beta-cell

surface chemically labeled with the near-infrared fluorochromes for near-infrared noninvasive imaging of

the pancreatic beta-cell mass.

Brogren CH, Al-Shamary N, Sefeld M, Briat A.

The Bartholin Institute, Rigshospitalet, Copenhagen Biocenter, Denmark, 2Main Imaging Facility,

Animascope, Archamps, France


Earlier research in-vitro and in-vivo with the monoclonal autoantibody IC2 has demonstrated a unique

specificity to insulin-producing pancreatic β-cells. Promising preclinical noninvasive imaging results have

been obtained in mice by SPECT and BLI. The native IC2 IgM antibody has been proteolyticly fragmented

and recombinant chimeric and engineered formats created. F(ab')2µ , Fab, chimeric humanized rIC2-hIgG1

and diabody (rFv)2 formats exist for near-infrared fluorochrome and PET isotope conjugation. A small size

tracer is better suited for in vivo targeting due to a faster excretion rate of the excess of unbound tracer.

Our goal is to develop a clinic diagnostic noninvasive method to quantitatively determine residual

functional β-cell mass in vivo for diabetes diagnostic, imaging islet transplants and insulinoma tumors and

to monitor therapeutic treatment with β-cell growth promoters such as GLP-1 analogs. The aim of this

study is to determine in vitro binding of IC2-VivoTag conjugates to pancreatic β-cells and find the optimal

molar fluorochromes to antibody ratio (F:P) dosage and timing for imaging applications.

Metode:

Chemical coupling of 3 different fluorochromes, Perkin-Elmer VivoTag-S 680 or VivoTag-S 750 and Licor

IRDye 800CW were done to either 0.5 or 1 mg of each of the purified immunoglobulin formats, 4 formats of

IC2 and 3 formats of control human and rat immunoglobulin’s, respectively. The F:P molar ratio was

calculated used Nanodrop spectrometry and varied from 1:1 for 15:1 depending on the antibody size and

choice of fluorochrome. Recently, initial step have been done for 89Zr- immunoPET imaging through

conjugating and chelating the chimeric rIC2-IgG1 and native IC2-Fab formats aiming to optimize a

translational preclinical method hopefully clinical applicable in the near future.

Resultater:

Both normal, NOG and prediabetic NOD mice were used for noninvasive near-infrared imaging of the

pancreatic beta-cell mass, and so far a factor 26 in pancreatic specificity obtained with the IC2-Fab format is

the best result world-wide obtained by any modality and tracer.. In vitro both pancreatic mouse and rat

βTC-tet and RIN-5AH tumors cells have demonstrated strong IC2-Vivotag conjugate binding. The negative

control αTC-16 did not show binding to the antibody VT conjugates. RIN-5AH showed a stronger binding

than βTC-tet cells.

Konklusion:

The previous successful beta-cell specific visualization in vivo by BLI was partly biased with unexpected in-

vivo β-cell uptake of the coelenterazine substrate for BLI. NIR-imaging with the non-β-cell specific GLP-1

agonist Exendin-4 VivoTag 750 conjugates can probably not with sufficient specificity be used for whole

body imaging, but need invasive intravital pancreatic laparoscopy. We believe that noninvasive NIR and PET

imaging suing smaller fragments of IC2 is a better approach for preclinical imaging of the β-cell mass in vivo.

JDRF grant 1-2008-1024 supported this study.

35

10. Weight reducing effects of liraglutide in mice are dependent on number of daily injections rather than

dose

Emilie Balk-Møller, Hannelouise Kissow

BMI, Københavns Universitet


Glucagon-like-peptide-1 (GLP-1) is a well described incretin hormone released from the intestine after oral

food intake. GLP1 receptors are localized in numerous tissues, including the central nervous system.

Liraglutide, a GLP-1 analogue, is used in type 2 diabetic treatment with great success, especially because it

is administered once daily. Beside the positive effects seen on blood sugar stability, weight loss is also

observed. Therefore it has been investigated for its usability as a weight reducing agent in obese patients.

The weight loss is dose dependent and effective doses are higher than those used in the diabetic

treatment. Unfortunately the adverse effects such as nausea and vomiting are also dose dependent. Since

the weight reducing effect is probably mediated through receptors in CNS, an approach to minimize the

adverse effects and hopefully increase the weight loss could be by a change in the administration

procedure. Therefore we investigated the response of dose and number of injection in relation to weight

loss and intestinal weight in mice.

Metode:

Female CD-1 mice (≈25-30g) were divided into five groups. One group was given a low dose (200µg/kg)

once daily, the second group the low dose twice daily, the third group was given a high dose (2mg/kg) once

daily and the forth group was given the high dose twice daily. A vehicle group was given PBS once daily.

Food intake and body weight was daily monitored. The treatment lasted for two weeks. Upon termination

intestines were removed, intestinal weight was recorded and tissues were fixated for histological analysis.

Resultater:

The first days after liraglutide treatment the mice had a large weight loss (10% of BW), but gained weight

thereafter. The weight loss was dependent of the number of injections rather than dose. The natural

weight gain was reduced in liraglutide treated mice compared to PBS. The effect seemed to rely on the

number of injections rather than being dose dependent, meaning that the weight curves was similar for the

high and low dose given once daily injection, and similar for the two groups given twice daily injections.

Even though the high dose was 10 times higher than low dose. Intestinal weight and the histological

investigations showed that the expected intestinal growth was clearly dose dependent, and unrelated to

number of injections.

Konklusion:

The present study indicates that GLP-1 receptors mediating the intestinal growth and the weight reducing

effect respond different to Liraglutide treatment. Therefore we suggest that it would be more effective to

treat patients twice daily with a low dose rather than the current standard. A possibility is that this might

improve the weight loss and reduce the side effects. This should be tested on humans in a clinical trial.

36

11. Glucagon-like peptide-1 (GLP-1) reduces mortality and improves lung function in a model of

experimental obstructive lung disease in female mice.

Niels-Erik Viby, Marie S. Isidor, Katrine B. Buggeskov, Steen S. Poulsen , Jacob B. Hansen and Hannelouise

Kissow

1Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen,

Denmark


The incretin hormone glucagon-like peptide-1 (GLP-1) is an important insulin secretagogue and GLP-1

analogues are used for the treatment of type 2 diabetes. GLP-1 displays anti-inflammatory and surfactant

releasing effects. Thus, we hypothesize that treatment with GLP-1 analogues will improve pulmonary

function in a mouse model of obstructive lung disease.

Metode:

Mice were sensitized with injected ovalbumin and treated with GLP-1 receptor (GLP-1R) agonists.

Exacerbation was induced with inhalations of ovalbumin and lipopolysaccharide. Lung function was

evaluated with measurement of enhanced pause (Penh) in a whole body plethysmograph. mRNA levels of

GLP-1R, surfactants (SFTPs), and a number of inflammatory markers were measured..

Resultater:

GLP-1R was highly expressed in lung tissue. Mice treated with GLP-1R agonists had a noticeably better

clinical appearance than the control group. Penh increased dramatically at day 17 in all control mice but the

increase was significantly less in the groups of GLP-1R agonist treated mice (p<0.001). Survival proportions

was significantly increased in GLP-1R agonist treated mice (p<0.01). SFTPB and SFTPA were down-regulated

and the expression of inflammatory cytokines were increased in mice with obstructive lung disease, but

levels were largely unaffected by GLP-1R agonist treatment.

Konklusion:

These results show that GLP-1R agonists have potential therapeutic potential in the treatment of

obstructive pulmonary diseases, such as chronic obstructive pulmonary disease, by decreasing the severity

of acute exacerbations. The mechanism of action does not seem to be modulation of inflammation and

SFTP expression.

37

12. Luminal glucose stimulates GLP-1 secretion from the isolated perfused rat small intestine by SGLT-1

and GLUT2 mediated uptake and L-type calcium channel activation

Rune Ehrenreich Kuhre, Charlotte Rasmussen, Berit Svendsen, Jens Juul Holst

NNF Center for Basic Metabolic Research, Section for Translational Metabolic Physiology, Faculty of Health

and Medical Sciences, University of Copenhagen.


Glucagon-like peptide-1 (GLP-1) is an incretin (insulin stimulating) hormone with many effects that can be

exploited for the treatment of type 2 diabetes. GLP-1 is produced by the intestinal L-cells, but it is only

recently that the underlying mechanisms of release are starting to be uncovered. In this study, we

characterize the mechanisms of glucose-induced GLP-1 secretion from the isolated perfused rat small

intestine.

Metode:

Male Wistar rats (≈300g) were anesthetized with Hypnorm®/Medazolam®. After lack of consciousness and

reflexes was established, the large intestine and distal small intestine were removed. The proximal small

intestine was perfused with a defined surrogate blood medium after insertion of a catheter into the

superior mesenteric artery. The gut was stimulated with luminal and vascular glucose in presence or

absence of a number of pharmacologic inhibitors/activators to investigate the molecular mechanisms of

glucose-stimulated GLP-1 secretion. Venous effluent was collected each minute and GLP-1 concentrations

were analyzed by radioimmunoassay (RIA).

Resultater:

Vascular glucose was without effect whereas luminal glucose stimulated GLP-1 release in a dose- and

absorption-dependent manner eventually resulting in opening of voltage-gated (L-type) calcium channels

with subsequent entry of extracellular Ca2+. The underlying mechanism involves both sodium coupled

glucose uptake by the sodium-glucose co-transporter 1 (SGLT1) (presumably resulting in sodium-dependent

depolarization) and electro-neutral (GLUT-2) mediated glucose uptake, causing closure of ATP-sensitive

potassium channels (KATP). Glucose does not seem to stimulate GLP-1 secretion by depolarization-

independent mechanisms, e.g. activation of GPCR’s coupled to Gq or Gαs pathways, as cell

hyperpolarization (diazoxide) abolished glucose-stimulated GLP-1 secretion.

Konklusion:

The present study provides a description of the mechanisms involved in glucose stimulated GLP-1

secretion. The virtue of the model employed the intact cell polarization and contact with physiological

neighbors and nerves, and at the same time allows for high-dose inhibition of molecular sites that cannot

be inhibited in vivo. Increased knowledge of the secretory mechanisms underlying GLP-1 secretion could

pave the way for T2D treatments based on stimulation of endogenous GLP-1 secretion.

38

13. Activation of renal GLP-1 receptors located in the afferent arterioles causes an increase in renal blood

flow

Jensen, E.P., S.S. Poulsen, H.Kissow, C.Deacon, J.J. Holst and C.M. Sorensen

University of Copenhagen


Glucagon-like peptide-1 (GLP-1) has a range of effects which are beyond those related to the pancreas and

glucose regulation including renal effects. It is unknown how these effects are mediated, but the GLP-1

receptor has been identified in numerous tissues outside the pancreas including the kidney. Therefore, it is

possible that the extra pancreatic effects are mediated through the GLP-1 receptor. However, the exact

cellular localization of the GLP-1 receptor in these extra pancreatic tissues is poorly described. The aim of

the present study was to investigate the localization of a possible renal GLP-1 receptor and to describe the

possible renal effects of activation of this GLP-1 receptor.

Metode:

In vivo autoradiography studies in both mice and rats with 125I-agonists of the GLP-1 receptor and a 125I-

antagonist of the GLP-1 receptor were carried out in order to localize specific GLP-1 binding and thereby

identify the localization of possible GLP-1 receptors. In isolated mouse kidneys, changes in the diameter of

the afferent arteriole arteriole were measured when GLP-1 was administered. In catheterized,

anaesthetized rats, changes in blood pressure (BP), renal blood flow (RBF) and diuresis were investigated

when GLP-1, both with and without the GLP-1 receptor antagonist Exendin 9-39, was administered directly

into the renal artery. The involvement of NOS and COX for GLP-1 mediated effects in both isolated mouse

kidney and catheterized rats was investigated by administration of with L-NAME and Indomethacin.

Resultater:

Specific binding of 125I-agonists and a 125I-antagonist GLP-1 was identified in the afferent arterioles. GLP-1

caused a dilatation of the afferent arteriole when administered into an isolated mouse kidney. GLP-1 also

increased BP and RBF independent of NOS and COX in anaesthetized, catheterized rats. The increase in RBF

was inhibited when GLP-1 receptors were blocked with Exendin 9-39 whereas the increase in BP was

present even after the GLP-1 receptors were blocked.

Konklusion:

GLP-1 increases RBF via dilatation of the afferent arterioles after specific binding to GLP-1 receptors located

on smooth muscle cells, in these arterioles.

39

14. Targeting the L-cell – Does G-protein Coupled Receptor 40 Activation Stimulate Glucagon-like-

peptide-1 Secretion?

Louise Wulff Christensen, Berit Svendsen, Jens Juul Holst

Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen.


G-protein coupled receptor 40(GPR40) is a lipid sensing receptor expressed on pancreatic β-cells and

enteroendocrine L-cells. While the GPR40 mediated mechanisms in the pancreatic islets have been studied

intensively, the effects of GPR40 activation in the gastrointestinal tract are still unclear. Glucagon-like-

peptide-1(GLP-1), secreted by L-cells, plays a central role in modern treatment of type 2 diabetes(T2DM) in

the form of GLP-1 enhancers and exogenous GLP-1 mimetics. Consequently, GPR40 could be a potential

target for novel L-cell secretagogues stimulating endogenous GLP-1 secretion. The aim of this study is to

explore how GPR40 activation affects GLP-1 secretion in the small intestine.

Metode:

Method: The effect of GPR40 activation on GLP-1 secretion was investigated using isolated, perfused small

intestines from male Wistar rats. GPR40 small molecule agonists (TAK-875, AMG-837 and AMG-1638

supplied by Merck) were administered through intraluminal and vascular routes, respectively. Effluents

from the portal vein were collected every minute in order to evaluate dynamic changes in GLP-1 secretion.

Resultater:

Vascular administration of 10 μM TAK-875 (n=6), 10 μM AMG-837 (n=6) and 1 μM (n=6) and 0.1 μM AMG-

1638 (n=7) all significantly increased GLP-1 secretion compared to basal levels (P<0.05). However, the GLP-

1 responses upon administration of partial agonists, TAK-875 and AMG-837, were comparable to vascular

administration of vehicle (n=6), due to the DMSO present. Intraluminal administration of the three GPR40

agonists separately (n=6) did not increase GLP-1 secretion (P>0.05).

Konklusion:

Conclusion: Vascular administration of the full GPR40 agonist, AMG-1638, significantly increased GLP-1

secretion from the isolated, perfused rat small intestine. Consequently, GPR40 activation may be a part of

future T2DM treatment strategies targeting L-cell secretion.

40

15. Impaired incretin effect and gastrointestinal-mediated glucose disposal in non-diabetic patients with

cirrhosis

Anders E. Junker (1,2), Lise L. Gluud(1), Jens J. Holst(2), Filip K. Knop(1,2), Tina Vilsbøll(1)

1)Diabetes Research Division, Department of Medicine, Gentofte Hospital, University of Copenhagen,

Denmark, 2)Department of Biomedical Science, The Panum Institute, University of Copenhagen, Denmark


Cirrhosis is often complicated by impaired glucose tolerance but the pathogenesis is not understood. We

evaluated the incretin effect and gastrointestinal-mediated glucose disposal (GIGD) in patients with

cirrhosis.

Metode:

Patients with cirrhosis (Child Pugh A and B, 50% men) and healthy controls underwent 1) 4h 50g-oral

glucose tolerance test (OGTT), and 2) isoglycaemic intravenous glucose infusion (IIGI). GIGD was calculated

as [100% × (glucoseOGTT - glucoseIIGI / glucoseOGTT)] and the incretin effect was calculated as [100% × C-

peptideOGTT - C-peptideIIGI / C-peptideOGTT)]. The homeostatic model assessment (HOMA) was used to

describes insulin resistance. Non-parametric statistics were used and results are summarised as

medians±interquartile range.

Resultater:

Ten patients with cirrhosis and ten matched controls were included (54±15 years; body mass index (BMI):

26±6 kg/m2 and 58±17 years; BMI: 29±1 kg/m2). Although HbA1c was similar in the two groups (38±6

mmol/mol vs. 34±6 mmol/mol p=0.11) patients with cirrhosis were more glucose intolerant (area under the

glucose curve 609±458 mmol/l×240min vs. 180±109 mmol/l×240min, p<0.01). Patients with cirrhosis were

more insulin resistant (3.7±4.9 vs. 2.6±1.4, p<0.05) and had an impaired incretin effect (35±44% vs.

55±30%, p<0.01). Isoglycaemia was achieved using 35±12 g of glucose in cirrhosis and 24±10 g in controls

(p<0.01) corresponding to GIGD of 30±23% and 52±20%, respectively (p<0.01).

Konklusion:

Non-diabetic patients with cirrhosis have an impaired incretin effect and GIGD. The findings may reflect

the changes in the sympathetic nervous system and the hormonal changes, which are seen in cirrhosis.

Additional researched is needed to further elucidate these questions.

41

16. The effects of liraglutide and ischemic postconditioning on myocardial salvage after ischemia-

reperfusion injury in pigs.

Ekström K1,2, Dalsgaard M3, Iversen KK1, Pedersen-Bjergaard U1, Vejlstrup NG3, Diemar SS1,2, Idorn M4,

Thorsteinsson B1, Engstrøm T3.

1Department of Cardiology, Nephrology and Endocrinology, Nordsjællands Hospital Hillerød, 2Faculty of

Health and Medical Sciences, University of Copenhagen. 3Department of Cardiology, Rigshospitalet. 4Center

for Cancer Immune Therapy, Department of Hematology, Herlev Hospital.


Acute ST-segment elevation myocardial infarction (STEMI) is routinely treated by acute primary

percutaneous coronary intervention (pPCI) in Denmark. Despite timely reperfusion, this may itself damage

the tissue (reperfusion injury). Conditioning with glucagon-like peptide-1 (GLP-1) analogues, used for

treatment of type 2 diabetes, has been shown to reduce reperfusion injury. Gradual restoration of blood

flow (ischemic postconditioning) provides protection of cardiac tissue following acute myocardial infarction

(MI). It has not yet been tested if combined postconditioning treatment with a GLP-1 analogue and

ischemic postconditioning offers additive protective effect on the myocardium. We here present

preliminary results.

Metode:

58 non-diabetic female Danish Landrace pigs (60±10kg) were randomly assigned to four groups. MI was

induced by occlusion of the left anterior descending artery (LAD) for 45 minutes in all groups. Group 1

(n=14) was treated with i.v. liraglutide after 15 minutes of ischemia until reperfusion. Group 2 (n=17)

received liraglutide treatment concomitant with ischemic postconditioning, performed after 45 minutes of

ischemia. Group 3 (n=15) was treated with ischemic postconditioning, and group 4 (n=12) served as

controls.

Resultater:

No intergroup differences in relative infarct size were detected (overall mean 57 ± 3%; p=0.68). Overall

mortality was 34% (CI: 25-41%) including 26% post-intervention, with no intergroup differences (p=0.99).

Occurrence of VF was 59% (CI: 25-80%) including 39% post-intervention with no intergroup differences

(p=0.65).

Konklusion:

No cardioprotective effects of liraglutide, ischemic postconditioning or combined treatment were found.

Thus, based on our preliminary data, we cannot support a class effect of GLP-1 analogues in

cardioprotection. Neither an additive effect of additional treatment with ischemic postconditioning could

be demonstrated.

42

17. Liraglutide is associated with a decreased risk of acute myocardial infarction in type 2 diabetes

mellitus patients.

Søren Gregersen1, Jakob Starup-Linde1,5, Jan Scheel-Thomsen2, Michael Gejl4, Peter Vestergaard1,3.

1. Department of Endocrinology and Internal Medicine (MEA), Aarhus University Hospital


Diabetes mellitus (DM) is associated with an increased risk of cardiovascular events. The study aims at

examining antidiabetic drugs and their association with acute myocardial infarction (AMI) in patients with

DM.

Metode:

A nested case-control study was conducted. Cases were patients with DM who subsequently suffered from

AMI; controls were DM patients with no subsequent AMI after DM diagnosis. Using the Danish National

Hospital Discharge Register, we included DM patients with information on date of DM diagnosis, date of

AMI, and comorbidities. From the Central Region of Jutland, Denmark, medication use and biochemical

parameters were collected. Analysis was performed by unconditional logistic regression.

Resultater:

16,397 DM patients were included. Insulin, biguanides, β-cell stimulating drugs, dipeptidyl peptidase 4

(DPP-4) inhibitors and the glucagon-like peptide-1 agonist, liraglutide were all associated with a decreased

risk of AMI. The associations were also present when the analyses were restricted to type 2 diabetes. Both

liraglutide and biguanides reduced risk of AMI in patients with type 2 DM. The effect was not tied to patient

biochemical values, e.g. cholesterol or glucose-control.

Konklusion:

The decreased AMI risk may represent beneficial, pleiotropic effects of liraglutide.

43

18. Near-normalization of glycaemic control with a glucagon-like peptide-1 receptor agonist in

combination with physical exercise: a randomized double-blinded placebo-controlled clinical trial

Pernille Mensberg*1,2, Signe Nyby*1,2, Peter G. Jørgensen3, Heidi Storgaard1, Jacob C. Sivertsen3, Magnus

T. Jensen3, Bente Kiens2, Erik A. Richter2, Filip K. Knop1 and Tina Vilsbøll1.

1Diabetes Research Division, Department of Medicine, Copenhagen University Hospital Gentofte, Denmark.

2Department of Nutrition, Exercise and Sports, Sec of Molecular Physiology, University of Copenhagen,

Denmark. 3Department of Cardiology, Copenhagen University Hospital Gentofte, Denmark. * P.M and S.N.

contributed equally to this work


Background and aim: Exercise with supervised training has positive effects on glycaemic control in type 2

diabetes. Treatment with glucagon-like peptide-1 receptor (GLP-1R) agonists improves glycaemic control

and decrease body weight in type 2 diabetes. We aimed to investigate whether exercise combined

withGLP-1R agonist treatment could have additive effects in patients with type 2 diabetes.

Metode:

A total of 33 untrained obese patients with type 2 diabetes (23 men, duration of diabetes (mean±SD): 5±4

years (range: 0.5-20); age: 56±10 years; body weight 99±16 kg; body mass index: 32±4 kg/m2; fasting

plasma glucose (FPG): 10.1±2.8 mmol/l and HbA1c: 65±14. mmol/mol (8.1±1.3%)) treated with diet only

(n=3) or metformin (n=30) were included. Patients were randomised to liraglutide and exercise (1.8 mg

once-daily, exercise+liraglutide) or saline and exercise (exercise+placebo) for 16 weeks. Both groups had

three supervised training sessions per week (60 min); two spinning sessions and one session with resistance

training.

Resultater:

After 16 weeks HbA1c decreased by 22±14 mmol/mol (2.0±1.2%) with exercise+liraglutide and 3±10

mmol/mol (0.3±0.9%) with exercise alone (p<0.001). FPG reduction was greater with exercise+liraglutide

(3.4±2.3 mmol/l) than with exercise+placebo (0.3±2.6 mmol/l) (p=0.010). Significant body weight reduction

was seen with exercise+liraglutide (3.4±2.9 kg, p<0.001), whereas exercise+placebo had no significant

impact on body weight (-1.6±3.2 kg, p=0.064). Similar reductions in body fat were seen in both groups

(exercise+liraglutide: 34±6 to 32±7%, p<0.001; exercise+placebo: 37±6 to 35±7%, p<0.001). Similar

increases in maximal oxygen uptake were observed in both groups (exercise+liraglutide: 2.9±0.9 to 3.4±1.1 l

O2/min, p<0.001; exercise+placebo: 2.5±0.7 to 2.9±0.8 l O2/min, p=0.002), corresponding to approximately

17% increase in physical fitness in both groups.

Konklusion:

Conclusion: In patients with type 2 diabetes inadequately controlled on diet and/or metformin, supervised

physical exercise combined with liraglutide treatment for 16 weeks resulted in near-normalization of

glycaemic control, significantly body weight reduction and improved body composition.

44

19. Persistent AS160 and TBC1D1 phosphorylation in human skeletal muscle 30 min after a single bout of

exercise

Mikkel H. Vendelbo1,2, Andreas B. Møller1,3, Jonas T. Treebak4, Lars C Gormsen2, Jørgen F. P.

Wojtaszewski5, Jens Otto L. Jørgensen1, Niels Møller1, Niels Jessen1,3,6

1Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark


Regulation of Rab-GTPase activating proteins (Rab-GAPs), AS160 and TBC1D1, plays an important role for

glucose uptake in skeletal muscle. Rab-GAP activity of these proteins is thought to be regulated by

phosphorylation that affect the inhibitory effect of the Rab-GAP. This will allow for GDP to GTP exchange in

specific Rab GTPases and subsequent GLUT4 mobilization to the cell surface and increased glucose uptake.

Exploring the regulation of AS160 and TBC1D1 may therefore increase our understanding of substrate

metabolism.

Metode:

Eight healthy males were studied on two occasions: 1) in the resting state and 2) in the hours after a one

hour bout of ergometer cycling (65% VO2peak). 240 min into both experimental days a hyperinsulinemic

euglycemic clamp was initiated. We obtained muscle biopsies during basal and insulin-stimulated

conditions and investigated site-specific phosphorylation of AS160 and TBC1D1.

Resultater:

Phosphorylation of AS160 on Ser341, Ser588, Thr642, Ser704, and Ser751, and of TBC1D1 on Ser237 and

Thr596 was increased after exercise. Insulin stimulation increased AS160 phosphorylation on all sites.

Exercise augmented phosphorylation levels on Ser341, Ser704, and PAS during insulin stimulation, while a

trend was observed on Ser751. No additional exercise effect was observed on Thr642, and no significant

insulin effect was observed after exercise on Ser588. Insulin increased TBC1D1 Thr596 with no additional

exercise effect, and no insulin effect was observed on Ser237. Phosphorylation of AMPK Thr172 and Akt

Thr308 and Ser473 were not significantly changed after exercise. However, phosphorylation of the AMPK

target site Ser79 on Acetyl-CoA Carboxylase was increased 30 min after exercise, and Akt phosphorylation

was increased during insulin stimulation. Glucose rate-of-disappearance was unaffected by prior exercise

but increased during the hyperinsulinemic euglycemic clamp.

Konklusion:

Phosphorylation of TBC1D1 persists after exercise, and insulin-stimulated AS160 phosphorylation is

increased after two-legged aerobic exercise in human skeletal muscle.

45

20. Regulation of glycogen synthase during exercise and exercise recovery in skeletal muscle of

overweight subjects with and without Type 2 diabetes: Effects of insulin.

Andreas James Thestrup Pedersen1, Janne Rasmus Hingst2, Kurt Højlund1, Martin Friedrichsen2, Jonas

Møller Kristensen1, 2, Jørgen F.P. Wojtaszewski2

1Section of Molecular Diabetes & Metabolism, Department of Endocrinology, Odense University Hospital,

and Institute of Clinical Research, University of Southern Denmark. DK-5000 Odense C, Denmark.

2Molecular Physiology Group, Department of Nutrition, Exercise, and Sports, August Krogh Centre,

University of Copenhagen, Copenhagen, Denmark.


Insulin and exercise stimulate skeletal muscle glycogen synthase (GS) through dephosphorylation. The

phosphorylation patterns induced by these stimuli have not been studied comprehensively in insulin-

resistant human muscle. Notably, the effect of insulin on GS phosphorylation in the post-exercise condition

has not previously been examined in type 2 diabetes (T2D). The objective of this study was to examine the

effect of exercise per se and insulin with and without previous exercise on GS phosphorylation and

activation in muscle from type 2 diabetic and control subjects, and to relate these parameters to changes in

whole body glucose metabolism.

Metode:

Thirteen men with T2D and 14 glucose-tolerant males were examined twice by euglycemic-

hyperinsulinemic clamps (4-h, 40 mU/min/m2) to asses glucose disposal rates (GDR) in the rested state and

3 hours after 60 min of cycling exercise at 70% of peakpulmonary oxygen uptake, respectively. GS

activation and site-specific phosphorylation were measured in vastus lateralis muscle obtained before and

immediately after exercise as well as before and during insulin stimulation in either the resting condition or

in the recovery period from exercise.

Resultater:

Insulin and exercise increased GS fractional velocity (FV) by approx. 2-fold and 3-fold, respectively, with no

significant differences found between groups. Both stimuli caused significant dephosphorylation of GS at

sites 3a + 3b, with exercise additionally decreasing site 2 + 2a phosphorylation. In both groups, GS activity

did remain elevated vs the rested state 3 h into recovery from exercise, with prior exercise also enhancing

subsequent insulin-stimulated GS activity. After 3 h of recovery from exercise, reduced GS FV was found

among diabetic compared with control subjects in concert with hyperphosphorylation of sites 2 + 2a. This

defect was not rescued by subsequent insulin stimulation. Post-exercise, increases in glucose storage

and/or reductions in glucose oxidation were found within both groups in the basal and insulin-stimulated

state.

Konklusion:

For obese subjects with and without T2D, the prolonged effect of exercise on muscle GS activation, likely

mediated via site 2 + 2a and site 3a + 3b dephosphorylation, may have contributed to subsequent

alterations found in whole-body glucose handling, with increased glucose storage and/or reduced glucose

oxidation found within both groups vs the rested condition.

46

21. Molecular mechanisms of exercise-induced autophagy in human skeletal muscle – effect of substrate

availability

A.B. Møller(a,b), M.H. Vendelbo(b), B. Christensen(b,c), B.F. Clasen(a,b), J.O. Jørgensen(b), N. Møller(a,b)

and N. Jessen(a,b)

(a) Research Laboratory for Biochemical Pathology, Institute of Clinical Medicine, Aarhus University,

Denmark. (b) Medical Research Laboratory, Department of Internal Medicine and Endocrinology, Aarhus

University Hospital, Denmark. (c) Section of Sport Science, Department of Public Health, Aarhus University,

Denmark.


Exercise has been demonstrated as a potent inducer of autophagy in human and rodent skeletal muscle,

and the beneficial metabolic adaptations induced by exercise training are reliant on normally regulated

autophagy in mice. The molecular mechanism by which autophagy is induced by exercise in skeletal muscle

remains largely unknown. However, studies conducted in cultured non-muscle cells suggest an important

role of Unc-51 like kinase-1 (ULK1) in activation and suppression of autophagy. ULK1 is negatively regulated

by the mammalian target of rapamycin complex 1 (mTORC1) by phosphorylation at Ser757, and positively

regulated by AMP-activated protein kinase (AMPK) by phosphorylation at Ser555. Thus, as exercise strongly

activates AMPK, signaling though AMPK/ULK1 represents a potential mechanism by which autophagy is

induced in response to exercise in human skeletal muscle.

Metode:

The purpose of the present study was: 1) to examine potential molecular mechanisms of exercise-induced

autophagy in human skeletal muscle, and 2) to examine the effect of substrate availability on exercise-

induced activation of these mechanisms. Methods: Eight healthy subjects were investigated twice in a

randomized crossover study. Subjects completed one hour cycling exercise at 50% VO2-max either with

continuous glucose infusion (1g/kg/h), or following a prior 36 hour fasting period. Skeletal muscle biopsies

were sampled on three occasions: i) before, ii) immediately after, and iii) 30 minutes after exercise. Blood

samples were collected continuously throughout the protocol.

Resultater:

Glucose infusion increased plasma glucose levels during exercise compared to the fasting condition, while

fasting increased plasma free fatty acid (FFA) levels during exercise compared to the glucose condition.

Exercise significantly increased ULK1 phosphorylation at Ser555 independently of glucose and FFA levels,

while no differences were observed at Ser757. Increased AMPK Thr172 and ACC Ser79 phosphorylation

were observed after exercise on both experimental days, whereas mTOR Ser2448 phosphorylation was

elevated 30 min after exercise at the glucose infusion day. LC3BII/LC3B-I ratio and LC3B-II protein

expression decreased following both exercise interventions.

Konklusion:

Exercise induces ULK1 Ser555 phosphorylation in human skeletal muscle independently of glucose and FFA

levels in a pattern that mirrors AMPK activation and ACC Ser79 phosphorylation. These results suggest

signaling though AMPK/ULK1 as a potential mechanism of exercise-induced autophagy.

47

22. Growth Hormone (GH)-infusion and fasting both reduce mRNA expression of G0/G1 Switch Gene 2

(G0S2) in human subjects

Peter K. Brask-Thomsen1, Birgitte Nellemann2, Mikkel H. Vendelbo2, Thomas S. Nielsen2, Ann M. Bak2,

Steen B. Pedersen2, Berthil F. F. Clasen1, Niels Møller2, Esben T. Vestergaard2, Niels Jessen1 2 and Jens

Otto L. Jørgensen2.

1) Research Laboratory for Biochemical Pathology, Aarhus University, Aarhus, Denmark and 2) 2)

Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark


Context: Growth hormone (GH) induces lipolysis in adipose tissue but the exact mechanism behind this is

unknown. Adipose Tissue Triglyceride Lipase (ATGL) is the rate-limiting enzyme in lipolysis in adipocytes.

The protein product of G0/G1 Switch Gene 2 (G0S2) has recently been identified as an inhibitor of ATGL.

We have recently shown that following 72 h of fasting GH-levels increase three-fold while G0S2 protein

levels are reduced in humans suggesting that GH might regulate lipolysis through the reduction of G0S2.

Objective: Our objective was to investigate how fasting and/or GH affected mRNA expression and protein

levels of G0S2 and ATGL in human subcutaneous adipose tissue.

Metode:

Eight healthy male subjects were studied four times in a randomized, single-blinded parallel design: Saline,

GH, Fasting (36h), and GH+Fasting (GH-infusion following a 36 h fast). GH (30 ng x kg-1 x min-1) or saline

was infused throughout the study day (270 minutes). Subcutaneous adipose tissue biopsies were collected

at t=120. ATGL and G0S2 protein levels and mRNA expression in adipose tissue were assessed by western

blot analysis and real-time RT-PCR, respectively.

Resultater:

GH-infusion significantly reduced G0S2 mRNA expression in the basal state by 40 % and fasting reduced

mRNA expression by 50 %. The combination of GH+Fasting tended to decrease G0S2 mRNA expression

even further but the interaction did not reach significance (p=0.051). We observed a significant main effect

of fasting on G0S2 protein levels but no effect of GH-infusion. In addition, fasting significantly decreased

ATGL mRNA expression under saline- as well as GH-infusions (by 20 % and 40 % respectively) but this did

not translate into changes in ATGL protein-levels.

Konklusion:

Fasting and GH-infusion both reduced G0S2 mRNA expression and the combined effect of GH+Fasting

tended to be reduced even further. Fasting had a main effect on G0S2-protein levels but no such effect was

observed for GH-infusion which may reflect the short duration of the GH-infusion. Our data suggests that

downregulation of G0S2-mRNA expression may contribute to increased lipolysis during fasting and GH

stimulation.

48

23. Regulation of ANGPTL4 in human muscle- and adipose tissue

Rikke Viggers, Ann Mosegaard Bak, Niels Møller, Jens Otto Lunde Jørgensen, Niels Jessen

Medical Research Laboratory and Research Laboratory for Biochemical Pathology at Institute of Clinical

Medicine, Aarhus University Hospital, Nørrebrogade 44 building 3, 8000 Aarhus C.


Angiopoietin-like protein 4 (ANGPTL4) encodes a glycosylated, cleaved and secreted protein with ramified

effects on human metabolism. ANGPTL4 improves fasting-induced intracellular adipocyte lipolysis in

response to glucocorticoids through a stimulation of cAMP-dependent signaling. Moreover, ANGPTL4

expression is stimulated by fatty acids (FA’s) and inhibits lipoprotein lipase (LPL) activity in fat and muscle

tissues. Taken together, ANGPTL4 appears to favor intracellular adipocyte lipolysis at the expense of VLDL-

TG hydrolysis, but the physiological implications remain unclear.

Metode:

Biopsies obtained from clinical studies with healthy subjects, obese patients and type 2 diabetes (T2DM)

were analyzed and quantified for ANGPTL4 gene expression by PCR.

Resultater:

In adipose tissue, ANGPTL4 mRNA was increased by more than 50% in healthy young men during a 36 hour

fast compared to basal state (p<0.05), which was accompanied by elevated serum FFA levels. Furthermore

ANGPTL4 mRNA in adipose tissue was significantly increased in patients with T2DM compared to healthy

controls (p<0.05).

Konklusion:

Our data demonstrate that stimulation of lipolysis in both healthy and diabetic subjects is associated with

increased ANGPTL4 mRNA levels in adipose tissue. This is in agreement with a proposed role of ANGPTL4 as

a stimulator of lipolysis. A greater insight in the mechanisms regulating the uptake and release of FA?s is

paramount to understand the development of metabolic dysfunctions. Data on ANGPTL4 status in human

tissues are scarce and it is our hope to increase the knowledge of the physiological effects and regulations

of ANGPTL4 by detecting the protein under conditions and disorders in which the metabolic state is altered

and manipulated.

49

24. Intravenous catheters, causes elevated IL-6 locally.

Karen Fjeldborg, Steen Bønløkke Pedersen, Bjørn Richelsen

Department of Endocrinology and Internal Medicine, MEA (THG)


Several studies have described an increase in blood levels of interleukine-6 (IL-6) after different kind of

interventions, e.g. dietary interventions and exercise. In a preliminary study we found indications that an

intravenous catheter could increase the level of IL-6 measured in the blood taken from this catheter. We

aimed to characterize whether acute dietary factors as well as placing an intravenous catheter alone affect

the blood level of IL-6 (and other cytokines).

Metode:

In a cross-over trial with 24 subjects the effects of acute dietary interventions were investigated (high-

sucrose drinks, high fat diet etc.). Blood samples were measured at baseline and continuously 4-h post

intake from an i.v. catheter. Moreover, 10 lean subjects had fastened blood samples taken continuously

over a 6 hour period from an i.v. catheter without any intervention. A direct venous puncture in the

opposite arm was taken after 6 h

Resultater:

The level of IL-6 increased significantly after intake of high-sucrose and high fat diets with about 140%

(P<0,001), and with a lag time of about 3 hours after the intervention. Moreover, intake of water had

similar elevating effect on IL-6. Placing an i.v. catheter increased the level of IL-6 to similar level as in the

intervention groups. IL-6 was elevated after 3 h up to 6 h compared with baseline (p<0.05). Blood samples

taken by direct venous puncture in the opposite arm were not elevated but similar to baseline levels.

Besides IL-6 no other cytokines was affected by placing the i.v. catheter.

Konklusion:

We found that IL-6 is elevated in blood samples taken from an intravenous catheter that have been placed

for more than 3 h without any other interventions. IL-6 may be produced locally by the vessel wall around

the catheter due to local inflammation. Articles that describe a 2-3-fold increase in IL-6 after different

interventions should be reconsidered, if blood samples are obtained through an i.v. catheter.

50

25. Impaired insulin-mediated VLDL-triglyceride Kinetics in Overweight/Obese men with Non-alcoholic

Fatty Liver Disease

Poulsen MK1 , Nellemann B1, Pedersen SB1, Grønbæk H2, Nielsen S1

Department of Endocrinology and Internal Medicine, Aarhus University Hospital


Non-alcoholic fatty liver disease (NAFLD) is an obesity-associated condition characterized by increased fasting hepatic

VLDL-TG secretion as well as insulin resistant glucose and fatty acid metabolism. Moreover, obese subjects without

NAFLD (NAFLD-) seem protected against the metabolic abnormalities of obesity. In addition, basal and insulin

suppressed VLDL-TG secretion rates are increased in type-2-diabetic men compared with healthy men matched for

BMI and age and precedes reduced insulin suppression of endogenous glucose production (EGP) in insulin resistant

upper body obese men. It is unclear whether insulin suppression of VLDL-TG secretion differs between obese men

with NAFLD (NAFLD+) and NAFLD-. Moreover, no information exists regarding whole body basal and insulin-mediated

VLDL-TG oxidation. The purpose of this study was to compare basal and insulin-mediated VLDL-TG and glucose kinetics

in overweight/obese men with and without NAFLD.

Metode:

Twenty-seven obese (BMI > 28 kg/m2) men, 18 NAFLD+ and 9 NAFLD- determined by MR spectroscopy, were

included. 14C-labeled VLDL-TG and 3H-labeled glucose tracers were applied in a hyperinsulinemic-euglycaemic clamp

in combination with indirect calorimetry, blood and breath samples, to determine VLDL-TG and glucose kinetics. Dual-

X-ray absorptiometry scan was used to assess body composition.

Resultater:

As expected, liver fat content was elevated in subjects with NAFLD+ compared with NAFLD- (19.8 vs. 3.7%, p < 0.001)

whereas age and body composition did not differ between groups. VLDL-TG secretion, oxidation and plasma

concentration were comparable in NAFLD+ and NAFLD- men during the basal state whereas all parameters were

significantly greater in NAFLD+ compared with NAFLD- men during hyperinsulinemia (secretion: 45.5[21.8-143.5] vs.

11.1[1.8-87.0]µmol/min, P=0.009, oxidation: 37.4[15.4-102.8] vs. 10.0[1.6-50.9]µmol/min, P=0.008, concentration:

0.56 ± 0.08 vs. 0.23 ± 0.07 µmol/L, P=0.01). VLDL-TG clearance was similar in the two groups both in the basal state

and during hyperinsulinemia. The absolute insulin-mediated suppression of VLDL-TG secretion (basal vs. clamp) was

similar, whereas the absolute suppression of VLDL-TG oxidation and concentration was significantly lower in NAFLD+

men compared with NAFLD- men (oxidation: 0.42[-7.5-20.4] vs. -11.8[-14.2-7.9]µmol/min, P=0.002, concentration: -

0.08±0.03 vs. -0.2±0.03 µmol/L, P=0.009). The percent decrease in VLDL-TG secretion, oxidation and concentration

was significantly less in NAFLD+ compared with NAFLD- men (secretion: -33.1 vs. -63.7%, P<0.001, oxidation: +7.1 vs. -

44.0%, p<0.001, concentration: -12.3 vs. -55.7%, p<0.001) whereas the absolute and the percent insulin-mediated

decrease in VLDL-TG clearance were similar in the two groups. Isotopically determined insulin-mediated glucose

disposal rate (GDR) was significantly decreased in NAFLD+ compared with NAFLD- men (GDR: 3.9±0.3 vs. 5.5±0.8

mg/kg/min, P=0.027). Conversely, basal GDR was comparable in the two groups as well as EGP in both the basal state

and during hyperinsulinemia. Basal insulin and free fatty acids (FFAs) were comparable in the two groups. However,

the FFA was significantly greater in NAFLD+ as compared to NAFLD- during hyperinsulinemia (0.04±0.01 vs. 0.03±0.01

mmol/L, P=0.038).

Konklusion:

Overweight/obese men with NAFLD+ are characterized by insulin resistant suppression of VLDL-TG secretion and

oxidation but unchanged clearance compared with NAFLD- men resulting in greater plasma VLDL-TG concentration.

Compared with EGP, the inability of NAFLD+ men to suppress VLDL-TG secretion and oxidation during

hyperinsulinemia seems to be an early pathophysiological manifestation of male NAFLD+.

51

26. Gastrointestinal-mediated glucose disposal in total pancreatectomised patients

Asger Lund1,4, Jonatan I. Bagger1,4, Mikkel Christensen1,4, Magnus Grøndahl1, Elisabeth R. Mathiesen2,

Carsten P. Hansen3, Jan Storkholm3, Steen Larsen1, Jens J. Holst4, Tina Vilsbøll1 and Filip K. Knop1,4

1Diabetes Research Division, Department of Medicine, Gentofte Hospital, 2Center for Pregnant Women with

Diabetes, Department of Endocrinology, Rigshospitalet, 3Department of Gastrointestinal Surgery,

Rigshospitalet, 4Department of Biomedical Sciences, Faculty of Health sciences; University of Copenhagen,

Denmark


Gastrointestinal-mediated glucose-disposal (GIGD) after oral glucose tolerance test (OGTT) reflects the

percentage of glucose disposal caused by the oral route of glucose administration. It accounts for as much

as 60-70% in healthy subjects. Mediators of GIGD include the gut incretin hormones, neural reflexes, first-

pass hepatic uptake of glucose and perhaps at present unknown factors. It is likely that incretin-mediated

potentiation of pancreatic insulin secretion constitutes a major contributor to GIGD, but so far it has not

been possible to discriminate between pancreatic and extrapancreatic mechanisms underlying GIGD. We

aimed to evaluate the impact of extrapancreatic effects on GIGD.

Metode:

Data from 7 total pancreatectomised patients (age: 60±4 years; body mass index (BMI): 22.3±1.4 kg/m2;

HbA1c: 63±4 mmol/mol (mean±SEM)) and 6 healthy control subjects (age: 57±3 years; BMI 22.9±0.8 kg/m2;

HbA1c: 32±1 mmol/mol) were included in the present preliminary analysis. Participants were examined

over two experimental days: a 75 g-OGTT and a corresponding isoglycaemic iv glucose infusion (IIGI).

Differences between administered glucose during OGTT and IIGI within the group of pancreatectomised

patients were used to evaluate the impact of extrapancreatic mechanisms on GIGD.

Resultater:

In healthy control subjects 28±2 g of glucose was infused intravenously to copy the plasma glucose profile

from the 75 g-OGTT, resulting in a GIGD of 63±2%. In the total pancreatectomised patients we used 76±3 g

of glucose to copy the plasma glucose profile from the 75 g-OGTT, resulting in a GIGD of -2±4% (i.e. that the

pancreatectomised subjects disposed of iv and oral glucose similarly).

Konklusion:

While these data are preliminary, the low GIGD in pancreatectomised patients suggests that

extrapancreatic factors do not play a major role in the GIGD. The need for a larger glucose load on the IIGI

day could however point to the existence of gut-derived factors (e.g. gut derived glucagon) contributing to

a worsening of oral glucose tolerance in pancreatectomised patients.

52

27. Metabolic Effects of an Amino Acid infusion during LPS Exposure mimicking acute Infection in

Humans

N. Rittig, E. Bosjnak, HH. Thomsen, B. Richelsen, JO. Jørgensen, N. Møller


Acute inflammation is catabolic and increases protein loss. This study was designed to test whether a

continuous amino acid infusion could counteract these metabolic effects.

Metode:

Eight healthy males randomly underwent 3 different interventions: Control/placebo, LPS injection (E. Coli

lipopolysaccharide, 1 ng/kg), and LPS + amino acid infusion (2.5 g/kg/day). Metabolic parameters were

measured after 4 h in and after a 2h hyperinsulinemic euglycaemic clamp. Glucose, fat, and protein

metabolism were quantified by isotope tracer dilution, forearm arterio-venous differences and by indirect

calorimetry. Muscle and fat biopsies were obtained for signaling analysis.

Resultater:

On both days LPS caused a similar degree of inflammation with a significant increase in plasma cortisol

levels (185.9±50.0 ng/ml), temperature (2.6±1.6 °C), and pulse (37.3±6.0 bpm) compared to placebo.

Energy expenditure increased with ≈ 500 kcal/day (CI 368.5;608.0) on the days with LPS compared to

placebo. When adding amino acids to LPS there was a significant increase in protein oxidation of 176.4

kcal/day (CI 61.6;291.1) compared to placebo. The glucose clamp caused an increase in glucose oxidation

and a decrease in fat oxidation in all groups, the insulin levels being lower when comparing LPS alone with

placebo (p<0.001) and tending to be lower between LPS + amino acids compared to placebo (p=0.062). The

glucose infusion rate (GIR) did not differ between the two days of LPS (0.94 mg/kg/min, CI -0.22;2.10).

Konklusion:

LPS caused a significant degree of inflammation and a catabolic response with an 28 % increase in energy

expenditure and amino acid supplementation further increased protein oxidation by 38 %. Thus i.v

administration of amino acids during acute inflammation has distinct metabolic effects on substrate

utilization and may have a future clinical role as an anabolic agent.

53

28. Adverse pregnancy outcome and mitochondrial dysfunction in women with subclinical

hypothyroidism.

Anne-Dorthe Feldthusen, Palle Lyngsie Pedersen, Jacob Larsen, Tina Toft Kristensen, Jan Kvetny.

Gynækologisk-obstetrisk afdeling & Mitokondrieforskningsenheden, Næstved Sygehus.


It is well documented that overt hypothyroidism is associated to adverse pregnancy outcome, but studies

of subclinical hypothyroidism (subhypo) have demonstrated conflicting results. Since the symptoms of

subhypo can be very discreet, it is possible that pregnant women will be undiagnosed and the risk of

subhypo probably underestimated. The aim was to examine adverse pregnancy outcome in pregnant

women with subhypo and the relation to a possible mitochondrial dysfunction as thyroid hormones are

known to regulate mitochondrial function.

Metode:

Third trimester pregnant women (n=113) not receiving any thyroid medication were included in this study.

All participants were interviewed, thyroid status was measured, and the mitochondrial membrane potential

and reactive oxygen species (ROS) was measured by flow cytometry of stained mononuclear blood cells. A

group of non-pregnant euthyroid women (n=42) was used as euthyroid controls. All participants had

concentrations of thyroid hormones (fT4 and tT3) within the reference range. Adverse pregnancy outcome

was defined as preterm delivery, preeclampsia, placental abruption, Apgar score less than 7 points 1

minute past labour or postpartum haemorrhage.

Resultater:

The prevalence of subclinical hypothyroidism among pregnant women was 17% and the number of overall

adverse pregnancy outcome was significantly increased (p=0.02) compared to euthyroid women.

Preeclampsia, poor Apgar score and postpartum haemorrhage were significantly more frequent in the

subhypo group compared to the euthyroid group (p=0.04, p=0.001 and p=0.03, respectively), and more

women gave birth after 41 weeks of gestation compared to the euthyroid group (p=0.04). Compared to

euthyroid controls a physiological up regulation of mitochondrial function was observed in euthyroid

pregnant women. This was impaired in pregnant women with subhypo. Unrelated to thyroid status

pregnant women had increased ROS compared to euthyroid controls.

Konklusion:

We speculate that the unfavourable effects on mitochondrial function in women with subclinical

hypothyroidism could be associated with higher prevalence of adverse pregnancy outcome.

54

29. Monitoring and evaluation of the Levothyroxin replacement therapy in pregnant women with

hypothyroidism.

Julia Hubaveshka, Luba Freja Liubov Michaelsson, Birte Nygaard.

Department of Internal Medicine O, Endocrine Unit, Herlev Hospital.


During pregnancy an increased daily substitutive dosage of Levothyroxin(L-T4) is required in hypothyroid

patients in order to meet the maternal needs and secure a normal foetal development. The usual increase

of L-T4 dosage is 25 – 30% typically in the first trimester. The aim of the study was to evaluate the

treatment and efficiency of the clinical control of patients with hypothyroidism during pregnancy. The

secondary aim was to investigate the number of dysregulated patients as well as the number of pregnancy

complications.

Metode:

A retrospective study of 93 consecutive pregnant women with hypothyroidism (mean age: 35,0 ± 4,7 SD)

followed at the outpatient clinic in the Endocrinology Unit, Herlev Hospital during 2012. Fifty-five patients

were known in the clinic before the pregnancy and 38 were new referrals from the primary sector. For 26

patients it was the first pregnancy, for 30 it was the second one, for 22 – third pregnancy and for the

remaining patients it was the 4 pregnancy or more. Thyroid function was evaluated every 4th weeks.

Resultater:

Eighty-six patients had autoimmune hypothyroidism, 4 had hypothyroidism after radioactive iodine

treatment and 3 after thyroid surgery. Eighty- three of the women were in L-T4 replacement therapy

before the pregnancy and 10 started L-T4 during pregnancy. The number of patients with S-TSH of more

than 4 mU/l during the pregnancy was 36, however, in 25 only one measurement with a slight increase in S-

TSH was present. Of the eleven women having more than one increased values of S-TSH, 5 had poor

compliance, despite increased care and 5 were not monitored in the clinic before the pregnancy. The

patients with increased S-TSH levels in the beginning of the pregnancy had a tendency to be over treated,

13 women were registered with at least one S-TSH measurement less than 0.1 mU/l during the pregnancy.

From this group, 3 women had pregnancy complications.

Konklusion:

Thyroid function of hypothyroid women should be monitored upon confirmation of conception and closely

followed during pregnancy. L-T4 dose should be increased early during pregnancy. We suggest that, if the

patient is monitored in the primary sector, the increase of L-T4 dosage should be started by the general

practitioner before the first visit in an endocrinological clinic in order to secure optimal TSH levels early

during the pregnancy.

55

30. Antithyroid behandling i tidlig graviditet giver betydende risiko for medfødte misdannelser. Et dansk

nationalt studie af 1.820 eksponerede børn.

Stine Linding Andersen, Jørn Olsen, Chun Sen Wu og Peter Laurberg

Endokrinologisk Afdeling, Aalborg Universitetshospital, Aalborg og Sektion for Epidemiologi, Institut for

Folkesundhed, Aarhus Universitet, Aarhus


Antithyroid (ATD) behandling af maternel hyperthyroidisme i tidlig graviditet kan være associeret med en

øget risiko for medfødte misdannelser hos barnet. En særlig embryopati med karakteristiske ansigtstræk og

svære misdannelser er beskrevet i litteraturen i relation til methimazol (MMI) og carbimazol (CMZ).

Hvorvidt propylthiouracil (PTU) er teratogent er fortsat uafklaret.

Metode:

Nationalt studie på basis af danske registre inkluderende alle børn levendefødt i Danmark fra 1996-2008

(n=817.093). Maternelle indløste ATD recepter blev identificeret (eksponering) samt diagnoser (ICD-10)

med medfødte misdannelser registeret i Landspatientregisteret før barnet fyldte 2 år (udfald). Børnene blev

inddelt i følgende eksponeringsgrupper: PTU i tidlig graviditet (n=564); MMI/CMZ i tidlig graviditet

(n=1.097); MMI/CMZ og PTU (skift i tidlig graviditet, (n=159)); ingen ATD i graviditeten (ATD behandling,

men ikke i graviditeten, (n=3.543)) og ikke-eksponerede (aldrig ATD eller substitutionsbehandling,

(n=811.730)). Multivariat logistisk regression (justeret for en række maternelle karateristika inkl. diabetes)

blev anvendt til at estimere justeret odds ratio (OR) med 95% konfidensinterval (95% CI) for medfødte

misdannelser hos eksponerede vs. ikke-eksponerede børn.

Resultater:

Prævalensen af medfødte misdannelser var høj efter eksponering for ATD i tidlig graviditet (PTU 8,0%;

MMI/CMZ 9,1%; MMI/CMZ og PTU 10,1%; ingen ATD i graviditeten 5,4%; ikke-eksponerede 5,7%; p<0,001).

Både MMI/CMZ (justeret OR 1,66 (95% CI 1,35-2,04)) og PTU (1,41 (1,03-1,92)) behandling i tidlig graviditet

var associeret med en øget risiko for medfødte misdannelser og også gruppen af børn, hvis mor var skiftet

mellem MMI/CMZ og PTU i tidlig graviditet havde en høj risiko (1,82 (1,08-3,07)). Både MMI/CMZ og PTU

var associeret med misdannelser i urinvejene og PTU, men ikke MMI/CMZ, med misdannelser i ansigt- og

halsregionen (sinus, fistler og cyster). Choanal atresi, øsofagus atresi, omfalocele, ductus vitellinus

anomalier og aplasia cutis (MMI/CMZ embryopati), var hyppigt forekommende blandt MMI/CMZ

eksponerede børn (kombineret justeret OR 21,8 (95% CI 13,4-35,4)); men MMI/CMZ var også associeret

med misdannelser af øjne og hjerte.

Konklusion:

Både MMI/CMZ og PTU havde teratogent potentiale med 2-4 ekstra tilfælde af medfødte misdannelser pr

100 levendefødte børn. Spektret af malformationer var forskelligt for de to typer af ATD og skift fra

MMI/CMZ til PTU i tidlig graviditet syntes ikke at beskytte. Nye ATD med færre bivirkninger bør udvikles.

56

31. Brug af antithyroid medicin bør begrænses i tidlig graviditet og ophøre før 6. graviditetsuge.

Peter Laurberg & Stine Linding Andersen

Endokrinologisk Afdeling, Aalborg Universitetshospital, Aalborg


Antithyroid medicin (ATD) anvendes til behandling af hyperthyroidisme under graviditetet, men

behandlingen er associeret med en øget risiko for medfødte misdannelser. Vi evaluerede muligheden for at

undgå misdannelser efter ATD behandling.

Metode:

Detaljeret gennemgang af misdannelser opstået efter skift fra Methimazol (MMI) til Propylthiouracil (PTU)

før graviditetsuge 11.

Resultater:

To store studier (et Japansk retrospektivt hospitalsstudie baseret på journalgennemgang og vort eget

danske nationale registerstudie), som begge inkluderede > 1000 eksponerede børn, rapporterede 2,0-3,4%

flere tilfælde af medfødte misdannelser hos børn eksponeret for MMI i tidlig graviditet. Det drejede sig ofte

om specifikke og alvorlige misdannelser. PTU behandling var associeret med 2,3% flere tilfælde af

medfødte misdannelser i det danske studie. Det drejede sig om andre og mindre alvorlige misdannelser end

efter MMI eksponering. I det Japanske studie fandt man pga. metodeforskel ingen association med PTU

behandling.

I vort danske studie var der 149 børn, hvis mor var skiftet fra MMI til PTU i tidlig graviditet før

graviditetsuge 11, hvilket er det anbefalede ifølge nuværende internationale guidelines. Men risikoen for

misdannelse var høj i denne gruppe af børn (13/149). Den type misdannelser, der er associerede med MMI,

forekom hos børn hvis mor var skiftet til MMI relativt sent efter graviditetens indtræden (median dag 63

(95% CI 60-69) vs. ingen medfødte misdannelser dag 43 (40-46, p=0,016). Der var to tilfælde af den PTU

associerede type misdannelser registreret hos børn hvis mor var skiftet i løbet af graviditetsuge 6. I det

japanske studie, var der 5 børn med MMI associerede malformationer, hvor maternel ATD behandling var

ophørt i første trimester og bortset fra et tilfælde af aplasia cutis, observerede man ingen MMI associerede

misdannelser når ATD behandlingen var ophørt før graviditetsuge 7.

Konklusion:

Både MMI og PTU behandling i tidlig graviditet førte til medfødte misdannelser hos 2-3% af de eksponerede

børn. De MMI associerede misdannelser syntes mest alvorlige. Vi anbefaler, 1. ATD behandling begrænses

mest mulig i første trimester (graviditetsuge 5-10), 2. der udarbejdes skriftlig instruks til fertile kvinder i

ATD behandling om at a) ophøre med ATD behandlingen indenfor den første uge efter at menstruationen

er udeblevet, hvis graviditet er en mulighed, b) udføre graviditetstest samme dag og c) omgående kontakte

læge, 3. hvis ATD er nødvendigt i tidlig graviditet: brug PTU og 4. hvis graviditet er planlagt: skift fra MMI til

PTU før graviditet.

57

32. Abdominal circumference is higher in children born of women with polycystic ovary syndrome than

controls

Hanne Mumm, Dorte Glintborg, Jens Aage Sørensen, Lise Lotte Torvin Andersen, Dorte Møller Jensen,

Marianne Andersen

Endokrinologisk afdeling M, Odense Universitetshospital


Background: Polycystic ovary syndrome (PCOS) is associated with hyperandrogenemia, insulin resistance,

central obesity, and gestational diabetes mellitus (GDM). Aim: To investigate body composition in children

born of women with PCOS compared to controls. To study the risk of adverse obstetric outcomes in women

with PCOS.

Metode:

Methods: Prospective cohort study including a well characterized group of women with PCOS and singleton

pregnancies at Odense University Hospital during 2003-2011 (n = 208) and a date-of-childbirth matched

control group (n= 1,040). Anthropometric data from the children was recorded along with data on maternal

age, parity and pre-gestational body mass index (BMI) and adverse obstetric outcomes.

Resultater:

Abdominal circumference was higher in children born of women with PCOS than in controls (median 34 cm

vs. 33 cm, p< 0.05) and remained significant after adjusting for possible confounders including maternal

age, parity, GDM, and BMI. Birth weight was comparable in children born of women with PCOS vs. controls.

Women with PCOS had higher pre-gestational BMI than controls (median 25.9 vs. 23.2 kg/m2, p< 0.001).

There was no difference in offspring gender, gestational age at delivery, parity, or maternal age at birth.

The risk of GDM was increased in women with PCOS vs. controls (5.8 % vs. 1.6 %, p< 0.05) and remained

significant after adjusting for confounders. Body composition in children born of mothers with PCOS and

maternal pregnancy complications were not predicted by individual Rotterdam criteria.

Konklusion:

Conclusions: Abdominal circumference was higher in children born of women with PCOS than in controls.

58

33. Lower levels of placental growth hormone in early pregnancy in type 1 diabetic women giving birth to

large for gestational age infants

1,2Lene Ringholm, 3,4Anders Juul, 4,5Ulrik Pedersen-Bjergaard, 4,5Birger Thorsteinsson, 1,4,6Peter Damm,

1,2,4Elisabeth R. Mathiesen

1Center for Pregnant Women with Diabetes, Rigshospitalet, Copenhagen, 2Department of Endocrinology,

Rigshospitalet, Copenhagen,3Department of Growth and Reproduction, Rigshospitalet, Copenhagen,

4Faculty of Health and Medical Sciences, University of Copenhagen, 5Endocrinology Section, Department of

Cardiology, Endocrinology and Nephrology, Nordsjællands Hospital Hillerød, 6Department of Obstetrics,

Rigshospitalet, Copenhagen


To evaluate whether high levels of placental growth hormone (GH) and Insulin-like Growth Factor-I (IGF-I)

are associated with development of large for gestational age (LGA) infants in pregnant women with type 1

diabetes.

Metode:

Observational study of 107 consecutive pregnant women with type 1 diabetes (median duration 16 years

(range 1-36), HbA1c 6.6% (4.9-10.5) in early pregnancy). At 8, 14, 21, 27 and 33 weeks blood was sampled

for measurements of placental GH, IGF-I and HbA1c. LGA was defined as birth weight >90th percentile.

Resultater:

Throughout pregnancy the levels of placental GH and IGF-I were similar in 51 (48%) women delivering LGA

infants (birth weight 3930 g (3295-5620)) compared with the remaining women (3198 g (2040-3880))

except at 8 weeks where placental GH levels were lower in the women with LGA infants (1.1 ng/ml (0.1-4.3)

vs. 1.7 (0.3-11.7), p=0.02) whereas IGF-I levels were similar (p=0.63). Gestational age at first blood sampling

was similar in women with and without LGA (60 days (37-89) vs. 62.5 (42-94), p=0.26). LGA was more

frequent in multiparous vs. primiparous women (34 (67%) vs. 17 (33%), p=0.001), but was not associated

with pre-pregnancy BMI or HbA1c during pregnancy. At multivariate logistic regression analysis, placental

GH concentration at 8 weeks was associated with LGA (OR 0.5 (95% CI: 0.2-0.9), p=0.03), i.e. a doubling of

placental GH levels implied a halving of the risk of having a LGA infant.

Konklusion:

Elevated levels of GH or IGF-I did not contribute to the development of LGA infants in women with type 1

diabetes. Unexpectedly the levels of placental GH were lower in early pregnancy in women with LGA

infants compared to the remaining women. It remains speculative whether lower levels of placental GH

reflect delayed fetal growth in early pregnancy.

59

34. Morbidity and mortality in offspring born to mothers with type 1 diabetes.

Sine Knorr1, Kirstine Stochholm1, Zuzana Vlachova2, Birgitte Bytoft3, Tine Dalsgaard Clausen4, Rikke Beck

Jensen5, Peter Damm3, Henning Beck-Nielsen2, Dorte M. Jensen2, Claus Højbjerg Gravholt1,6

1 Dept. of Endocrinology and Internal Medicine, Aarhus University Hospital. 2 Dept. of Endocrinology,

Odense University Hospital. 3 Center for Pregnant Women with Diabetes, Dept. of Obstetrics, Rigshospitalet,

University of Copenhagen. 4 Dept. of Gynecology and Obstetrics, Hilleroed Hospital, University of

Copenhagen 5 University Dept. of Growth and Reproduction, Rigshospitalet, University of Copenhagen. 6

Dept. of Molecular Medicine, Aarhus University Hospital.


Maternal type 1 diabetes (T1DM) in pregnancy is associated with an increased risk of stillbirth, perinatal

mortality and congenital malformations. The current study aims at determining the long-term

consequences of T1DM in pregnancy on offspring mortality, morbidity and use of medication.

Metode:

During 1992-1999 pregnant women with T1DM were reported to the Danish Diabetes Association. We used

this registry to identify the children of women with pregestational T1DM (index children n=1300) and

through Statistics Denmark 100 controls (n=128.594) for each index child.

Resultater:

Mortality: Overall mortality was significantly increased for index children (HR=2.07, CI=1.34-3.22; P=0.001).

Morbidity: For index children total morbidity after 1 month of age was increased (HR=1.19 CI=1.12-1.28;

P<0.0001). When dividing the diagnoses in ICD-10 chapters HR was significantly increased in chapters

relating to infection, blood/immune system, endocrinology, ear, circulation, musculoskeletal system,

perinatal, congenital malformations and unspecified. Only in the chapter describing skin diseases HR was

significantly decreased. When excluding admissions before the age of one year total morbidity was still

significantly increased with a HR of 1.10 (CI=1.03-1.17, P=0.003) and divided into ICD-10 chapters morbidity

after 1 year of age was significantly increased in the following chapters: infections, endocrinology, ear,

musculoskeletal system, perinatal, congenital malformations and the chapter with unspecified conditions.

Medication: The overall use of medication was increased for index children (HR 1.086 CI=1.02-1.16;

P=0.011) and use of medication in seven out of 14 ATC-groups was significantly increased.

Konklusion:

T1DM during pregnancy have long-term implications on offspring health with an increased risk of mortality,

morbidity and use of medication.

60

35. Foot protection in bed in patients with diabetic pressure ulcers and serious comorbidity.

Anne Rasmussen, Per Holstein, Kirsten Engelhard Nielsen, Martin Ridderstråle.

Steno Diabetes Center, DK 2820 Gentofte, Denmark


Background and aim: Diabetic patients with pressure ulcers especially on the hindfoot or malleoles, often in

the form of decubitus require effective off-loading also in bed, possibly in wheelchair as a supplement to

conventional measures. The aim of this study was to present and evaluate a foot-protection device

supplied form our diabetic foot clinic.

Metode:

Methods: A retrospective study was undertaken for the period 1. September 2011 through 31. August

2012. All information was assessed from an electronic patient record system.

Resultater:

During the one year study period 32 patients had presented 37 foot ulcers witch were treated with a foot

protector for use in bed and/or wheelchair. Altogether 43 devices were supplied. Twenty-one patients

were men, 11 were women, median age 66,8 years (range 35-88 years), 53% had type 1 diabetes, 41% had

type 2 diabetes, 6% were not classified. Mean duration of diabetes was 31,9 years (range 2-73 years).

HbA1c was 67,3 mmol/mol (range 43-98 mmol/mol). Ten (31%) patients were smokers. The patients had

severe comorbidity and seven (22%) had undergone a contralateral major amputation. Fourteen (44%)

developed the ulcer during a hospital admission or in bed at home, 5 (16%) patients had the ulcer from the

shoes, in 12 (41%) patients the cause was unclear, 1 (3%) patient had pressure ulcer from the wheelchair.

Twenty (62%) had a vibrations sensation >50 volt. 19 (59%) patients had no palpable foot pulses and had

median toe pressure of 44 mmHg (10-81 mmHg). Localisation of the ulcers was: 26 on the heel, 7 on the

malleoles, 3 on the lateral side of the foot and 1 on the lateral side of the 5. toe. The ulcers were classified

according to the University of Texas wound classification system: 6 patients had stage 1A: 15 1B, 1 1C, 2 1D,

3 2B, 4 2D, 5 3B and 1 had stage 3D. Twenty-eight (87%) patients had therapeutic sandals or removable

cast including individually made insoles, 3 (9%) patients used their own shoes. Seven (22%) used a

wheelchair. Twenty (62%) patients healed their foot ulcers within a median time of 16 weeks (2-40 weeks);

At present 4 (13%) patients still have foot ulcers, 3 (9%) have undergone major amputation and 5 (16%)

patients have died with a foot ulcer.

Konklusion:

Conclusion: In our setting the foot protector is a useful device for avoiding pressure to exposed wounds

during bed res allowing acceptable healing results and avoiding leg amputation in of these cases. The

device is reasonably cheap (73 euro), easy to handle and it keeps stable position during patients

movements. We need a controlled study, but offer this satisfactory device for the time being. It is also

supplied as a prophylactic measure against decubitus in fragile patients.

61

36. Effects of Leucopatch™, an Autologous, Leucocytes and Platelet Rich Fibrin Patch, in Patients with

Hard-to-Heal Diabetic Foot Ulcers. A pilot study.

Magnus Löndahl1,2, Lise Tarnow3,4,11, Tonny Karlsmark5, Rasmus Lundquist6, Anna Marie Nielsen7,

Morten Michelsen8, Anders Nilsson9, Mariusz Zakrzewski10, Bo Jörgensen5.

1Department of Endocrinology, Skåne University Hospital, Lund, Sweden, 2Department of Clinical Sciences

in Lund, Lund University, Lund, Sweden, 3Steno Diabetes Center A/S, Gentofte, Denmark, 4Health, Aarhus

University, Aarhus, 5Bispebjerg University Hospital, Copenhagen, Denmark, 6Reapplix Aps, Birkerød,

Denmark, 7Odense University Hospital, Odense, Denmark, 8Herlev Hospital, Herlev, Denmark, 9Ängelholm

Hospital, Ängelholm, Sweden, 10Kolding Hospital, Kolding, Denmark 11 Nordsjællands Hospital, Hillerød,

Denmark


Leucopatch™ is a leukocyte and platelet rich Fibrin patch that provides concentrated blood cells and signal

substances to the surface of an ulcer. It is produced by centrifugation of the patient's own venous blood

without addition, using the Leucopatch™ device.

The aim of this pilot multicentre cohort study was to evaluate effects of Leucopatch™ in patients with hard-

to‐heal diabetic foot ulcers.

Metode:

Non-ischemic Wagner grade 1 or 2 diabetic foot ulcers with a duration of more than 6 weeks and a maximal

area of 10 cm2 were included. Patients with >40% ulcer area change during a two‐week run-in period were

excluded. LeucoPatch™ was applied once weekly for up to 19 treatments or until the foot ulcer was

completely epithelized. The primary endpoint was healing within 20 weeks.

Resultater:

Complete epithelisation was achieved in 34% (per‐protocol analysis:36%) at 12 weeks and 52% (59%) at 20

weeks. In patients with ulcer duration less than 6 months 73% of ulcers healed within 20 weeks. Patients

with healed ulcers had larger ulcer area reduction during the first two treatment weeks compared to non‐

healers. Adverse events were mild and rare.

Konklusion:

Leucopatch™ is well‐tolerated, feasible to use and has a potential in the armamentarium of the diabetic

foot ulcer treatment, provided this outcome is confirmed in an appropriately powered randomized clinical

trial.

62

37. Magnetic resonance imaging for volumetric evaluation of diabetic polyneuropathy: A methodological

pilot study

Michael Vaeggemose MSc PhD-stud, Steffen Ringgaard MSc PhD, Knud Yderstraede MD PhD, Niels Ejskjaer

MD PhD, Henning Andersen MD PhD Prof

Department of Neurology, Aarhus University Hospital, Denmark


Twofold: To develop MRI as a tool for detecting neuropathy and to investigate a possible relationship

between nerve volume and the presence of diabetic polyneuropathy.

Metode:

T2w spectral selection attenuated inversion recovery (SPAIR) images (0.57x0.57x3mm) were acquired to

measure the extent of the focal nerve lesions at 3 Tesla. The MR scans consisted of 30 axial slices of the

sciatic nerve in mid-thigh level. Four type II diabetic patients with polyneuropathy (DPN) 2 type II diabetic

patients (nDPN) without neuropathy and 4 healthy control (HC) subjects were included. The presence of

neuropathy was determined based on clinical examinations.

Resultater:

The MR T2-weighted images did not show an increased SI in the sciatic nerve fascicles of DPN 0.19 (0.13-

0.26), nDPN 0.21 (0.19-0.22) and HC 0.14 (0.12-0.19), muscles of DPN 0.25 (0.17-0.16), nDPN 0.20 (0.13-

0.26) and HC 0.15 (0.15-0.16) or in the blood vessels of DPN 0.69 (0.58-0.73), nDPN 0.64 (0.48-0.80) and HC

0.68 (0.66-0.78). Volumetric examination of the sciatic nerves showed an increased nerve volume of the

DPN patients 5.91 (5.00-8.91) compared to nDPN 3.15 (2.69-3.60) and HC 3.58 (2.96-4.23) (p-value = 0.03).

Konklusion:

It proved feasible to describe the sciatic nerve using MRI and volumetric examination of the sciatic nerves

showed a statistical significant increase in nerve volume in diabetic polyneuropathy compared to non-

neuropathic patients and healthy control subjects. Ongoing and future studies will further develop the use

of MRI to visualize peripheral nerves in diabetic neuropathy.

63

38. Soluble Urokinase Plasminogen Activator Receptor is associated with diabetes and diabetic

complications in patients with type 1 diabetes

S Theilade1, S Lyngbæk2, TW Hansen1, J Eugen-Olsen3, M Fenger3, P Rossing1, 4, 5 and JL Jeppesen2

1Steno Diabetes Center, DK, 2Glostrup Hospital, DK, 3Hvidovre Hospital, University of Copenhagen, DK,

4Aarhus University, DK, 5University of Copenhagen, DK


To investigate associations between soluble urokinase plasminogen activator receptor (suPAR) and diabetic

complications in type 1 diabetes.

Metode:

Cross-sectional study of 676 type 1 diabetes patients (301(55%) females, mean±SD age 55±13 years) and 51

non-diabetic controls (23(55%) females, 47±13 years).

suPAR was measured in baseline samples (suPARnostic ELISA; ViroGates, Denmark). Diabetic complications

were previous cardiovascular disease (CVD) (myocardial infarction, revascularisation, peripheral arterial

disease and stroke), autonomic dysfunction (heart rate variability during deep breathing <11

beats/minute), albuminuria (urinary albumin excretion rate (UAER) ≥30 mg/24-hours) or increased arterial

stiffness (pulse wave velocity ≥10 m/s). Multivariate analyses were adjusted for gender, age, systolic blood

pressure, estimated glomerular filtration rate, UAER, HbA1c, total cholesterol, body mass index, high

sensitivity C-reactive protein, antihypertensive treatment and smoking.

Resultater:

Median(range) suPAR levels in controls vs. patients: 2.3(1.1-3.6) vs. 3.5(1.1-15.1) ng/ml (adjusted p<0.001),

in controls vs. normoalbuminuric patients: 2.3(1.1-3.6) vs. 3.0(1.1-10.5) ng/ml (adjusted p<0.001); in

normoalbuminuric patients with short vs. long diabetes duration (>10 years): 2.6(1.1-10.5) vs. 3.4(1.7-7.1)

ng/ml (adj. p<0.001), in normo- (<30 mg/24-hours), micro- (30-299 mg/24-hours) and macroalbuminuric

(≥300 mg/24-hours) patients: 3.0(1.1-10.5), 3.7(1.6-15.1) and 4.9(1.8-13.2) ng/ml (adj. p<0.001).

suPAR levels were higher in patients with vs. without CVD (n=144(21.3%)), autonomic dysfunction

(n=349(59.2%)), albuminuria (n=357(53.1%)) and increased arterial stiffness (n=297(47.2%)) (adj. p≤0.024).

Per 1 SD increase in logsuPAR the odds ratios for complications were: CVD 1.4(1.1-2.0), autonomic

dysfunction 1.5(1.1-2.1), albuminuria 1.7(1.1-2.6) and increased arterial stiffness and 1.4(1.0-2.1) (adj.

p≤0.039).

Konklusion:

suPAR is associated with type 1 diabetes, diabetes duration and diabetic complications, independently of

other risk factors. suPAR may be a novel risk marker in the management of diabetes.

64

39. Ficolin B in Diabetic Kidney Disease

Charlotte Berg Holt, Jakob Appel Østergaard, Steffen Thiel, Troels Krarup Hansen

Medicinsk Forskningslaboratorier, Institut for Klinisk Medicin, Århus Universitetshospital, Nørrebrogade 44,

byg.3, 8000 Aarhus C


The innate immune system has adverse effects in diabetes and cardiovascular disease. More specifically,

the complement system plays a key role through errouneous complement activation possibly due to

hyperglycaemia. Recently a direct cause-effect relationship between MBL and worsening of diabetic kidney

damage has been described. Both MBL and ficolins induce activation of the complement system through

the lectin pathway by binding to specific glycosylations. Normally these are not found on human cells in

sufficient density and configuration to activate complement. It is speculated that hyperglycaemia-induced

acceleration of glycation may produce ligands for lectin binding, thus inducing complement activation and

thereby damage of the kidney. We hypothesise that ficolin B exerts undesirable kidney damage in diabetes

as seen for MBL.

Metode:

We induced diabetes in age matched female wildtype mice and ficolin B knockout mice with intraperitoneal

streptozotocin (STZ) injections. Two non-diabetic control groups, wildtype and ficolin B knockout, were also

included. Eighteen weeks after diabetes was established spot urine and blood samples were collected

before the animals were sacrificed and the kidneys were dissected. Urinary albumin was measured with

ELISA and urinary creatinine was measured with an in-house high performance liquid chromatography.

Resultater:

In the wildtype mice the kidney weighed 24% more in the diabetic mice compared to the nondiabetic mice.

In the ficolin B knockout mice the comparable difference in kidney weight was 29% (p=0.60). Similarly,

diabetes led to an increase in albumine-to-creatinine ratio, but no effect of deficiency of ficolin B was

observed. In the wildtype mice the ACR was 32.5 mg/g higher in diabetic mice compared to the controls.

This increase in ACR was estimated to 62.5 mg/g in the ficolin B knockout mice (twoway ANOVA, p=0.21).

We found no effect of diabetes on the glomerulus fraction (p=0.46), why it was not relevant to test for

effectmodification of the glomerulus fraction caused by ficolin B.

Konklusion:

The diabetic induced effects on kidney weight, glomerulus volume and albumin-creatinine ratio were not

modified by the presence of ficolin B. In conclusion, ficolin B did not interact with the effects of diabetes on

the kidney.

65

40. Circulating levels of mid regional pro-adrenomedullin (MR-proADM) are not associated with major

cardiovascular events or renal failure in patients with type 1 diabetes

Pernille Holmager1, Ulrik Pedersen-Bjergaard2, Anne-Sophie Sejling2, Birger Thorsteinsson2,3, Jens

Faber1,3, Caroline Kistorp1,3.

1. Centre of Endocrinology and Metabolism, Herlev University Hospital, Herlev, Denmark 2. Department of

Cardiology, Endocrinology and Nephrology, Nordsjaellands Hospital, Hillerød, Denmark 3. Faculty of Health

and Medical Sciences, University of Copenhagen


Endothelial dysfunction is associated with both macro- and microvascular events in patients with type 1

diabetes (T1D). Adrenomedullin is a 52 amino acid peptide, which is expressed in various tissues, including

vascular endothelium, and may play a role in the pathogenesis of diabetic vasculopathy. This peptide can

be measured in plasma as the stable fragment of the pro hormone mid-regional pro-adrenomedullin (MR-

proADM). The aim was to study if MR-proADM levels can predict major cardiovascular events (MACE) or

renal failure (RF) in T1D.

Metode:

We measured MR-proADM in 264 patients with T1D (59.5 % men, mean age 44 ± 13 years) who were

followed for a median of 12 years with respect to MACE and RF. At baseline 1 patient had MACE, and no

patients had RF, Plasma MR-proADM–levels were measured using a commercial ELISA assay

(Thermofisher). Median concentrations of MR-proADM were 0.36nmol/l (range 0.29-0.43 nmol/l). MACE

was defined as myocardial infarction, stroke, heart failure, CV deaths or unstable angina pectoris. Renal

failure was defined as a doubling of plasma creatinine during follow-up, development of chronic renal

disease, stage 1-5 or requirement of dialysis. The median duration of diabetes was 19 years (range 11-28),

mean (SD) s-creatinine was 80 (20) micromolar and 54 (20.5%) of the patients received ACE-inhibitor or

angiotensin II receptor antagonist therapy.

Resultater:

During follow-up, 44 patients developed MCE and 19 patients developed RF. There was no association

between MR-proADM levels and s-creatinine, r = -0.087, P = 0.22. S-creatinine levels were neither elevated

in MACE patients (88 (46) micromolar vs. 80 (18) micromolar, P = 0.56) nor in RF patients (90 (32)

micromolar vs. 79 (19) micromolar, P = 0.19). There was no difference in MR-proADM levels in patients

developing MCE compared to those who did not (0.39 nmol/l (0.30-0.49) vs. 0.35 nmol/l (0.29-0.43), P =

0.37). Development of RF was not associated with elevated MR-proADM levels (0.32 nmol/l (0.29-0.39

nmol/l) vs. 0.36 nmol/l (0.29-0.43 nmol/l), P = 0.42. The Cox regression analysis showed that doubling of

MR-proADM levels were neither a significant predictor of MACE (HR 1.2 (0.6-2.1), P = 0.64) nor of RF (HR

1.2 (0.5-2.7), P = 0.74). S-creatinine levels were predictors of RF (HR 1.03 (1-1.05), P = 0.008), but not MACE

(HR 1.00 (1.00-1.01), P = 0.35).

Konklusion:

MR-proADM concentrations were not associated with incident MACE or RF in the present T1D cohort.

66

41. Effect of Aldosterone Receptor Blockade on Galectin 3 in Patients with Diabetic Nephropathy

Morten Lindhardt1, Maria Lajer1, Hiddo Jan Lambers Heerspink2, Peter Rossing1,3,4 and Rudolf A. de

Boer2.

1Steno Diabetes Center, Gentofte, Denmark; 2University Medical Centre, University of Groningen,

Netherlands; 3University of Aarhus, Denmark and 4University of Copenhagen, Denmark.


Background: Fibrosis and expansion of extra cellular matrix in the kidney is part of the pathogenesis of

diabetic nephropathy. Plasma galectin-3 (p-gal3) is linked to fibrogenesis in the heart and kidney, and

treatment with spironolactone has beneficial effect in patients with heart failure. We hypothesize, that a

potential beneficial effect of spironolactone on fibrosis in diabetic nephropathy is mediated through a

reduction in p-gal3.

Metode:

Methods: A post-hoc analysis of three clinical controlled double masked intervention trials all with

randomisation to either spironolactone or placebo for 8 weeks in a cross-over design. The first trial consist

of 25 patients with 1 DM and macroalbuminuria, the second consist of 23 patients with type 2 DM and

macroalbuminuria and the third consist of 21 patients with type 1 DM and microalbminuria. Mean (SD) age

of 53 years (10.8) and a mean duration of DM of 28 years (14.6).

Resultater:

As previously reported albuminuria was reduced with 30, 33 and 60% in the three trials. P-gal3 was

associated with GFR in the placebo period (R2=0.42 p<0.0001). Mean (95% CI) level of plasma p-gal3 after

treatment with spironolactone was 16.0(14.7-17.4) and after placebo 15.5(14.3-16.7). In an unadjusted

mixed model, the effect of treatment insignificant increased p-gal3 by 1.03 ng/ml (1.02-1.05) (p=0.074).

However, when adjusted for after treatment values of mean 24h systolic blood pressure, 24h urine albumin

excretion, 51Cr GFR, Hba1c and cholesterol, the treatment effect on p-gal3 was attenuated (p=0.69).

Patients with p-gal3 below the median in the placebo period had a greater reduction in albuminuria 31.3%

(25.1-37.6) vs. those above 8.8%(-2.9-20.4), p=0.021.

Konklusion:

Conclusions: Galectin 3 was associated with GFR. Spironolactone for two months reduced albuminuria but

did not change p-gal3 levels. This suggests an initial effect mediated by hemodynamic changes, whereas an

effect on fibrosis may require a longer treatment period or p-gal3 is not affected by spironolactone. Low

level of p-gal3 was associated with greater reduction in albuminuria.

67

42. Low-density lipoprotein cholesterol is associated with fracture risk in diabetes patients – a nested

case-control study

Jakob Starup-Linde1,2 , Soeren Gregersen 2, Peter Vestergaard 1,3

(1) Clinical Institute, Aalborg University, Fredrik Bajers vej 5, 9220 Aalborg


Diabetes Mellitus is associated with an increased risk of fractures, which is not explained fully by bone

mineral density and common risk factors. The aim of this study is to investigate the association of

medication and biochemical markers on the risk of fracture in a diabetes population.

Metode:

Nested case-control study based on Danish diabetes patients from The Danish National Hospital Discharge

Registry. The cases of the study were diabetes patients with a fracture (n= 24,349) and controls were

diabetes patients with no fracture (n=132,349). A total of 2,816 diabetes patients were available for an

analysis of patient characteristics, co-morbidities, biochemical parameters and drug usage.

Resultater:

Patient age at the time of diabetes diagnosis, a diagnosis of previous fracture, an alcohol related diagnosis,

total cholesterol level, and the usage of antidepressants, antiepileptics and insulin all increased the odds of

fracture. Low-density lipoprotein cholesterol (LDL) levels decreased the odds of fracture, where the level of

3.04-5.96 mmol/l was optimal with regard to fracture risk.

Konklusion:

LDL may add to the understanding of fractures in diabetes patients and it may be added to current fracture

risk models in diabetes patients.

68

43. Changes in body weight, hormonal status, and physical activity during cannabinoid treatment in

patients with severe, enduring anorexia nervosa: results from a randomised, controlled study

Alin Andries, Bibi Gram, Jan Frystyk, Allan Flyvbjerg, René Klinkby Støving

Center for Eating Disorders, Department of Endocrinology, Odense University Hospital, Odense


The severe underweight in chronic anorexia nervosa (AN) results in complex neuroendocrine disturbances.

The cannabinoids are emerging as a novel approach to the treatment of severe cachexia, but their anabolic

effect on the impaired hormonal systems in AN is poorly understood. The aim of the present study was to

investigate the effects of synthetic cannabinoid agonist treatment on body weight, hormonal status and

physical activity in patients suffering from severe and enduring AN.

Metode:

Twenty-four patients with chronic AN received dronabinol, 2.5 mg twice daily and matching placebo during

4 weeks, separated by a wash-out period with a similar length. Changes in body weight were assessed as

the main outcome of the study. Variations in the metabolic activity of GH-IGF-1-, hypothalamic-pituitary-

adrenal-axis, and adipose tissue were estimated by analysing changes in the secretion of IGF-1, free urinary

cortisol (UFC), leptin, and adiponectin. Physical activity was assessed by accelerometry, performed during

the last week of each intervention.

Resultater:

Dronabinol induced a weight gain of 0.73 kg (P<0.01) above placebo. The levels of bioactive IGF-1 remained

unaffected by dronabinol, while the UFC excretion was moderately decreased. The levels of plasma leptin

increased with 15% (P<0.05) during dronabinol intervention, being linearly and positively associated with

the levels of physical activity.

Konklusion:

Dronabinol treatment modestly improved the nutritional status in patients suffering of severe and enduring

AN, in the absence of severe adverse affects. Furthermore, our results revealed a moderating effect of

dronabinol on the UFC excretion in this group of severely ill patients

69

44. Bone status in patients with anorexia nervosa and relationship with biochemical findings and findings

at psychiatric interview

Stine Aistrup Eriksen Msc (1), Hanne Prietzel MD (5), Jenna Rosenqvist Ibsen MD (3), Marlene Briciet

Lauritsen MD DrMedSc (4,5), Peter Vestergaard MD PhD DrMedSc (1,3), Gry Kjærsdam Telléus Cand. Psych.

(2,6)

(1) Clinical Institute, Aalborg University, Denmark, (2) Section of Eating Disorders, Department of Psychiatry,

Aalborg University Hospital, Denmark, (3) Department of Endocrinology, Aalborg University Hospital,

Denmark, (4) Research Unit for Child and Adolescent Psychiatry, Aalborg University Hospital, Denmark, (5)

Clinic for Child and Adolescent Psychiatry, Aalborg University Hospital, Denmark, (6) Unit for Psychiatric

Research, Aalborg University Hospital, Denmark


Aim: The aim of the present study was to investigate bone status and biological mechanisms involved in the

negative impact of Anorexia Nervosa (AN) on bone.

Metode:

A total of 30 AN patients (27 women and 3 men) with a mean age of 20.9±5.8 years from Aalborg University

Hospital and who underwent bone scans were included in the study. Biochemical data, dual-energy X-ray

absorptiometry (DXA), as well as general health and medical information was collected during the period

2009 to 2011 via local and national clinical databases in Denmark and analysed in a cross sectional study.

Resultater:

The AN patients had a mean BMI of 17.4±2.4 (kg/m2) and a mean Z-score in lumbar spine and hip of -

1.5±1.1 and -1.6±1.3, respectively. Hip Z-score decreased with duration of disease and there was a positive

correlation between serum 25-hydroxy-vitamin D level and spine Z-score but not hip Z-score. Bone Mineral

Density (BMD) did not seem to change with time since diagnosis. Additionally, a negative correlation

between serum 25-hydroxy-vitamin D levels and serum total alkaline phosphatase levels was found. A

serum 25-hydroxy-vitamin D level below 50 nmol/l was associated with increased alkaline phosphatase

levels.

Konklusion:

Bone density is decreased in AN, and the main determinant for hip and spine BMD is duration of disease.

Long duration could thus be a factor referral for DXA. The lack of a change in BMD with time since diagnosis

could indicate an irreversible bone loss. As for patients without AN, patients with AN display biochemical

signs of increasing bone turnover expressed as higher levels of total alkaline phosphatase at serum 25-

hydroxy-vitamin D below 50 nmol/l. This indicates normal responsibility of the osteoblasts to malnutrition.

70

45. Whey, Casein, and Post-Prandial Lipaemia; a 12-week, randomized, parallel-controlled, human

intervention study

Bohl M., Gregersen S., and Hermansen K.

Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Tage-Hansens Gade.


Whey protein improves postprandial lipid metabolism in humans with abdominal obesity.

Metode:

A 12-week, randomized, double-blinded, human intervention study was performed. The daily intake of milk

protein (whey or casein) was 60 g and the milk fat (different fatty acid composition) was 63 g. 63 subjects

were randomized into one of four diets. A high fat meal was consumed and changes from intervention

baseline in post-prandial triglyceride, ApoB-48, free fatty acids, insulin, and glucose were measured. Two-

way ANOVA was used as statistical model.

Resultater:

52 subjects completed the study. Baseline characteristics did not differ significantly between groups. Mean

change in post-prandial triglyceride from baseline did not change significantly between groups consuming

whey or casein. However, mean incremental area under the curve for ApoB-48 decreased significantly to

whey compared to casein (by 431 mg/L, p=0.025). We observed no significant change in post-prandial TG,

free fatty acids, glucose, or insulin.

Konklusion:

12-week whey consumption resulted in a decreased post-prandial chylomicron response to the high fat

meal, while no change in TG was detected. This indicates a beneficial effect on PPL of whey compared to

casein.

71

46. First report of cases treated with the EndoBarrier gastrointestinal liner in Denmark

Ulrich Rohde (1), Ebbe Langholz (1), Peter Vilmann (2), Steffen U. Friis (1), Tina Vilsbøll (1) and Filip K. Knop

(1)

1: Diabetes Research Division, Department of Medicine, Gentofte Hospital, 2: Unit of Gastrointestinal

Surgery, Herlev Hospital; University of Copenhagen


The EndoBarrier gastrointestinal liner or duodenal-jejunal bypass sleeve (DJBS) is a novel endoscopic

deployable and removable device that has been developed to treat obesity and type 2 diabetes. It consists

of a 60 cm long liner of impermeable flouropolymer, open at both ends, and a proximal anchor that fixates

the device to the wall of the duodenal bulb. Here we report the first cases of obese patients (with and

without type 2 diabetes) treated with DJBS in Denmark.

Metode:

Inclusion criteria included age between 18 and 65 years, obesity with or without type 2 diabetes. Exclusion

criteria included anticoagulant therapy, inflammatory bowel disease, ulcers, pancreatitis, severe heart or

lung diseases, or infection with Helicobacter Pylori. So far we have implanted DJBS in 6 subjects during

general anaesthesia.

Resultater:

Of the 6 subjects implanted with the DJBS, 1 subject had the device removed after 5 weeks due to device

obstruction that manifested as prolonged

abdominal pain, nausea and vomiting. The remaining 5 subjects consisted of 4 men (1 with type 2 diabetes)

and 1 woman (mean age [range]: 54 [46-63] years; body weight: 103 [89-116] kg; body mass index (BMI):

33.9 [29.9-36.5] kg/m2. Mean HbA1c among the normal glucose tolerant subjects amounted to 34 [31-38]

mmol/mol. The patient with type 2 diabetes was slightly dysregulated on metformin (HbA1c 50 mmol/mol;

duration of diabetes 4 years). All participants experienced mild to moderate, transient abdominal

discomfort or pain, nausea or vomiting and/or episodes of fever after implantation. One month post-

implantation body weight and BMI were reduced by 3.1 [-0.1-5.4] kg and 1.0 [range 0-1.7] kg/m2,

respectively. In the patient with type 2 diabetes HbA1c normalised (43 mmol/mol) and the metformin dose

was decreased by 50%.

Konklusion:

These preliminary data show that treatment with DJBS can be handled in a Danish hospital setting and may

lead to weight loss in obese subjects and improvement of glycaemic control in type 2 diabetes.

72

47. Effect of gut-hormone inhibition on energy intake, glucose tolerance and pulse rate after Roux-en-Y

Gastric Bypass surgery

Maria Saur Svane, Kirstine Bojsen-Møller, Carsten Dirksen, Nils Bruun Jørgensen, Christoffer Martinussen,

Jens Juul Holst, Sten Madsbad

Hvidovre Hospital, Dept. of Endocrinology


To examine the effect of gut hormone inhibition energy intake, glucose tolerance and pulse rate after Roux-

en-Y Gastric Bypass (RYGB) surgery using the somatostatin-analog octreotide.

Metode:

A 53-year old male was examined 1 month after RYGB on two separate days with a patient-blinded

subcutaneous injection of either saline or 100 mg octreotide. Thirty minutes after the injection a liquid

mixed meal test was performed with blood sampling for 4 hours, followed by an ad libitum meal test of

pasta with meat sauce (532 kJ/100 g). The patient was instructed to eat until pleasant satiety during the ad

libitum meal. The primary end-point was difference in energy intake on the two study days. Blood samples

were analyzed for glucose, insulin, C-peptide, GLP-1 and glucagon. Blood pressure and pulse rate were

frequently assessed during the meal test.

Resultater:

Octreotide strongly inhibited postprandial release of hormones illustrated by insulin and C-peptide

secretion (iAUCinsulin: saline 49.8 nmol×L-1×min, octreotide −17.5 nmol×L-1×min ; iAUCC-peptide: 337

nmol×L-1×min, −99.0 nmol×L-1×min). Energy intake at the ad libitum meal test was markedly increased on

the octreotide test day, with a 58% increase (saline 230 g, octreotide 364 g). The profile of plasma glucose

was right-shifted with a delayed time to peak (saline 50 min, octreotide 150 min), unchanged peak plasma

glucose (saline 9.8, octreotide 9.7 mmol×-1L), but the incremental area under the curve increased by 75%

(saline 385, octreotide 675 nmol×L-1×min). On the day of saline injection a post-prandial pulse increment

of +22 beats×min-1 was observed, which was abolished by octreotide injection. Systolic blood pressure

showed a 10 mmHg decrease after the meal at the saline day, which was not seen on the octreotide day.

Konklusion:

Inhibition of gut hormone secretion after RYGB results in a markedly increased energy intake illustrating

the importance of gut hormones in appetite regulation postoperatively. Moreover, octreotide results in a

changed postprandial glucose profile and abolishes the post-prandial pulse rate increment.

73

48. Acute and long-term changes in leptin and ghrelin concentrations after Roux-en-Y gastric bypass

Nils Bruun Jørgensen, Carsten Dirksen, Kirstine Bojsen-Møller, Siv Hesse Jacobsen, Maria Svane, Jens Juul

Holst, Sten Madsbad, Trine Ryberg Clausen

Dept. of Endocrinology, Hvidovre Hospital, Hvidovre


Ghrelin stimulates and leptin inhibits energy intake. With diet-induced weight loss, ghrelin concentrations

increase and leptin concentrations decrease, thus working to promote energy intake. Here we describe

acute and long-term changes in concentrations of both hormones before and after a Roux-en-Y gastric

bypass (RYGB)-induced weight loss.

Metode:

25 morbidly obese patients (13 T2D/12 NGT) were examined with a liquid mixed meal tests before (pre)

and 1 week (1 wk), 3 months (3 mo) and 1 year (1 y) after RYGB. Fasting and postprandial blood samples

were drawn for 4 hours.

Resultater:

Since neither fasting nor meal-dependent changes in ghrelin or leptin concentrations differed between

NGT/T2D patients, data were pooled.

Weight loss gradually increased with time from surgery (1 wk: 2.3±0.3% (p<0.001); 3 mo: 14±0.8%

(p<0.001); 23±1.7% (p<0.001)).

Fasting ghrelin concentrations decreased 1 week and 3 months after RYGB but returned to preoperative

levels after 1 year (pre: 67±11 pg/ml; 1 wk: 23±4 (p<0.001); 3 mo: 46±6 (p=0.001); 1 y: 64±7 (p=0.97)). One

year, but not 1 week after RYGB there was a positive correlation between fasting ghrelin concentrations

and weight loss (RS=0.42, p<0.05). Postprandial ghrelin suppression was reduced 1 week after RYGB, but

then gradually increased (I-AUC ghrelin: -4373±1215 pg·min/ml; -1189±281 (p<0.001); -3647±654 (p=0.25);

-4569±514 (p=0.45)). There was a trend towards a negative correlation between weight loss and meal-

induced ghrelin suppression one year after surgery (RS: -0.37, p=0.11).

Fasting leptin concentrations decreased immediately after RYGB with no further decrease after 3 months or

1 year (40±6 ng/ml; 21±3 (p=0.005); 21±3 (p=0.002); 19±3(p<0.001)). One year but not 1 week

postoperatively, there was a negative correlation between fasting leptin concentrations and weight loss

(RS=-0.60, p<0.01).

Konklusion:

Fasting ghrelin and leptin concentrations decreased in a weight loss independent manner 1 week after

RYGB. One year after RYGB fasting leptin and ghrelin concentrations correlated to weight loss as would be

expected. There was a trend towards ghrelin suppression being greater in patients with greater weight

losses. These hormonal changes may influence post RYGB energy intake.

74

49. Beta-cell function in response to oral and intravenous challenges after Roux-en-Y gastric bypass

Kirstine N Bojsen-Møller 1,2, Carsten Dirksen 1,2, Nils B. Jørgensen 1,2, Siv H Jacobsen 1,2, Annette K Serup

3, Peter H Albers 3, Dorte L Hansen 1, Dorte Worm 1, Lars Naver 4, Viggo B Kristiansen 4, Jørgen FP

Wojtaszewski 3, Bente Kiens 3, Jens J Holst 2,5, Erik A Richter 3, Sten Madsbad 1

1 Department of Endocrinology, Hvidovre Hospital, 2 Novo Nordisk Foundation Centre for Basic Metabolic

Research, University of Copenhagen 3 Department of Nutrition, Exercise and Sports, University of

Copenhagen,4 Department of Surgical Gastroenterology, Hvidovre hospital, 5 Department of Biomedical

Sciences, University of Copenhagen


The aim of this study was to elucidate the physiological changes responsible for improved glycaemic control

after Roux-en-Y gastric bypass (RYGB). We examined changes in beta-cell function in response to

intravenous (iv) and oral challenges throughout the first year after surgery to determine whether improved

beta-cell function depends on an oral stimulus.

Metode:

We studied 10 obese subjects with type 2 diabetes (T2D) (BMI 38.9 ± 1.6 kg/m2 mean ± sem) and 10 obese

subjects with normal glucose tolerance (NGT) (BMI: BMI 40.2 ± 0.8 kg/m2) before, 1 week, 3 months and 1

year after RYGB using the intravenous glucose glucagon test (GGT). The GGT consisted of an iv bolus of 50%

glucose (wt/vol) resulting in ΔP-glucose of +13.5±4.0 (mean ± SD) mmol/l (without differences between

groups or study visits) followed by injection of 1 mg glucagon iv after 2 min and blood sampling for a total

of 12 min. Oral glucose tolerance tests (OGTTs, 75 g in 5 min) were performed before, 3 months and 1 year

after surgery. Acute insulin response (AIR=ΔC-peptide0-max) to GGT and insulinogenic index (IGI=ΔC-

peptide0-30/ΔGlucose0-30) from OGTT were used to assess beta-cell function. Insulin sensitivity was

assessed by 4 hour hyperinsulinemic (40 mU/m2/min) euglycemic (5.5 mmol/l) clamps with [6,6-2H2]-

glucose co-infusion. Insulin sensitivity (RdClamp/InsulinClamp) was used to calculate two disposition

indices, DIiv and DIoral, from AIR and IGI, respectively.

Resultater:

Glycaemic control improved after RYGB in patients with T2D (HbA1c T2D: pre 7.0±0.3%, 3 mo 5.9±0.2

p<0.01, 1y 5.7±0.2 p<0.01, NGT: 5.4±0.1, 5.3±0.1 p=ns, 5.3±0.1 p=ns). Insulin secretion after the

intravenous challenge was unchanged after RYGB in patients with T2D (AIR: pre 1463±279 pM, 1 wk

1502±440 p=ns, 3 mo 1799±396 p=ns, 1y 1572±395 p=ns), while DIiv increased at 3 months and 1 year due

to concomitant improvements in insulin sensitivity. In subjects with NGT, insulin secretion after the iv test

decreased postoperatively (AIR: 4117±772, 3040±668 p<0.05, 3167±748 p<0.01, 3022±804 p<0.05), while

DIiv remain unchanged. In response to oral glucose, insulin secretion increased in T2D after RYGB (IGI: pre

189±60 pM/mM, 3 mo 341±60 p<0.01, 1y 266±55 p<0.05) and was unchanged in NGT (IGI: 788±79,

747±119 p=ns, 770±93 p=ns). Secretion of glucagon-like peptide-1 (GLP-1) increased after RYGB in both

groups in response to oral glucose, while secretion of glucose-dependent insulinotropic polypeptide (GIP)

was largely unaltered.

Konklusion:

Insulin secretion increased after RYGB, but only in patients with type 2 diabetes and only in response to

oral glucose. After an iv challenge, insulin secretion was unchanged post-operatively in patients with type 2

diabetes, while it decreased in subjects with NGT, likely as an adaptation to improved insulin sensitivity.

Improved beta-cell function after RYGB is thus linked to the oral and not the iv route of administration,

underscoring the importance of the changed gut anatomy and exaggerated GLP-1 secretion.

75

50. Autoreactivity and distribution between naïve and memory cell compartments of circulating Th17

cells and type-1 regulatory T cells in autoimmune thyroid disease.

Birte Kristensen1,2,, Laszlo Hegedüs2 , Hans O?Madsen3, Terry Smith4, and Claus H. Nielsen1.

1Institute for Inflammation Research, Department of Rheumatology, Copenhagen University Hospital,

Copenhagen, Denmark


The principal aim is to investigate the ability of two important self-antigens expressed by the thyroid,

namely thyroglobulin (TG) and thyroid peroxidise (TPO), to induce IL-17 and IL-10 production in circulating

CD4+ T cells from patients with Hashimoto thyroiditis (HT) or Graves’ disease (GD), or from healthy donors.

Given the role of pro-inflammatory cytokines in determining the balance between Th17 cells and type-1

regulatory T cells (Tr1 cells), we also assessed the concomitant induction of IL-6-producing CD4+ T cells.

Finally, we determined whether the self-reactive Th17 and Tr1 cells represent re-activated memory cells or

can differentiate de novo from the pool of circulating naïve T cells.

Metode:

Mononuclear cells were isolated from healthy controls as well as individuals with HT or GD. The MNCs were

stimulated with either human TG or human TPO. The MNCs were stimulated for 18 or 48 hours depending

on the measured cytokine. All samples were stained with the appropriate extracellular and intracellular

antibodies and acquired by FACS Canto. All samples were analysed on the corresponding FACS Diva

software.

Resultater:

In the naïve CD4+ T cell compartment TG induced significant IL-17 production by cells from HT patients only

(median: 8.5 / 10,000 cells). TPO also induced IL-17 production by 3 per 10,000 naïve CD4+ T cells from HT

patients, and by no naïve CD4+ T cells from GD patients or controls (HT vs. controls: p=0.009). Neither TG

nor TPO induced IL-6 production by naïve or memory CD4+ T cells. There was a tendency that TG induces IL-

10 production by 3 per 10,000 CD4+ T cells in the HT group, compared to none in the GD patient group

(P=0.07) and 1.9 per 10,000 naïve CD4+ T cells in the controls. Correspondingly, TG induced IL-10

production by 6 per 10,000 memory CD4+ T cells from HT patients compared with 1 per 10,000 memory

CD4+ T cells among GD patients (P=0.048) and 3 per 10,000 memory T cells among the controls.

With polyclonal stimulation such as anti-CD3/anti-CD28 there was a significant production of IL-17 among

HT patients (P<0.05). This was not seen among the GD patients or controls.

Konklusion:

In conclusion, IL-17 production can be induced by TG and TPO in naïve CD4+ T cells from donors with HT

but not from those individuals with GD. This finding supports a role for TG-driven Th17 T cell activation in

the pathogenesis of HT. TG also induced IL-10 production by CD4+ T cells in healthy controls and HT

patients, suggesting a potential contribution of self-antigen-specific Tr1 cells to peripheral tolerance.

76

51. Di-ethylhexyl-phthalate (DEHP) is metabolised by human thyroid cells and may influence

thyroglobulin secretion

Juliana Frohnert Hansen (1), Marianne Brorson (1), Marie-Louise Hartoft-Nielsen (1), Malene Boas (2)

Katharina M. Main (2), Hanne Frederiksen (2), Jacob Hofman-Bang (1), Åse Krogh Rasmussen (1), Ulla Feldt-

Rasmussen (1)

1: Department of Medical Endocrinology, PE 2132, Rigshospitalet, University of Copenhagen, Denmark 2:

Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Denmark


Phthalates are suspected to influence thyroid function in epidemiologic and experimental animal studies.

The aim of our study was to investigate the ability of primary human thyroid cell cultures to metabolise

phthalates and a possible concentration-response effect of phthalates on thyroglobulin (Tg) secretion.

Metode:

Human thyrocytes obtained from thyroidectomies were cultured to confluent monolayers. These were

exposed to DEHP in concentrations 10-9 to 10-4 M, with thyroid stimulating hormone (TSH) (1 IU/l) for 24,

48 or 72 h. DEHP metabolites and Tg in cell supernatants were quantified (liquid chromatography-tandem

mass spectrometry and ELISA, respectively). Results are shown as mean ± SD and statistical analyses were

performed using two-way anova (SAS-institute).

Resultater:

Cell cultures metabolised DEHP to its primary metabolite mono-ethylhexyl-phthalate (MEHP). Conversion

varied depending on the DEHP-concentration used, from only 1.2 ±0,6% at 10-4 M, to 72.8 ±21.2% at 10-7

M (n= three cultures from one individual).

No influence was found on TSH-stimulated Tg-secretion after 72 h DEHP-exposure (p=0,86) (n= five cell

cultures in single determination) compared to control and independent of the concentration of DEHP used.

Preliminary results, however, suggested an influence to occur sooner, i.e. after 24 h (n= one cell culture in

single determination).

Konklusion:

DEHP is internalised and metabolised by primary human thyroid cell cultures to varying degrees depending

on the concentration, indicating an active saturable process. Though no influence on Tg-secretion after 72 h

DEHP-exposure could be found, preliminary time studies indicate that an influence occurs earlier.

77

52. Pendrin autoantibodies, using a radioligand binding assay, are detected with low frequency in

patients with autoimmune thyroid disease and are undetectable in normal controls

Brix TH (1), Hegedüs L (1), Weetman AP (2), Kemp EH (2)

(1) Department of Endocrinology and Metabolism, Odense University Hospital, DK-5000 Odense, Denmark &

(2) Department of Human Metabolism, the Medical School, University of Sheffield, Sheffield S10 2RX, United

Kingdom.


Mediating the efflux of iodide through the thyroid follicular cell, pendrin is a transmembrane protein

located at the apical end of the thyrocyte. Using an immunoblotting assay, 81% of Japanese patients with

autoimmune thyroid disease (AITD), both Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), had

autoantibodies against pendrin (PAb), in contrast to 9% in healthy controls. Two recent studies, in AITD

patients from Tunisia (using an immunofluorescence assay and an ELISA) and the United Kingdom (using a

radioligand binding assay), demonstrated PAb prevalences of <10%.

Metode:

To investigate a Danish AITD population for the presence of PAb, using a radioligand binding assay, in order

to study whether variations in PAb prevalence are related to differences in methodology or the studied

populations.

Resultater:

Sera from 93 (56 GD and 37 HT) patients and 230 healthy controls were evaluated for PAb reactivity. Ten of

93 AITD patients (11%) and none of the healthy controls had PAb (p<0.001). Subdividing according to cause

of AITD yielded similar results (12.5% of GD patients and 8.1% of HT patients had PAb, p>0.05). Serum was

available from 37 twin pairs with AITD (4 concordant for GD; 26 discordant for GD; 7 concordant for HT).

Only 4 twin pairs had PAb. Of these, 2 twin pairs, who were concordant for HT, were discordant for PAb. In

the remaining 2 pairs who were discordant for GD, the GD twin was PAb positive and the healthy co-twin

negative.

Konklusion:

Pendrin autoantibodies were not found in healthy individuals. PAb, detected using a sensitive radioligand

binding assay, are uncommon in Danish AITD patients and do not differ in frequency between GD and HT.

The low frequency of positive PAb does not allow an analysis of heritability of PAb, despite our utilization of

a twin design. Pendrin autoantibodies are not a useful marker for diagnosis of AITD and differences

between available studies seem to rely on assay differences. The role of these antibodies needs further

study.

78

53. Psychiatric morbidity before and after the diagnosis of hyperthyroidism: A nationwide register-based

study

Frans Brandt, Marianne Thvilum, Dorthe Almind, Kaare Christensen, Anders Green, Thomas Heiberg Brix

and Laszlo Hegedüs

Department of Endocrinology and Metabolism, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense

C, Denmark


Context: Thyroid hormones are essential for the normal development of the fetal brain, while

hyperthyroidism in adults is associated with mood symptoms and reduced quality of life. However, our

knowledge regarding the association and temporal relation between hyperthyroidism and mental disorders

is ambiguous. Objective: To investigate the association and temporal relation between hyperthyroidism

and psychiatric morbidity.

Metode:

Design: From nationwide Danish health registers 2631 hyperthyroid individuals were matched 1:4 with non-

hyperthyroid controls and followed for a mean of 6 years (range 0-13). Data on psychiatric morbidity was

obtained by record linkage with the National Danish Patient Register and the Danish National Prescription

Registry. Logistic and Cox regression models were used to assess the risk of morbidity before and after the

diagnosis of hyperthyroidism, respectively. All Cox analyses were adjusted for education level and the

degree of co-morbidity, as measured by the Charlson score.

Resultater:

Prior to the diagnosis of hyperthyroidism, such individuals had an increased prevalence of hospitalization

with psychiatric diagnoses (Odds ratio, OR 1.33; 95 CI: 0.98-1.80) and increased prevalence of treatment

with antipsychotics (OR 1.17; 95% CI: 1.00-1.38), antidepressants (OR 1.13; 95% CI: 1.01-1.27) or anxiolytics

(OR 1.28; 95% CI: 1.16-1.42). After the diagnosis of hyperthyroidism, there was a higher risk of

hospitalization with psychiatric diagnoses (Hazard ratio, HR 1.51, 95% CI: 1.11-2.05), and an increased risk

of being treated with antipsychotics (HR 1.46; 95% CI: 1.20-1.79), antidepressants (HR 1.54; 95% CI: 1.36-

1.74), or anxiolytics (HR 1.47; 95% CI: 1.27-1.69).

Konklusion:

Conclusions: Hyperthyroid individuals have an increased risk of hospitalization with psychiatric diagnoses

and being treated with antipsychotics, antidepressants, and anxiolytics, both before and after the diagnosis

of hyperthyroidism.

79

54. Iodine fortification may influence the age-related change in thyroid volume – a longitudinal

population-based study (DanThyr).

Anne Krejbjerg1, Inge Pedersen1, Lena Bjergved2,3, Allan Carlé1 Torben Jørgensen2, Hans Perrild3, Lars

Ovesen4, Lone Rasmussen5, Nils Knudsen3 og Peter Laurberg1.

1Department of Endocrinology, Aalborg Hospital, Aalborg. 2Research Centre for Prevention and Health, The

Capital region of Denmark, Glostrup. 3Department of Endocrinology and Gastroenterology, Bispebjerg

University Hospital, Copenhagen. 4Department of Gastroenterology, Slagelse Hospital, Slagelse.

5Department of Nutrition, National Food Institute, Technical University of Denmark, Søborg.


Objectives: To evaluate the relation between thyroid volume and aging in two regions with respectively

mild (Copenhagen) and moderate (Aalborg) iodine deficiency at baseline.

Metode:

Methods: In a longitudinal population-based study (DanThyr) we examined 2,465 adults before (Cohort

1a,1997) and after (Cohort 1b, 2008) the Danish iodine fortification of salt (2000). Furthermore, data from

a second cross-sectional study (Cohort 2) that took place 4-5 years after mandatory iodization (2004-2005)

was used to compare age associated differences in thyroid volume in the two population cohorts studied in

the DanThyr program. Ultrasonography was performed by the same sonographers using the same

equipment, after controlling performances. Participants treated for thyroid disease were excluded from

analyses.

Resultater:

Overall, median thyroid volume had increased in Copenhagen (11.8 to 12.2 mL, p=0.001) and decreased in

Aalborg, although not significantly (13.3 to 13.1 mL p=0.07) during the 11-years of follow-up. In both

regions there was an age-related trend in individual changes in thyroid volume from baseline to follow-up;

thyroid volume increased in women <40 years of age and decreased in women >40 years of age. In a

multivariate regression model, higher age at entry was a predictor (p<0.05) for thyroid volume decrease

>20% during the follow-up period (women aged 40-45 years: OR 4.3 (CI 2.2-8.2); women aged 60-65 years:

5.8 (2.9-11.6)) and individuals of higher age were also less likely to have an increase in thyroid volume

(women aged 40-45 years: 0.2 (0.1-0.3); woman aged 60-65: 0.3(0.2-0.4)).

In analyses limited to women aged 30-32 and 40-42 years, we compared geometric mean thyroid volume in

participants of C1a, C2 and C1b. In C1a thyroid volume was significantly higher among women aged 40-42

years compared to women aged 30-32 year (12.3/14.5 mL, p<0.001) whereas no significant difference was

observed in C2 (11.4/11.8 mL, p=0.3) or in C1b (12.7/12.4 mL, p=0.5).

Konklusion:

Conclusions: Age dependent differences in thyroid volume and enlargement had levelled out after the

Danish iodization program. Thus, the previously observed increase in thyroid volume with age may have

been caused by iodine deficiency.

80

55. Increased psychiatric morbidity before and after the diagnosis of hypothyroidism: A nationwide

register study

Marianne Thvilum, Frans Brandt, Dorthe Almind, Kaare Christensen, Thomas H Brix, Laszlo Hegedüs

Odense Universitetshospital, Syddansk Universitet


Thyroid hormones are necessary for fetal brain development, while hypothyroidism in adults has been

associated with mood symptoms and reduced quality of life. Nevertheless, our knowledge regarding the

association and temporal relation between hypothyroidism and mental disorders is ambiguous. Our

objective was to investigate, at a nationwide level, whether a diagnosis of hypothyroidism is associated

with psychiatric morbidity.

Metode:

Observational cohort study. Based on record-linkage between different Danish health registers 2822

hypothyroid singletons each matched with 4 non-hypothyroid controls were identified and followed over a

mean period of 6 years (range 1-13). Additionally, we included 385 same sex twin pairs discordant for

hypothyroidism. Diagnoses of psychiatric disorders as well as treatment with antidepressants,

antipsychotics and anxiolytics were recorded. Logistic and cox regression models were used to assess the

risk of psychiatric morbidity before and after the diagnosis of hypothyroidism, respectively.

Resultater:

Prior to the diagnosis of hypothyroidism, such individuals had an increased prevalence of diagnoses with a

psychiatric disorders (Odds ratio, OR, 1.51; 95% confidence interval (CI): 1.12-2.04) and increased

prevalence of treatment with antipsychotics (OR 1.49; 95% CI: 1.29-1.73), antidepressants (OR 1.50; 95% CI:

1.35-1.67), or anxiolytics (OR 1.28; 95% CI: 1.16-1.41). After the diagnosis of hypothyroidism, patients had a

higher risk of being diagnosed with a psychiatric disorder (Hazard ratio, HR 2.40; 95% CI: 1.81-3.18), and an

increased risk of being treated with antidepressants (HR 1.30; 95% CI: 1.15-1.47) and anxiolytics (HR 1.27;

95% CI: 1.10-1.47), but not antipsychotics (HR 1.13; 95% CI: 0.91-1.41). Based on the twin data, we could

not demonstrate genetic confounding.

Konklusion:

Subjects with hypothyroidism have an increased risk of being diagnosed with a psychiatric disorder as well

as treatment with antidepressants, antipsychotics and anxiolytics both before and after the diagnosis of

hypothyroidism

81

56. Reference change values for the Hospital Anxiety and Depression Scale, SF-36 and hypothyroid score

in patients with stable subclinical hypothyroidism

Jesper Karmisholt 1, Stig Andersen 2 and Peter Laurberg 1

1 Dept. of Med. Endocrinology, Aalborg Universityhospital; 2 Dept. of Geriatric Medicine, Aalborg

Universityhospital


Subclinical hypothyroidism (SH) is a frequent condition and defined as serum values of thyrotropin (TSH)

above and with thyroxin (T4) within the reference limits. It is recommended that patients with hypothyroid

related symptoms and TSH between 5-10 mU/L should receive a L-T4 substitution treatment trial and

continue treatment if symptoms subside. However, in order to evaluate whether the observed difference in

symptoms is clinically relevant or just due to the expected variation, a description of the variation in such

symptoms in untreated patients with SH are needed. Such data for Hospital Anxiety and Depression Scale

(HADS), SF-36 and Zulewski hypothyroid score, previously lacking, is now provided.

Metode:

21 patients without previous thyroid disease and with TSH between 5-12 mU/L and T4 within the reference

range measured on two occasions, 3 months apart, were included to be prospectively studied. Patients

underwent clinical investigation, questionnaires, and blood sampling monthly for one year giving a total of

13 investigations. HADS and SF-36 are established questionnaires for anxiety/depression and quality of life.

The hypothyroid score is a systematic evaluation of presence or absence of 7 symptoms and 5 signs of

hypothyroidism. Reference Change Value (RCV) calculations were based on within-person variation (CV%)

and a clinical significance level of 90% and were calculated as: CV% x 1.65 x 2½

Resultater:

Five patients, one of which developed overt hypothyroidism, had a significant trend in TSH during the year.

These five patients were excluded from the RCV analyses. Median (interquartile range) data at inclusion of

the remaining patients (14/2 women/men) were: age 57(52-67) years, BMI 27(25-35) kg/m2, TSH 6.2(5.0-

8.0) mU/L, fT4 14(13-15) pmol/L. None of these data differed significantly between patients with or without

TSH trend. RCV for HADS were 95 %, PCS and MCS subscales of SF-36 were 12 % and 13 % respectively and

for the hypothyroid score, 186 %.

Konklusion:

We provide RCV data for questionnaires, which may be used for clinical evaluation of patients with SH. Due

to a rather large individual variation in the HADS questionnaire and the hypothyroid score in untreated SH

patients without TSH trend during a year, 95 and 190 % difference between two tests are needed in order

to be 90% confident that the difference observed is a true change and not due to chance. A change of 13 %

or more between two tests in the PCS and MCS subscales of SF-36 indicate a true and clinical significant

difference.

82

57. THE IMPACT OF GRAVES' DISEASE AND ITS TREATMENT ON HANDWRITING CHARACTERISTICS

Giampaolo Papi1,2, M.D. Ph.D., Cristina Botti3, Salvatore Maria Corsello2, M.D. Ph.D., Anna Vittoria

Ciardullo1, M.D., Alfredo Pontecorvi2, M.D. Ph.D., and Laszlo Hegedüs4

1Department of Internal Medicine, Thyroid Unit, “Ramazzini” Hospital, Azienda USL Modena, Modena,

ITALY, 2Chair of Endocrinology, Catholic University of Rome, Rome, ITALY, 3Lawyer and handwriting expert,

registered at the Association of Assessors at the Modena Court, Modena, ITALY, and 4Department of

Endocrinology, Odense University Hospital, Odense, DENMARK.


Thyroid hormones are crucial for metabolism of all tissues in man, including the nervous system and the

muscles, and could thus affect handwriting which is the synthesis of complex and fine movements.

Hyperthyroidism, characterized by symptoms such as tremor and weakness, could affect handwriting but

this has not been studied. The aim of this study was to evaluate handwriting characteristics before and

after therapy of hyperthyroid Graves' disease (GD).

Metode:

22 patients (15 women, 7 men) with untreated GD (median age: 44 yrs; range: 20-70 yrs) were asked to

write a “standard text” before and 12 months after being rendered euthyroid. The letters underwent a

standardized detailed analysis, through inspection and stereoscopic microscope and magnifying glass.

Resultater:

All patients demonstrated handwriting variations, perceptible even to direct observation. Graphological

examination showed statistically significant changes (before and after becoming euthyroid, respectively) in

the following parameters: size of letters (4.5±1.1 vs 5.9±1.3 mm; P<0.01), distance between letters

(62.9±1.1 vs 55.2±0.8; P<0.01), width of letters (1.75±0.06 vs 2.2±0.06 mm; P<0.01), distance between

words (216.2±3.2 vs 198.7±2.4 mm; P<0.01), extensions of letters (8.7±0.2 vs 7.7±0.2 mm; P<0.01), angles

(17±0.3 vs 15.8±0.4; P<0.01), groove depth (0.2±0.05 vs 0.4±0.05 mm; P<0.01).

Konklusion:

Hyperthyroid GD caused significant changes in handwriting in all patients. Recovery from hyperthyroidism,

a state of hypertrophic and contracted handwriting with several angles resulted in greater fluency and

fluidity of handwriting. Variations in handwriting should be included as signs/symptoms in hyperthyroidism

and the implications for the authenticity of a handwritten signature, e.g. in a will, considered.

83

58. Randomised controlled trial of the effect of long-term selenium supplementation on serum

thyrotropin concentrations in euthyroid Danish seniors

Kristian Hillert Winther1,2, Steen Bonnema2, Frederik Cold1, Søren Cold1, Mads Nybo3, Laszlo Hegedüs2

Department of Endocrinology and Metabolism, Odense University Hospital, Denmark


To investigate the effect of long-term selenium supplementation, in different doses, on serum thyrotropin

(s-TSH) concentrations.

Metode:

491 participants (236 females and 255 males, aged 60-74 yr; median 65 yr), from the region of Funen in

Denmark, were enrolled in the Danish PREvention of Cancer by Intervention with SElenium trial (DK-

PRECISE). It is a non-stratified, randomised, double-blinded, placebo-controlled, one-centre, multi-arm trial

with four groups (allocation ratio 1:1:1:1). Participants were randomised to an intake of 100 μg (N=124),

200 μg (N=122) or 300 μg (N=119) selenium-enriched yeast or matching yeast-based placebo tablets

(N=126) daily for five years. S-TSH and plasma selenium were measured at baseline, and after six months

and five years intervention.

Resultater:

Plasma selenium concentrations increased significantly, and dose-dependently, in the treatment groups

after six months and five years intervention. S-TSH did not change significantly in any treatment group after

six months intervention, but tended towards a significant decrease in the 300 μg per day group (P = 0.08).

After five years of intervention s-TSH decreased significantly in the 300 μg per day group (P = 0.02),

compared to baseline. However, the individual changes in s-TSH did not differ significantly between groups

after either six months or five years of intervention.

Konklusion:

Serum TSH concentrations decreased in the 300 μg per day group, suggesting a long-term dose-dependent

effect of selenium supplementation on thyroid function. The clinical and public health implications of this

finding are unclear, since individual changes in s-TSH concentrations did not differ between any groups.

Further studies are needed in order to clarify the implications for thyroid epidemiology of increasing

selenium intake in Denmark.

84

59. The correlation between biochemically assessed thyroid disease and all cause-mortality - The Danish

register-based OPENTHYRO study of 239,768 individuals-

Anne Sofie Laulund, Mads Nybo, Thomas Heiberg Brix, Bo Abrahamsen, Henrik Løvendahl Jørgensen, Laszlo

Hegedüs.

Endokrinologisk Forskningsenhed, OUH


INTRODUCTION Increased mortality in patients diagnosed with hypo- or hyperthyroidism has been

described in several studies. The aim of this population-based study was to investigate the correlation

between serum TSH and all-cause mortality.

Metode:

METHODS 239,768 individuals with a TSH measurement from hospitals and private practitioners from

Funen, Denmark from 01/01-1995 to 31/12-2010 were included in the study. All measurements were

performed at a single laboratory. Differences between the hypo, hyper and euthyroid groups were

analyzed using parametric statistics or categorical statistical methods as appropriate. Cox regression was

used for mortality analysis, and the Charlson index was used as a comorbidity score.

Resultater:

The hazard ratios (HR with 95% CI) for all-cause mortality at high and low levels of TSH were 1.28

(1.22;1.35), p<0.0001 and 2.22 (2.14;2.30), p<0.0001 respectively in the unadjusted setting. After adjusting

for age, sex, Charlson Index and point of sample collection, the association attenuated but remained

statistically significant (HR 1.08 (1.02;1.13), p<0.0001 and (HR 1.23 (1.19;1.28), p<0.0001 respectively).

Konklusion:

CONCLUSION Biochemically assessed hyper and hypothyroidisms were associated with increased all-cause

mortality both in the unadjusted and in the adjusted setting.

85

60. Development of autoimmune overt hypothyroidism is highly associated with childbirths and induced

abortions – but only in premenopausal women.

Allan Carlé, Inge Bülow Pedersen, Nils Knudsen, Hans Perrild, Lars Ovesen, Lone Banke Rasmussen, Torben

Jørgensen, and Peter Laurberg.


Reproductive risk factors have been intensively investigated for SLE and RA, but their role in development

of autoimmune hypothyroidism have not been clarified.

Metode:

We prospectively identified all women with incident autoimmune hypothyroidism in a Danish population

(n=117; median age=53.0 years), and simultaneously recruited from the same population age-, sex-, and

region-matched controls free of thyroid dysfunction (n=468). In conditional multivariate logistic regression

models, we analyzed the associations between development of autoimmune hypothyroidism and a number

of reproductive risk factors (age at menarche/menopause, years of menstruations, pregnancies,

spontaneous and induced abortions, childbirths, and years on oral contraceptives and postmenopausal

hormone replacement therapy). Smoking status, alcohol consumption, educational status, and family

history for hypothyroidism were included as possible confounders. Note that patients having

hypothyroidism diagnosed within one year post-partum were NOT included in the present study.

Resultater:

Patients having autoimmune hypothyroidism diagnosed before the age of <55 years self-reported higher

number of pregnancies, live births, and induced abortion than their euthyroid controls. In multivariate

regression models with zero events as reference, the adjusted odds ratios (95% CIs) for 1/2/≥3 pregnancies

were 1.72(0.56-5.32)/3.12(1.14-8.48)/4.51(1.65-12.3), for 1/2/≥3 live births ORs were 2.03(0.77-

5.37)/3.33(1.32-8,40)/3.31(1.27-8.63), and for 1/≥2 induced abortions ORs were 1.02(0.57-1.81)/2.69(1.27-

5.75). We found no association between disease development and reproductive risk factors in women

above 55 years of age.

Konklusion:

Previous childbirth and induced abortion were major risk factors for development of autoimmune overt

hypothyroidism in women aged up to 55 years. Thus, the increased risk for hypothyroidism after live births

extends longer than just to the one-year post-partum period.

86

61. Metabolic inflexibity in obese subjects: Unaltered insulin sensitivity after 72 h of fasting with and

without acipimox

Ann Mosegaard Bak1,2, Mikkel Holm Vendelbo1,3, Rikke Viggers1,4, Jørgen Rungby 2,5, Jens Otto Lunde

Jørgensen1,2, Niels Jessen2,4,6, Niels Møller1,2

1Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University,

2Department of Endocrinology and Internal Medicine (MEA), Aarhus University Hospital, NBG, 3Department

of Nuclear Medicine, Aarhus University Hospital, NBG, 4Research Laboratory for Biochemical Pathology,

Department of Clinical Medicine, Faculty of Health, Aarhus University, 5Department of biomedicine, Faculty

of Health, Aarhus University, 6Department of Molecular Medicine (MOMA), Aarhus University Hospital,

Skejby.


The term metabolic flexibility has been introduced to denote the physiological capability of switching

energy substrate metabolism between glucose and lipid utilization. Insulin resistant obese subjects are

metabolically inflexible and this deficit may precipitate the metabolic syndrome and type 2 diabetes. It is

well described that prolonged fasting induces insulin resistance. The intracellular mechanisms behind

metabolic inflexibility and insulin resistance remain unclear. In this study we aimed to investigate metabolic

flexibility in lean and obese subjects in response to 72 h of fasting with and without inhibition of lipolysis.

Metode:

In a randomized, cross-over design we investigated 9 obese and 8 lean healthy individuals 1) after 12 h of

fasting, 2) after 72 h of fasting, 3) after 12 h of fasting and a bolus injection of GH (0.005 mg/kg) 4) after 72

h of fasting with inhibition of lipolysis (acipimox) during the last 12 hours of the fast. A 2 hour

hyperinsulinemic euglycemic clamp was performed to evaluate insulin sensitivity. The respiratory exchange

ratio and resting energy expenditure were estimated by indirect calorimetry.

Resultater:

72 h of fasting reduced insulin sensitivity in the lean subjects. Inhibition of lipolysis during the last 12 hours

of the fast did not influence the level of insulin resistance. The obese individuals did not show any

significant changes in insulin sensitivity after 72 h of fasting with or without acipimox.

Konklusion:

Obese individuals are metabolically inflexible and fail to adjust insulin sensitivity to conditions of fasting

and acipimox exposure.

87

62. Effect of the primary human bile acid chenodeoxycholic acid and the bile acid sequestrant

colesevelam on glucose metabolism in patients with type 2 diabetes and in healthy control subjects

Morten Hansen1,2, Matthijs Scheltema1,3, David P. Sonne1,2, Jens J. Holst2, Tina Vilsbøll1 and Filip K.

Knop1,2

1) Diabetes Research Division, Department of Medicine, Gentofte Hospital, University of Copenhagen,

Hellerup, Denmark; 2) Department of Biomedical Sciences, Faculty of Health Sciences, University of

Copenhagen, Copenhagen, Denmark; 3) Department of Endocrinology and Metabolism, Amsterdam Medical

Center, University of Amsterdam, Amsterdam, the Netherlands


In patients with type 2 diabetes, rectal administration of bile acids, and oral bile acid sequestrants lower

blood glucose. We evaluated the effect of chenodeoxycholic acid (CDCA) and the bile acid sequestrant

colesevelam (COL) delivered by an intragastric tube on plasma glucose, insulin, C-peptide, gastric emptying

and gallbladder volume, in a placebo-controlled, double-blinded study.

Metode:

On 4 separate days 10 patients with type 2 diabetes (age (mean±SD): 62.3±7.4 years, BMI: 28.9±2.3 kg/m2;

HbA1c: 7.0±1.1%) and 10 matched healthy control subjects (age: 61.3±9.8 years, BMI: 28.2±3.2 kg/m2;

HbA1c: 5.5±0.4%) received 1) CDCA (1250 mg); 2) COL (3750 mg), 3) CDCA+COL, or 4) placebo; all

suspended in 100 ml of water with 1500 mg paracetamol (for evaluation of gastric emptying). During 180

min blood was drawn, gallbladder volume was evaluated by ultrasound, and appetite was evaluated by

visual analogue scale.

Resultater:

None of the interventions changed plasma glucose. In the patients with type 2 diabetes, CDCA, COL and

CDCA+COL increased C-peptide/glucose ratio significantly vs. placebo, with CDCA alone eliciting the most

pronounced effect. Also in the healthy subjects, CDCA alone elicited the highest C-peptide/glucose ratio.

CDCA slowed gastric emptying in both groups. COL tended to decrease gallbladder volume, whereas CDCA

tended to increase gallbladder volume. None of the interventions affected appetite.

Konklusion:

In conclusion, oral administration of CDCA increased insulin secretion (measured as C-peptide/glucose

ratio) and slowed gastric emptying. We speculated that these effects may be mediated by GLP-1.

88

63. High Intensity Interval Training Improves Insulin Mediated Glucose Clearance in Skeletal Muscle in

Patients with Type 2 Diabetes and healthy controls

Nielsen MB, Skaaby S, Andersen NB, Petersen HHH, Helge JW, Dela F

Xlab, Center for Healthy Ageing, University of Copenhagen, Denmark


Endurance training improves skeletal muscle insulin sensitivity. High intensity interval training (HIIT) is a

very time-efficient training modality with marked effects on maximal oxygen uptake (VO2max). Whether

this training modality also improves insulin mediated glucose uptake rates in patients with insulin

resistance is not known.

Metode:

14 patients with T2DM (age: 57 ± 2 years; BMI: 31 ± 1 kg/m2; VO2max: 29 ± 1 ml/min/kg) (mean ± SEM))

and 10 healthy matched controls (CON) (age: 55 ± 2 years; BMI: 31 ± 1 kg/m2; VO2max: 32 ± 1 ml/min/kg)

performed 8 one-legged HIIT sessions every other day. Each session consisted of 10 x 1 minute ergometer

bicycling at a workload (Watt) > 60 % of one-legged maximal workload and heart rate > 80 % of maximal

heart rate interspersed with 1 minute recovery. Tru-core muscle biopsies from m. vastus lateralis were

obtained before and immediately after a HIIT session to measure the glycogen content. Body composition

and lean leg mass before and after the training period were assessed using dual-energy X-ray

absorptiometry. 40 hours after the last HIIT session, a two-step isoglycemic, hyperinsulinemic (80 and 400

mU/min/m2) clamp was performed combined with the leg balance technique to measure insulin mediated

glucose clearance rates (GCR) in the trained (T) and untrained (UT) legs. Resultater:

Insulin mediated GCR were lower in T2DM compared with CON at baseline and during step 1. GCR was

higher in T compared with UT during step 1 in T2DM and CON (P < 0.05) and in CON (P < 0.05) during step

2, during which the difference between T and UT only approached significance (P = 0.07) in T2DM. HIIT

training was well tolerated and no adverse effects were seen. One HIIT session reduced glycogen content in

skeletal muscle in both T2DM (pre: 516 ± 30 vs. post: 377 ± 49 nmol/mg dry wt, P = 0.002) and CON (pre:

471 ± 23 vs. post: 313 ± 31 nmol/mg dry wt, P = 0.001). No differences in glycogen were detected between

the groups.

Konklusion:

HIIT improved insulin mediated GCR in skeletal muscle in both T2DM and CON after only 80 minutes of

effective exercise in 2 weeks. This time-effective training strategy may be attractive in the prevention and

treatment of T2DM. The significant reduction in muscle glycogen content after one HIIT session may be one

of the mechanisms behind the improvement.

89

64. Incidence of diabetes and diabetes complications among migrants in Denmark

Marit Eika Jørgensen1, Zaza Kamper-Jørgensen (1,2,3), Bendix Carstensen (1), Marie Norredam (2), Ib

Christian Bygbjerg (3), Gregers Stig Andersen (1)

(1) Steno Diabetes Center A/S, Department of Clinical Epidemiology, Gentofte, (2) Danish Research Centre

for Migration, Ethnicity and Health, Section for Health Services Research, Department of Public Health,

University of Copenhagen, (3) Department of International Health, Immunology and Microbiology Faculty of

Medicine and Health Sciences, University of Copenhagen


Background: Studies of diabetes in migrant populations have generally shown a higher prevalence

compared to the respective countries of origin, but incidence studies of diabetes complications are lacking.

The aim of the current study was to examine the incidence rates of diabetes and diabetes complications

among ethnic minorities in Denmark compared to the Danish background population.

Metode:

Methods: Information was obtained from linkage of the National Diabetes Register, the Danish Adult

Diabetes Database and the National Patient Register with information from the Central Personal Register

on country of origin. Age- and sex-specific incidence rates, mortality rates and standardised mortality ratios

relative to the non-diabetic part of the population were calculated by Poisson regression analysis, based on

follow up of the entire Danish population

Resultater:

Compared with Danes, the incidence of diabetes was about 2.5 times higher among migrants from Africa,

Asia and Middle East, whereas the incidence among migrants from Europe and America were some 20%

lower. For all groups the annual increase in incidence was about 3%, except for European migrants where it

was only 1.5%. The highest incidence of microvascular complications was observed among migrants from

Africa, Asia and Middle East (figure 1). Higher incidence rates of coronary heart disease were observed

among migrants from the Middle East and Asia compared to Danish diabetes patients (figure 2).

Konklusion:

Conclusion: The burden of diabetes and diabetes complications is greater among several ethnic minorities

in Denmark compared to Danes. Future studies will show whether differences are explained by risk factors

like smoking, metabolic risk factors, socio-economic status, educational level and quality of care.

Figure 1. Retinopathy Figure 2. Coronary Heart Disease

90

65. Insulintilfælde under behandling med sulfonylurinstof hos patienter med type 2-diabetes i Region

Hovedstaden

Sascha Pilemann-Lyberg1, Birger Thorsteinsson2, Ole Snorgaard3, Mette Zander4, Henrik Vestergaard5,6 og

Michael E. Røder1

1Medicinsk Afdeling F, Gentofte Hospital, 2Kardiologisk, Nefrologisk og Endokrinologisk afdeling,

Nordsjællands Hospital, Københavns Universitet, Hillerød, 3Endokrinologisk afdeling, Hvidovre Hospital,

4Endokrinologisk afdeling, Bispebjerg Hospital, 5Endokrinologisk afdeling, Herlev Hospital og 6NNF-CBMR.


Baggrund: Sulfonylurinstoffer (SU) anbefales fortsat i guidelines som mulig 2. valg ved behandling af type 2-

diabetes (T2DM). SU præparater er billige og veletablerede i behandlingen, men er associeret med

hypoglykæmi. Omfang, karakteristik og årsag til alvorlig indlæggelseskrævende insulintilfælde er ikke

undersøgt i klinisk praksis. Formål: At undersøge forekomst og omfang af indlæggelseskrævende

insulintilfælde hos patienter med SU-behandlet T2DM, samt deres karakteristika.

Metode:

Udtræk på diagnosekoder for patienter indlagt med hhv. hypoglykæmi eller T2DM eller hypoglykæmi

kombineret med diabetes i en periode på 2 år (2010-11). Undersøgelsen omfattede alle akuthospitaler i

Region Hovedstaden. Ved journalgennemgang inkluderedes patienter i behandling med SU, som

monoterapi eller i kombination med anden glukosesænkende behandling fraset insulin. Forbrugstal for SU-

præparater i samme periode blev opgjort fra Lægemiddelregisteret.

Resultater:

Det primære dataudtræk omfattede 3156 patienter. Heraf opfyldtes inklusionskriterierne af 163 patienter

(gennemsnitsalder 76,4 (53-97) år; 54% mænd). 49% blev behandlet med SU alene, 45% var i 2-

stofsbehandling med SU og metformin, og 6% var i 3-stofsbehandling. 74% af patienterne var i behandling

med glimepirid, 15% i behandling med glibenclamid, 6% fik gliplizid og 2% fik gliclazid.

60% af patienterne havde varierende grader af komplikationer til deres T2DM. 20% af patienterne havde

diabetisk nefropati eller nyreinsufficiens af anden årsag.

Hos 57% af patienterne var et uændret SU-indtag trods betydelig nedsat appetit eller ophør med

fødeindtag opgivet som sandsynlig årsag. 10% af de 163 patienter havde et medicinmisbrug, og 6% havde

indtaget en større mængde alkohol forud for indlæggelsen. 5% havde infektion på indlæggelsestidspunktet.

Hos 22% af patienterne blev der ikke dokumenteret en medvirkende årsag til insulintilfældet i journalen.

Konklusion:

Hyppigheden af indlæggelseskrævende insulintilfælde under behandling med SU synes relativt lav (og med

sendiabetiske komplikationer. Dog sås diabetisk nyreinsufficiens kun hos en mindre del af patienterne.

91

66. Prescribing Patterns of Antidiabetic Drugs within the First Year following Diagnosis of Type 2

Diabetes: Results from the DD2 study

Anil Mor1, Klara Berencsi1, Elisabeth Svensson1, Jørgen Rungby2, Jens Steen Nielsen3, Søren Friborg4, Ivan

Brandslund5, Jens Sandahl Christiansen6, Allan Vaag7, Henning Beck-Nielsen3, Henrik Toft Sørensen1, Reimar

Wernich Thomsen1

1Dept. of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital 2Dept. of Pharmacology,

University of Aarhus, 3Diabetes Research Centre, Dept. of Endocrinology, Odense University Hospital 4Dept. of

Endocrinology M, Odense University Hospital 5Dept. of Biochemistry, Lillebaelt Hospital 6Dept. of Internal Medicine

and Endocrinology, Aarhus University Hospital 7Dept. of Endocrinology, Rigshospitalet and Copenhagen University


Real-world data are sparse on prescribing patterns of antidiabetic drugs in cases of newly diagnosed type 2 diabetes

mellitus (T2DM) and on patient characteristics that may predict type of early pharmacotherapy.

Metode:

We studied 1,317 patients in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort with newly

diagnosed T2DM and at least one year of follow-up. We described the number and type of antidiabetic drugs

prescribed in the first year after T2DM diagnosis. Using Poisson regression, we calculated risk ratios (RRs) of treatment

with different antidiabetic drugs associated with baseline patient characteristics.

Resultater:

Of the 1,317 newly diagnosed T2DM patients, 198 (15%) did not use any antidiabetic drugs within the first year post-

diagnosis, 867 (66%) used only one drug, 197 (15%) used two drugs, and 55 (4%) used three or more drugs. Of the 867

patients on monotherapy, almost all (93%, 810/867) used metformin, while 3% (28/867) used insulin. Among the 252

users of two or more drugs in combination, metformin was the most frequently prescribed drug (94% of all

combination users, 237/252), followed by glucagon-like peptide-1 (GLP-1) receptor analogues (35%, 88/252), insulin

(31%, 77/252), and dipeptidyl peptidase 4 (DPP4) inhibitors (30%, 76/252). When we ranked individual types of

antidiabetic drugs used by our 1,317 T2DM patients, by far most the common was metformin as monotherapy

(61.5%), followed by combinations of metformin either with sulphonylureas (3.7%), with DPP4 (3.7%), with GLP-1

(3.3%), or with insulin (3.2%) (Figure). Insulin alone or in combination was prescribed to 8.0% of the T2DM patients.

Incretins were prescribed to 13.7% of the patients (DPP4, 6.7%; GLP-1, 7.0%), almost always as combination therapy.

The likelihood of receiving combination therapy with two or more drugs in the first year post-diagnosis was

substantially higher in T2DM patients aged <40 years at diagnosis (36%; RR = 2.58, 95% confidence interval (CI): 1.79-

3.70), and in those aged 40-59 years (23%; RR = 1.66, 95% CI: 1.31-2.11), compared with those aged 60 + years (14%).

T2DM patients with a high comorbidity level (Charlson Comorbidity Index score >=3) were at higher likelihood of

receiving combination therapy (30%, RR = 1.54, 95% CI: 1.05-2.26) than T2DM patients with no comorbidity (19%).

Weight gain > 30 kg since 20 years of age and lack of regular physical exercise also increased the likelihood of receiving

combination therapy during the first year post-diagnosis (RR = 1.42, 95% CI: 1.14-1.78 and RR = 1.42, 95% CI: 1.11-

1.82, respectively). Higher likelihood of receiving combination therapy also was observed in T2DM patients with

fasting blood glucose > 7 mmol/L at diagnosis (RR = 3.37, 95% CI: 2.43-4.68), HbA1c >=7.5 (RR = 3.85, 95% CI: 3.00-

4.94), and C-peptide < 300 pmol/L (RR = 1.78, 95% CI: 1.15-2.76).

Konklusion:

Within the first year after T2DM diagnosis, 85% of individuals are treated with any antidiabetic drug, most commonly

metformin (79%), an incretin (14%), or insulin (8%). Poor glycemic control and low C-peptide at T2DM diagnosis are

predictors of combination therapy at one year. Other important predictors are young age, comorbidity, obesity, and

lack of exercise.

92

67. Family history of diabetes and the association with demographic and anthropometric characteristics

among newly diagnosed diabetes type 2 patients: Results from the DD2 study

Elisabeth Svensson1, Klara Berencsi1, Simone Sander1, Anil Mor1, Jørgen Rungby2, Jens Steen Nielsen3,

Søren Friborg4, Ivan Brandslund5, Jens Sandahl Christiansen6, Allan Vaag7, Henning Beck-Nielsen3, Henrik

Toft Sørensen1, Reimar Wernich Thomsen1

1Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus,

Denmark 2Department of Pharmacology, University of Aarhus, Aarhus, Denmark 3Diabetes Research

Centre, Department of Endocrinology, Odense University Hospital, Odense, Denmark 4Department of

Endocrinology M, Odense University Hospital, Odense, Denmark 5Department of Biochemistry, Lillebaelt

Hospital, Vejle, Denmark 6Department of Internal Medicine and Endocrinology, Aarhus University Hospital,

Aarhus, Denmark 7,Department of Endocrinology, Rigshospitalet and Copenhagen University, Copenhagen,

Denmark


A positive family history of type 2 diabetes mellitus (T2D) increases the risk for developing T2D

approximately two-fold, likely due to both genetic and lifestyle factors. It is unknown how having a family

history of T2D is related to demographic and anthropometric factors at T2D debut, thus we aimed to

examine this.

Metode:

All participants in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort responded to a

questionnaire, in which detailed family history of diabetes (grandparents, parents, siblings and children)

was assessed. We examined the prevalence of having one or more first degree relatives (parent, sibling,

child) with diabetes, according to different demographic and anthropometric factors at T2D debut.

Resultater:

Of 2,718 T2D patients, 1,191 (44%) had one or more first degree family relatives with diabetes, including

377 (14%) with two or more first degree relatives. T2D patients were more likely to have diabetes affected

mothers (20%) or maternal grandparents (12%) than fathers (17%) or parental grandparents (8%). There

were more T2D women (50%) with a family history of diabetes than T2D men (39%). Individuals aged <40

years at their T2D debut were more likely to have a family history of diabetes (51%) as compared with

patients aged >=60 years at T2D debut (41%). In contrast, family history of T2D was evenly distributed

according to presence or absence of central obesity, BMI>30, large weight gain since age 20, and the

metabolic syndrome.

Konklusion:

Almost half (44%) of newly diagnosed T2D patients have a first degree family relative with diabetes. Our

results confirm previous findings, indicating that heredity is stronger on the maternal side. Having a family

history of diabetes is associated with female gender and younger age at T2D debut, whereas family history

does not appear to predict higher BMI, waist circumference or metabolic syndrome in our patients

93

68. Glucose lowering effects and low risk of hypoglycaemia in maturity onset diabetes of the young

patients when treated with a glucagon-like peptide-1 receptor agonist – a double-blind randomised

cross-over trial

Signe H. Østoft, Jonatan I. Bagger, Torben Hansen, Oluf B. Pedersen, Jens J. Holst, Filip K. Knop and Tina

Vilsbøll

Diabetes Research Division, Department of Medicine, Gentofte Hospital, University of Copenhagen


Hepatocyte nuclear factor 1α (HNF1A) gene mutations are the most common form of maturity-onset

diabetes of the young (MODY). HNF1A-diabetes is often treated with sulfonylurea, but with a high risk of

hypoglycaemia. Treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs) has a low risk of

hypoglycaemia, but has never been evaluated in patients with MODY.

Metode:

Fifteen patients with HNF1A-diabetes (7 women; age: 40±4 years (mean±SEM); body mass index (BMI):

25±1 kg/m2; fasting plasma glucose (FPG): 9.9±0.9 mM; HbA1c: 6.5±0.2% (48±3 mmol/mol)) were treated

for 6 weeks with GLP-1RA (liraglutide) + placebo (tablets), and glimepiride + placebo (injections) in

randomized order in a double-blind cross-over trial design. Both treatment periods were preceded by a 1-

week wash-out. Glimepiride was up-titrated every week in a treat-to-target manner and liraglutide was up-

titrated to 1.8 mg after 2 weeks. At baseline and at the end of each treatment period a standardised liquid

meal test including a 30-minute cycling test was performed.

Resultater:

FPG decreased similarly (p=0.624) during the treatment periods (-1.6±0.5 mM (liraglutide, p=0.012) and -

2.8±0.7 mM (glimepiride, p=0.003)). Postprandial glucose responses (incremental area under the curve)

were lower with glimepiride (430±171 min×mM) vs. liraglutide (637±164 min×mM, p=0.047) and lower

compared with baseline (746±131 min×mM, p=0.011). Eighteen episodes of hypoglycaemia (plasma

glucose≤3.9 mM) occurred during glimepiride treatment and 1 during liraglutide treatment.

Konklusion:

Six weeks glimepiride or liraglutide lowered FPG similarly in HNF1A-diabetes, whereas postprandial glucose

excursions were decreased more with glimepiride; at the expense of an almost 20-fold higher risk of

hypoglycaemia.

94

69. Pathophysiological phenotypes of clinically diagnosed type 2 diabetes

Jacob Volmer Stidsen1, Reimar W. Thomsen2, Jens Steen Nielsen1, Jørgen Rungby3, Sinna Pilgaard

Ulrichsen2, Klara Berensci2, Søren Friborg4, Ivan Brandslund5, Aneta A. Nielsen5, Jens Sandahl

Christiansen6, Henrik Toft Sørensen2 , Jan Erik Henriksen1, Henning Beck-Nielsen1

Diabetes Research Centre, Department of Endocrinology, Odense University Hospital, Odense, Denmark,

2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, 3Department of Pharmacology,

University of Aarhus, Aarhus, Denmark, 4Department of Endocrinology M, Odense University Hospital,

Odense, Denmark, 5Department of Biochemistry, Center Hospital Lillebaelt, Vejle, Denmark, 6Department of

Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark.


Objectives: Type 2 diabetes (T2D) can be considered a syndrome with several different pathophysiological

mechanisms leading to hyperglycemia. Nonetheless, T2D is currently treated according to algorithms as if it

was one disease entity. We investigated the prevalence of different pathophysiological phenotypes among

newly diagnosed T2D patients in Denmark.

Metode:

Based on baseline data from the DD2, a Danish national cohort study, we investigated 1048 incident T2D

patients. The diagnosis of T2D was made by general practitioners and outpatient clinics based on clinical

judgement. Specific phenotypes were classified into the following five hierarchical groups: Rare subtypes of

diabetes, latent autoimmune diabetes (LADA) (GAD antibody titer >= 20 IE/ml and not T1D), secondary

diabetes (recent history of pancreatitis, pancreatectomy or pancreas amylase > 65U/l, and GAD negativity),

steroid-associated diabetes (oral glucocorticoid-treated subjects) and genuine T2D. The homeostatic

assessment model (HOMA2) model was used to assess insulin sensitivity (HOMA2-S) and beta cell function

(HOMA2Beta). By this model genuine T2D was further phenotyped into three groups: insulinopenic T2D

(HOMA2beta<78.45% and HOMA2-S>=105.50%), classical T2D (HOMA2beta<78.45% and HOMA2-

S<105.50%) and hyperinsulinemic T2D (>=78.45% AND HOMA2-S<105.50%). Cut-off values were defined by

the median of HOMA2-S and HOMA2Beta in a healthy population from Vejle County.

Resultater:

Results: Age of our new T2D patients was 61 years (range 21-95 years), 57% were men. We found that

0.6% of our newly diagnosed T2D patients had rare subtypes of diabetes, 3.0% suffered from LADA, 3.9%

from secondary diabetes, 5.8% from steroid-associated diabetes and 86.7% had genuine T2D. When further

phenotyping the group of genuine T2D, we found that 11.7% of our cohort had insulinopenic T2D, 51 % had

classical T2D and 24.0 % had hyperinsulinemic T2D.

Konklusion:

Conclusion: T2D is a heterogeneous disease. Specific phenotypes of diabetes are found among newly

diagnosed T2D patients, and the largest group with genuine T2D can be further divided into three distinct

pathophysiological phenotypes.

95

70. Does intensive glycaemic control influence health-related quality of life in patients with type 2

diabetes? A systematic review with meta-analysis of randomised clinical trials

Bianca Hemmingsen, Søren S Lund, Christian Gluud, Allan Vaag, Thomas Almdal, Christina Hemmingsen,

Jørn Wetterslev

Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet,

Copenhagen University Hospital, Copenhagen, Denmark


Objective To assess the effects of targeting intensive versus conventional glycaemic control on health-

related quality of life in patients with type 2 diabetes.

Metode:

Design Systematic review with meta-analyses of randomised clinical trials. Data sources The Cochrane

Library, MEDLINE, Embase, Science Citation Index Expanded, Latin American Caribbean Health Sciences

Literature, and Cumulative Index to Nursing and Allied Health Literature until December 2012. We also

searched abstracts from major diabetes congresses, reference lists of included trials, (systematic) reviews,

meta-analyses, and health technology assessments and contacted trial authors, pharmaceutical companies,

and the US Food and Drug Administration homepage. Study selection Randomised clinical trials comparing

targeted intensive glycaemic control versus conventional glycaemic control in patients with type 2 diabetes.

Published and unpublished trials in all languages were included, irrespective of predefined outcomes. Data

extraction Two reviewers independently assessed studies for inclusion and extracted data related to study

methods, interventions, health-related quality of life, and risk of bias. Mean and standardised mean

differences with 95% confidence intervals (CI) were estimated with fixed- and random-effects models.

Resultater:

Twenty-eight randomised clinical trials including 34,912 participants with type 2 diabetes (18,717 to

intensive control versus 16,195 to conventional control) were included. Only eight of the trials assessed

health related quality of life in 7018 participants. All trials had high risk of bias. Health-related quality of life

scales varied among the included trials. Intensive glycaemic control did not significantly influence overall

health-related quality of life (mean difference 0.00, 95% CI -0.02 to 0.02; 2 trials, 2776 participants), mental

component of health-related quality of life (change from baseline; standardised mean difference 0.04, 95%

CI -0.09 to 0.18; 3 trials, 906 participants; end of follow-up values; standardised mean difference -0.09, 95%

CI -0.19 to 0.01; 4 trials, 1742 participants), or physical component of health-related quality of life (change

from baseline; standardised mean difference -0.06, 95% CI -0.21 to 0.08; 2 trials, 743 participants; end of

follow-up values; standardised mean difference -0.02, 95% CI -0.16 to 0.11; 3 trials, 813 participants).

Konklusion:

Conclusion In a systematic review of randomised clinical trials targeting intensive versus conventional

glycaemic control overall health-related quality of life, mental component of health-related quality of life,

or physical component of health-related quality of life were not significantly different between

interventions. However, different scales were applied among the trials and the risk of bias was high.

96

71. aBMD at the hip measured by DXA overestimate cortical vBMD assesed by QCT scans

Anne Kristine Amstrup, Tanja Sikjær, Leif Mosekilde, Lars Rejnmark

Medicinsk endokrinologisk afd (MEA) THG, Århus Universitetshospital


DXA scan has for many years been gold standard when analyzing areal bone mineral density (aBMD) in

osteoporotic patients. Risk of fractures increases as aBMD declines. However, although risk of fracture is

highest in patients with osteoporosis, it is well known that the majority of fragility fractures actually occur

in patients with osteopenia rather than osteoporosis. As aBMD is a projected 2 dimensional imaging

technique it does not differentiate between cortical and trabecular bone. 3D measures of bone by

quantitative computed tomography (QCT) is considered to measure true volumetric BMD (vBMD, mg/cm3).

Furthermore, this technique can distinguish between cortical and trabecular bone. Therefore, we looked at

correlation between aBMD by DXA and vBMD by QCT measured at the hip.

Metode:

In a cross-sectional study 125 postmenopausal women mean age 63 (range 56-82) were scanned by DXA

and QCT at the hip.

Resultater:

As expected linear regression of total hip measured by DXA and QCT showed a positive correlation between

aBMD and vBMD at trabecular and integrated site varying between 0.63 and 0.75 (p<0.01). However, linear

regression of aBMD and cortical vBMD showed a significant negative correlation (β=-0.56, p<0.01). The

inverse relation persisted even after adjusting for confounders such as BMI. Investigating the relation

between QCT volume and DXA aBMD showed a strong positive relation (β=0.70, p<0.01) as well as QCT

mass and aBMD (β=0.64, p<0.01).

Konklusion:

Our results indicate that 2D imaging by DXA provides a true measure of trabecular bone density, whereas

the inverse correlation between aBMD and cortical vBMD suggest that cortical bone strength may be

overestimate by aBMD. As most fractures occur in peripheral bones which are mainly composed of cortical

bone, these patients may actually have week cortical bone despite not being osteoporotic as assessed by

DXA.

97

72. External auditory canal and middle ear diseases in bisphosphonate-treated osteoporosis patients. A

Danish National Register Based Cohort Study

Anne-Luise Thorsteinsson1, Peter Vestergaard2,3, Pia Eiken1,4

1Dept. of Cardiology, Nephrology and Endocrinology, Nordsjællands Hospital-Hillerød, University of

Copenhagen, Hillerød, 2Clinical Institute, Aalborg University, 3Dept. of Endocrinology, Aalborg University

Hospital, 4Faculty of Health and Medical Sciences, University of Copenhagen


Eight cases of bisphosphonate-associated osteonecrosis of the external auditory canal have been reported

in case-reports. Our aim was to describe the incidence of external auditory canal and middle ear diseases in

Danish patients exposed to bisphosphonates in the treatment of osteoporosis.

Metode:

The study was based on Danish national registers. From 2003-2010, 131,794 patients had bisphosphonates

prescribed for treatment of osteoporosis. These cases were matched 3:1 for gender and age with a total of

395,382 persons unexposed to bisphosphonates. The primary outcome was disease in the external auditory

canal and middle ear, defined as first occurrence of an ICD10 hospital diagnosis code of destruction of

bones in the ear (H74.3B), cholesteatoma of the external auditory ear canal (H60.4) or cholesteatoma of

the middle ear (H71.9). The primary explanatory variable was bisphophonate exposure. A possible

association between bisphophonate treatment and disease in the ear – as well as any dose-response

relationship – was tested using a Cox proportional hazards model. The relationship between duration of

treatment with bisphosphonates and events was studied using Cox proportional hazard model and log Rank

test.

Resultater:

No cases of bone destruction were observed during the 7-year observation period in either group. Totally,

119 events of cholesteatoma in the ear were recorded after initiation of bisphosphonate therapy, 34 in the

external auditory canal and 85 in the middle ear. Cholesteatoma in the external auditory canal was more

frequent in the exposed than in the unexposed group (p<0.0001). A significant dose-event relationship

between incidence of cholesteatoma and dosage of bisphosphonates existed. Finally, we found a significant

association between duration of treatment and risk of cholesteatoma in both external auditory ear canal

and middle ear.

Konklusion:

Long-term use of oral bisphosphonates may be associated with an increased risk of cholesteatoma of the

external auditory canal and middle ear. The risk of cholesteatoma of the external auditory canal and middle

ear was positively associated with the dosage of bisphophonate. Our results showed no cases of

osteonecrosis of the external auditory canal or middle ear.

98

73. Osteoporosis in male respiratory patients

Rana Bibi1, Peter Laurberg2, Ulla Weinreich1, Eigil Husted Nielsen2

1 Dept. of Pulmonary Medicine, Aalborg University Hospital; 2 Dept. of Endocrinology, Aalborg University

Hospital


Background. Over the recent decades, osteoporosis in men has been increasingly recognised as a most

relevant clinical problem. Among patients with pulmonary disease, exposure to supraphysiological doses of

glucocorticoids is a major risk factor, but the prevalence of osteoporosis and other associated risk factors

among male patients suffering from non-malignant pulmonary disease, and not undergoing glucocorticoid

treatment, is sparsely described. Objective We aimed to estimate the prevalence of osteoporosis in a

population of middle-aged and elderly men referred to the regional medical pulmonary outpatient clinic,

and to describe the distribution of known risk factors for osteoporosis.

Metode:

Methods Clinically stable male patients, aged 50-85 years, with a history of respiratory disorder/symptoms

were recruited from the outpatient clinic for pulmonary medicine at the regional university hospital.

Patients with a history of, neoplastic disease within the last 5 years, and patients receiving systemic

glucocorticoid therapy less than 12 months before the study visit, were excluded. Included patients

underwent DXA of the lumbar spine and the hip and were asked to fill in a risk factor questionnaire.

Patients with osteopenia or osteoporosis were offered additional blood testing for secondary osteoporosis

and X-ray of the thoracolumbar spine

Resultater:

Sixty-four male patients with various non-malignant pulmonary diseases were included. Mean age was 64.9

years (range 50-83 years) and mean BMI 26.9 (range 18.1-39.4). All underwent DXA. Osteoporosis of the

lumbar spine, hip and femoral neck was found in 11, 5 and 7 patients, respectively, yielding a total of 14

(22%) patients with osteoporosis, while 33 patients (51%) had osteopenia. Seventeen patients (27%) had

normal BMD. Thirteen vertebral fractures (4 mild, 8 moderate and 1 severe) were found in 6 patients. The

overall mean number of self-reported risk factors was 1.5 (range 0-4) and did not differ between patients

with osteoporosis and patients with normal BMD.

Konklusion:

Conclusion The risk of osteoporosis should not be neglected in middle-aged and elderly male patients with

non-malignant pulmonary disease, even in the absence of glucocorticoid treatment. The estimated

osteoporosis prevalence in our study population was 22%, while osteopenia was present in another 51% of

patients, and 9% had one or more vertebral fractures. Hence, routinely DXA at referral may be indicated in

this patient group.

99

74. Frakturer og refrakturer fra et dansk perspektiv

Louise Hansen, Stine Aistrup Eriksen, Bente Lomholt Langdahl, Pia A Eiken, Kim Brixen, Bo Abrahamsen,

Jens-Erik Beck Jensen, Torben Harsløf og Peter Vestergaard

Danish Center for Healthcare Improvements, Aalborg Univeristet.


Formålet med dette studie var i et ti-årigt perspektiv, at undersøge sammenhængen mellem indeks og

efterfølgende frakturer, med særlig fokus på hoftefrakturen.

Metode:

Registerbaseret kohortestudie på dataudtræk fra Landspatientregisteret (LPR). Studiepopulationen var alle

danskere over 50 år, som i perioden 01.01.01-31.12.11 havde pådraget sig en fraktur . Frakturerne blev

aggregeret i tolv grupper, eksempelvis radius/ulna (ICD-10: DS52.x) og ankel (ICD-10: DS82.8x). For alle

typer indeksfrakturer i perioden 01.01.01-31.12.01 blev frekvensen af efterfølgende frakturer i perioden

01.01.02-31.12.13 undersøgt. For at tage højde for dødeligheden blev analysen gennemført efter aktuar-

metoden (per kalenderår).

Resultater:

Fra 2001 til 2011 steg det samlede antal frakturer fra 44.402 til 49.741. I perioden faldt antallet af hofte

frakturer fra 11.098 til 9.306, mens antallet af radius/ulna frakturer steg fra 9.972 til 13.751. De resterende

frakturtyper forblev forholdsvis uændret. Der var flere kvinder end mænd i kohorten (71,1 %).

Gennemsnitsalderen for fraktur varierede mellem 62,6 år±10,2 år (fod) og 80,3 år±9,9 år (hofte).

Incidensraten varierede i perioden fra 2001 til 2011 afhængigt af frakturtype fra 0,3 % (patella) til 6,2 %

(radius/ulna).

Incidensraten for indeks/efterfølgende fraktur af samme type var højere sammenlignet med

indeks/efterfølgende fraktur af anden type. Uafhængigt af alder var den ti-årige frakturrate for

efterfølgende hoftefraktur efter en hofte indeksfraktur meget høj (20-45 %). Antallet af vertebrae indeks

fraktur med efterfølgende vertebrae fraktur var generelt lav (<20 %), dog med en stigning for personer

mellem 60 og 69 år hvor 85 % af personer med vertebrae indeksfraktur oplevede et nyt vertebrae fraktur.

I aldersgruppen 70+ udgjorde hoftefrakturer hhv. 32 % og 38 % af det samlede antal efterfølgende frakturer

for kvinder og mænd, uafhængig af indeksfraktur. Før 70 år var efterfølgende frakturer oftest af samme

type som indeksfrakturen; 31 % for begge køn.

Patienter med hoftefrakturer havde en generel høj dødelighed i den 10 årige periode der fulgte efter

indeksfrakturen på hhv. 45 % og 58 % for kvinder og mænd. For indeks/efterfølgende fraktur af samme

type var dødeligheden højere for mænd end kvinder.

Konklusion:

Frakturraten, for nye frakturer af samme type som indeksfrakturen, er generelt høj i den efterfølgende 10-

årige periode. Dette er særligt udtalt for hoftebrud, hvor 38,4 % pådrager sig et nyt hoftebrud i løbet af en

10-årig periode.

100

75. Risiko for infektioner og cancersygdom hos patienter med postoperativ hypoparathyreoidisme

Line Underbjerg, Tanja Sikjaer, Leif Mosekilde, Lars Rejnmark

Medicinsk-Endokrinologisk Afdeling, MEA, Aarhus Universitetshospital, Tage-Hansens Gade


Hypoparathyreoidisme (HypoPT) er en relativ sjælden sygdom karakteriseret ved lave niveauer af PTH og

plasma calcium, som oftest skyldes komplikationer til halskirurgi. Grundet mangel på PTH er patienterne

ikke i stand til at aktivere D-vitamin, hvorfor sygdommen typisk behandles med tilskud af aktivt D-vitamin

(alphacalcidol). Da D-vitamin i nogle studier er vist at beskytte mod infektioner og cancersygdom

undersøgte vi om risikoen for disse sygdomme hos patienter med HypoPT adskiller sig fra risikoen i

baggrundsbefolkningen.

Metode:

Cases (patienter med HypoPT) blev identificeret gennem et dataudtræk Fra Landspatientregisteret (LPR) og

danske regioners receptdatabase. Alle identificerede mulige cases fik gennemgået deres journal mhp.

verificering af diagnosen. I nærværende studium inkluderede vi kun patienter som havde pådraget sig

HypoPT som en komplikation til halskirurgi udført på baggrund af non-maligne sygdomme. Fra

baggrundsbefolkningen fik vi tre alders- (± 2-år) og kønsmatched kontroller for hver case. Fra LPR fik vi et

udtræk på alle diagnosekoder på alle identificerede cases samt deres matchede kontroller.

Resultater:

Ud af en population på 5.336.394 personer fandt vi 688 patienter som var diagnosticeret med kronisk

postoperativ HypoPT grundet kirurgi for non-maligne sygdomme mellem 1988 til 2012, svarende til en

prævalens på 22/100.000. Risikoen for infektioner var signifikant øget blandt cases sammenlignet med

kontroller, HRUkorrigeret 1,42 (1,20;1.67). Korrektion for tidligere infektioner ændrede ikke resultatet HR

1,20 (1,10;1,54). Undersøgelse af de kumulerede infektioner (figur) viser at cases har signifikant flere

infektioner sammenlignet med kontroller.

Den oveordnede risiko for cancersygdom var ikke øget blandt cases, HRukorrigeret 0,83 (0,61;1,13), om end

risikoen for gastrointestinal cancer var signifikant reduceret blandt cases, HRGI,Ukorrigeret 0.63

(0,44;0,93), korrektion for tidligere cancer ændrede ikke resultatet HR 0,62 (0,42;0,92).

Konklusion:

Patienter med post-operativ HypoPT grundet kirurgi for non-malign sygdom har en signifikant øget risiko

for infektioner men en mindsket risiko for gastroinstestinal cancer sammenlignet med raske kontroller.

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101

76. Low thyrotropin levels as a predictor of major osteoporotic fractures – The OPENTHYRO register

cohort

Abrahamsen Bo, Jørgensen Henrik L, Laulund Anne Sofie, Nybo Mads, Brix Thomas H, Hegedüs L

Odense Patient data Explorative Network, Institute of Clinical Research University of Southern Denmark,

Denmark


The relationship between hyperthyreosis and osteoporotic fractures remains controversial, particularly in

men. The study hypothesis was that persons whose baseline TSH was below reference (0.3 IU/L) would

have an increased risk of fractures even after adjusting for comorbid conditions and known risk factors for

fracture.

Metode:

Open, register-based cohort study including all patients with a TSH measurement in the country of Funen in

the period 01/01-1996 to 31/12-2010 using 1995 as a run-in year, after exclusion of patients with known

thyroid or pituitary disorders. All TSH assays were done in the same lab, which served all hospitals and GP

practices in the county. Fracture outcomes were collected from the National Patient Discharge Register up

to 30/11-2012.

Resultater:

The study population consisted of 9,217 persons (4%) with low TSH and 222,138 (96%) with normal TSH.

During a median follow-up time of 7.5 years, 16,543 persons (13.5% of the low TSH group and 6.9% of the

normal TSH group) sustained at least one major osteoporotic fracture. A single low TSH at baseline was

associated with an increased risk of hip fractures (adj HR 1.16, 95% CI 1.07-1.26, p<0.001) while the

association with major osteoporotic fractures was not statistically significant after adjustment for

confounders (HR 1.06, 95% CI 0.99-1.12, p=0.058). Though there was no statistical interaction with gender,

the increased risk of hip fracture was not statistically significant if the analysis was restricted to men (adj

1.17, 95% CI 0.95-1.42, p=0.14). We found a significant association between duration of hyperthyreosis and

fracture risk; for each six months in which the mean TSH value was low (<0.3 IU/L), hip fracture risk

increased by a factor 1.07 (adj HR, 95% CI 1.04-1.10, p<0.001) and major osteoporotic fracture risk by a

factor of 1.05 (adj HR, 95% CI 1.03-1.07, p<0.001).

Konklusion:

In a population based observational cohort, a single, first measurement of low TSH (<0.3 IU/L) in a patient

without known thyroid disease was associated with an increased long term risk of hip fracture, which

remained significant after adjusting for confounders. Moreover, the risk of both hip fracture and major

osteoporotic fractures increased exponentially by the length of time during which TSH had remained low.

102

77. Hyponatremia and Bone Mineral Density: A Cross-Sectional Study

Kruse C1; Eiken P2,3; Vestergaard P1,4,5

Aalborg University Hospital, Department of Endocrinology, Denmark


To evaluate the association between hyponatremia and osteoporosis in humans.

Metode:

Data was pooled from national blood sample databases and Dual-energy X-ray absorptiometry scan data

from a Danish Centre from November 2004 to February 2013. Hyponatremia was defined as [Na+] < 135,

while normonatremia was defined as Na+ = [135-145].

Resultater:

853 in- and outpatients were included. 69 were hyponatremic (8.1%). Total hip bone mineral density

(BMD), total hip T-score, total lumbar spine T-score and total lumbar spine BMD were all significantly lower

in hyponatremia compared with normonatremic patients after adjustment for age, gender and body mass

index. Adjusted Odd Ratio of T-score-diagnosed osteoporosis was significantly increased among

hyponatremic patients at both the total hip and total lumbar spine region. Using multiple regression,

[Na+]<135 mmol/L was significantly associated with total hip BMD, total hip T-score, total lumbar spine

BMD and total lumbar spine T-score. Hyponatremia was significantly associated with biochemical markers

of inflammation (elevated total white blood cell count, erythrocyte sedimentation rate and C-reactive

protein), systemic acidosis (lower standard-HCO3-) and hematological abnormality (elevated platelet count

and lactate dehydrogenase).

Konklusion:

Presence of hyponatremia significantly increases the risk of concurrent osteoporosis at both the total hip

and lumbar spine in humans. Decreasing values of [Na+] significantly reflects in decreasing total hip and

lumbar spine BMD and T-scores.

103

78. Effekten af per oral mætningsdosis af vitamin D3 på serumkoncentration af vitamin D3

Cand.med. Rasmus Bo Jansen og ovl., klinisk lektor, dr.med. Ole Lander Svendsen

Endokrinologisk Ambulatorium, Bispebjerg Hospital.


Behandling af D-vitamin mangel kan indledes med en mætningsdosis af cholecalciferol. Vi har tidligere

forsøgt at beregne størrelsen af den optimale dosis med en algoritme, men vi underestimerede

behandlingsdoserne. Adskillige nyligt publicerede studier indenfor feltet danner tilsammen et billede af, at

denne underestimering forekommer, hvis man ikke tager højde for fedtopløseligheden af D-vitamin. Vi har

derfor, på baggrund af tidligere behandlingsdata, udviklet en ny model, som bl.a. tager højde for dette ved

at indarbejde BMI:

Antal kapsler(cholecalciferol á 20.000 IU)=(165*BMI*(70-[25OHvit.D]))/20.000

Metode:

Patienter med svær D-vitamin mangel (25-OH-D-vit. < 25 nmol/L). Til sammenligning er anvendt historiske

kontroller ifa. 60 ptt. behandlet med Dekristol kapsler á 20.000 IU cholecalciferol, ud fra et tidligere,

lignende forsøg, hvor vi testede den oprindelige algoritme.

Metode: Interventionsforsøg med højdosis cholecalciferol. Efter den initielle mætningdosis blev ptt. sat i

behandling med 1520 IU cholecalciferol x 1 dgl., og de blev fulgt med blodprøver efter 1 uge, 3 uger og 3

mdr.

Resultater:

I alt 29 patienter gennemførte studiet. Baseline for 25-OH-D-vit. var 22,6 nmol/L, og patienterne blev givet

en mætningsdosis på i gennemsnit 10,7 caps of Dekristol (i.e. 212.000 IU cholecalciferol). Data viser en

stigning i 25-OH-D-vit. på 55,9 nmol/L (range 113,0, SD 29,79), til en slutværdi på 78,5 nmol/L efter 21 dage

– ikke signifikant forskelligt fra idealværdien på 80 mol/L (P=0,46). Den biokemisk acceptable range er sat til

50-120 nmol/L, og 83% af værdierne ligger inden for dette interval efter 21 dage (7% under og 10% over).

Sammenlignet med de historiske kontroller ses en signifikant højere stigning i 25-OH-D-vit. - 55,9 nmol/L

versus 34,9 nmol/L (P<0,001). Hvis vi sammenligner data mod standardintervallet for sufficient vitamin D

niveau (mellem 50-80 nmol/L), har vi 52% af slutværdierne i dette studie i denne zone, mod 39% i vores

oprindelige studie.

Konklusion:

Vi konkluderer, at man, ved at tage højde for BMI, får man et bedre estimat over, hvor stor en

mætningsdosis patienter med D-vitamin mangel har brug for. Man ser dog fortsat en stor spredning af

slutværdierne.

Vi anbefaler, på baggrund af ovenstående, brugen af algoritmer i stil med vores, til udregning af

mætningsdoser med cholecalciferol. I daglig praksis benytter vi en omskrevet version af algoritmen,

optimeret til en aktuelt tilgængelige dosering af cholecalciferol:

Antal dråber cholecalciferol ”Glostrup” D3 vitamin á 300.000 IU/g =

(70-[s-25-OH-vitamin D3+D2](nmol/L)) x BMI x 0,02

104

79. Resveratrol increases vBMD at the spine in obese men: A randomized controlled trial

MJ Ornstrup, T Harsløf, T Kjær, SK Paulsen, BL Langdahl, SB Pedersen

Department of Endocrinology and Internal Medicine MEA, Aarhus University Hospital, Tage-Hansens Gade,

Aarhus


Resveratrol (RSV) is a natural compound, especially found in redwine. RSV promotes osteoblastic

differentiation in vitro, reduces osteoclast activation, and in rodent studies RSV protects against the bone

loss normally seen in relation to ovarectomy and immobilization. Only one human study, of obese men, has

adressed the effects on bonemetabolism in vivo, showing isolated increase in bone-specific alkaline

phosphatase (BAP) after four weeks of treatment. We hypothesize that RSV treatment will positively

affect bone turnover and improve BMD in obese men, and aim to show this in a randomized controlled

trial.

Metode:

A randomized, placebo-controlled, double-blind study, including 76 obese (BMI: 33.7±0.4) men with

metabolic syndrome. Participants were randomly assigned to either placebo, low-dose RSV (75mg), or high-

dose RSV (500mg) twice daily for four months. At baseline and after four months of treatment we did

blood- and urine- sampling, bonemarrow aspiration, DXA scans, QCT scans, pQCT scans, and MR

spectroscopy. After one and two months of treatment we checked compliance, and did blood- and urine-

sampling.

Resultater:

Vitamin D levels were analysed at all four timepoints to determine if all three groups were compatible.

Unfortunately, the low-dose RSV group turned out significantly different in vit D levels over time (p=0.01),

which reflects seasonal differences in the three groups inclusion timepoints. Therefore we can only

compare placebo versus high-dose RSV.

Plasma calcium levels were significantly lower in the high-dose RSV group compared to placebo, after 2

months of treatment (p=0.03), resulting in slightly higher PTH levels in the high-dose RSV group (non-

significant). Also, bone-specific alkaline phosphatase increased around 16% (p<0.0001) after 1-4 month of

treatment with high-dose RSV, which can probably be explained by either increased boneformation or

increased mineralization of bonetissue. Osteocalcin also increased about 6%, but this was not significant

(p=0.11). P1NP and CTx were not affected. No difference were seen between groups on aBMD spine and

hip (DXA), nor vBMD on hip (QCT), but vBMD (QCT) on spine were significantliy increased in the high-dose

RSV group with 3,67% (-7,22;-0,125) (p=0,043).

Konklusion:

These preliminary results indicate that RSV can increase BMD, by either stimulating boneformation or

promoting mineralization of bonetissue in obese men, after only 4 months of treatment. We need more

longterm studies to see effects after ex 12 months of treatment, and if the same effect is seen in ex

postmenopausal women, it could turn out to have great potential as a new anti-osteoporotic drug.

105

80. Vitamin D treatment in primary hyperparathyroidism: a randomized placebo controlled trial

Lars Rolighed, Lars Rejnmark, Tanja Sikjaer, Lene Heickendorff, Peter Vestergaard, Leif Mosekilde, and Peer

Christiansen.

Aarhus Universitetshospital


Low vitamin D (25OHD) levels are common in patients with primary hyperparathyroidism (PHPT) and

associated with higher PTH levels and hungry bone syndrome following parathyroidectomy (PTX). However,

concerns have been raised on the safety of vitamin D supplementation in terms of aggravated

hypercalcemia and hypercalciuria and subsequent renal function impairment. We aimed to assess safety

and effects of supplementation with high doses of vitamin D in patients with PHPT. We hypothesized that

PHPT patients would benefit from vitamin D treatment with a PTH decrease, reduction of bone turnover,

and improvement of bone mineral density (BMD) prior to PTX.

Metode:

Using a double-blinded design, we randomized 46 PHPT patients to a daily supplement with 70 microgram

(2800 IU) of cholecalciferol or identical placebo for 52 weeks. Treatment was administered 26 weeks prior

to PTX and continued for 26 weeks after PTX. We analyzed changes in BMD, trabecular bone score (TBS),

blood and urinary measures of bone turnover and calcium metabolism.

Resultater:

Patients had a mean age of 58 (range 29-77) years and 35 (76%) were women. Preoperatively, 25OHD

increased 88% (from 50 to 94 nmol/L) in the treatment group, whereas levels decreased slightly by 9%

(from 57 to 52 nmol/L) in the placebo group (p<0.001). Compared with placebo, vitamin D treatment

decreased PTH significantly by 17% prior to PTX (p=0.01), lumbar spine BMD increased by 2.5% (p=0.01),

and CTx decreased by 22% (p<0.005). Trabecular bone score did not change in response to treatment, but

improved following PTX. Postoperatively, PTH remained lower in the cholecalciferol-group compared with

the placebo group (p=0.04). Plasma creatinine and plasma and urinary calcium did not differ between

groups.

Konklusion:

Daily supplementation with a high vitamin D dose safely improves vitamin D status and decreases PTH in

PHPT patients. The vitamin D treatment is accompanied with reduced bone resorption and improved BMD

before operation.

106

81. Biochemical markers of bone turnover in diabetes patients- a meta-analysis, and a methodological

study on the effects of glucose on bone markers.

Peter Vestergaard1,4, Stine Aistrup Eriksen1, Simon Lykkeboe3, Aase Handberg3, Jakob Starup-Linde1,2

(1) Clinical Institute, Aalborg University, Fredrik Bajers vej 7, 9220 Aalborg


Context: Diabetes Mellitus is associated with an increased risk of fractures. However; the increased fracture

risk does not seem to be related to low bone mineral density, thus certain patterns of bone turnover

markers may prove useful in the prediction of fractures. The aim of this meta-analysis was to compare

existing literature regarding changes in bone markers among diabetics compared to healthy controls. To

exclude that blood glucose levels among diabetes patients could influence the assays used for determining

bone turnover markers, a methodological study was performed.

Metode:

Data sources: Medline at Pubmed Embase, Cinahl, Svemed+, Cochrane library and Bibliotek.dk was

searched in August 2012. Study selection: The studies should examine biochemical bone turnover among

diabetes patients in comparison to controls in an observational design. Data extraction: By two reviewers.

Methodological study: Fasting blood samples were drawn from two individuals. Glucose was added to the

blood samples in different concentrations and OC, CTX and procollagen type 1 amino terminal propeptide

were measured after 0,1, 2 and 3 hours.

Resultater:

Data synthesis and results: 22 papers fulfilled the criteria for the meta-analysis. From the pooled data in the

meta-analysis the bone markers osteocalcin (OC) (-1.15 ng/ml [-1.78,-0.52]) and C-terminal cross-linked

telopeptide (CTX) (-0.14 ng/ml [-0.22, -0.05])were significantly lower among diabetes patients than non-

diabetes patients, however other markers did not differ. All markers displayed very high heterogeneity by

I2 statistics. In the methodological study the addition of glucose did not significantly change the bone

markers neither by level of glucose nor with increasing incubation time.

Konklusion:

Conclusion: Biochemical bone markers are poor predictors of fractures in diabetes. The dissociative pattern

of biochemical bone markers of bone formation and bone resorption present in diabetes patients is thus

not caused by glucose per se but may be modulated by unknown factors associated with diabetes mellitus.

107

82. Markedly Elevated 24-hour Ambulatory Blood Pressure in Healthy Male Carriers of Arg82Cys in

CD300LG Identifies the Gene as a Possible Novel Regulator of Blood Pressure

Julie Støy, Ulla Kampmann, Arne Hørlyck, Lotte Ibsen, Nils Magnusson, Jørgen Rungby, Per Løgstrup

Poulsen,Ivan Brandslund, Cramer Christensen, Niels Grarup, Torben Hansen, Oluf Pedersen, Niels Møller

Medicinsk Endokrinologisk Afdeling, NBG, Aarhus Universitets Hospital


Each of the components of the metabolic syndrome has been scrutinized in GWA-studies with a large

number of genetic variants identified that exert a subtle effect on disease susceptibility. The possibility that

the different aspects of the metabolic syndrome share overlapping causative genes was recently explored

in a whole exome sequencing study of 2000 Danish individuals. Two amino acid polymorphisms were found

to associate with type 2 diabetes (MACF1 and COBLL1), and one with HDL-cholesterol levels (CD300LG). In

the present study, a cardiovascular phenotype characterization of carriers of the risk-allele in CD300lLG was

performed.

Metode:

20 healthy males with the CD300LG rs72836561 CT genotype were matched on age and BMI with 20

healthy males with the CC genotype. 24-hour ambulatory blood pressure, carotid intima-media thickness

(CIMT), and fasting blood samples were evaluated.

Resultater:

CT-carriers had a higher mean 24-hour systolic blood pressure (122.2 mmHg (range 117.2-127.2) versus

114.7 (111.2-118.1); p=0.013) and a higher 24-hour diastolic blood pressure (76.6 mmHg (73.7-79.6) versus

71.8 (70.0-73.6); p=0.005) compared to the CC-carriers. 24-hour mean arterial pressure was also higher for

CT-carriers (p=0.006). There were no differences between the groups in heart rate, heart rate variability,

pulse pressure, or nighttime dipping. Ultrasonography of the carotid artery showed a tendency to higher

CIMT measures among CT-carriers, but none of the measures reached statistical significance. A panel of

vascular endothelial markers revealed significantly higher levels of metalloproteinase-9 in CT-carriers than

in CC-carriers (P = 0.006).

Konklusion:

Carriers of the CD300LG rs72836561 CT genotype have substantially elevated 24-hour ambulatory blood

pressure and points to CD300LG as a potential novel regulator of blood pressure in healthy males.

108

83. Treatment of subclinical hyperthyroidism with radioiodine: MRI-evaluated effect on the heart

Peter Dall Mark (stud. med.), Mikkel Andreasen, Claus Leth Petersen, and Jens Faber.

Department of Medicine O, Endocrine unit, Herlev University Hospital; Department of Clinical Physiology,

Frederiksberg Hospital, and Faculty of Health Sciences, University of Copenhagen.


Background: Subclinical Hyperthyroidism (SH) is defined as reduced serum TSH combined with normal

thyroid hormone levels. Even though such patients report only vague or no symptoms, SH is associated

with increased mortality and major cardiovascular events including atrial fibrillation. Aim: To evaluate

cardiac mass and function before and after normalization of TSH levels using MRI technique with a high

precision. End-points: Cardiac output (CO), left ventricular mass (LVM), left ventricular ejection fraction

(LVEF) and heart rate (HR). Except HR all end-points were related to body surface area.

Metode:

Eleven women and one man (age in mean = 59 years) with SH due to nodular goiter were studied. All SH

subjects were otherwise healthy without hypertension and did not receive any medication. Eight healthy

subjects with similar age and gender served as matched controls. The SH subjects were studied before and

after routine treatment with radioiodine in order to normalize their thyroid function as measured by TSH,

as well as to reduce compression symptoms from their goiter.

Resultater:

The median TSH level increased from 0.10 to 0.88 mU/l, the mean T4 level decreased from 109 to 81

mmol/l and the mean T3 level from 2.06 to 1.35 mmol/l (ped TSH levels: CO decreased 7% from 3.48 to

3.24 L/min/m2 (p=0.017); LVM decreased 5% from 54 to 51 g/m2 (p=0.034); HR decreased 10% from 81 to

73 bpm (p=0.001).

Konklusion:

Obtaining euthyroidism in otherwise healthy patients with SH as demonstrated by normalized TSH levels,

resulted in a decrease in CO and HR as well as LVM with no change in LVEF. Our data support that SH is a

condition in which early treatment should be considered.

109

84. Cerebrovascular event rate after radioiodine therapy

la Cour JL1, Jensen LT1, 2, Nygaard B3

1 Section of Clinical Physiology, Department of Diagnostics, Glostrup Hospital, University of Copenhagen; 2

Department of Clinical Physiology and Nuclear Medicine Herlev Hospital, University of Copenhagen; 3

Section of Endocrinology, Department of Medicine, Herlev Hospital, University of Copenhagen;


External fractionated radiotherapy of head and neck cancer increases the risk of arteriosclerosis /stenosis

of the carotid artery and increases the cerebrovascular event rate. The lower limit to induce these changes

is believed to be 2 Gy. We recently showed that radioiodine therapy (RAI) exposes the carotid arteries to an

average of 4-50 Gy/GBq pr GBq orally administrated (dose rate of 4.2 Gy/day). Acknowledging that RAI

treated hyperthyroid patients have an increased cerebrovascular morbidity, we tested the hypothesis that

some of the increased morbidity arises from radiation induced atherosclerosis.

Metode:

A cohort of 5,027 RAI treated (4,001 hyperthyroid and 1,026 euthyroid (goiter)) with a total amount of 131I

administrated below 2,000 Mbq was age and gender matched with 20,540 controls though National Danish

Patient Register. Data on occurrence of a cerebrovascular event (stroke without hemorrhage (where

possible), amaurosis fugax and TIA) and death where collected. By comparing controls with both

hyperthyroid and euthyroid we tested, whether thyroid disease or radiation contribute to increased

cerebrovascular event rate. Cox regression models were applied to assess the risk of morbidity. When

appropriate the analyses where adjusted for age and Charlson’s comorbidity score at time of treatment and

sex.

Resultater:

Average follow up time was 12.0 years (median 11.1; interquartile range 10.7). The mean age was 61

(median 61.4; interquartile range 22), 14.3% were men, and the average amount of 131I administrated

were 498 MBq (median 400; interquartile range 304). Total number of events was 4119. Compared with

controls all RAI-treated had an increased risk of cerebrovascular events HR =1.29 (CI 1.20 – 1.39). When

adjusting for Charlson’s comorbidity score and atrial fibrilation this difference remained (HR 1.20 (CI 1.12-

1.30). Increased risk of cerebrovascular events where seen both among hyperthyroid (HR 1.35; CI 1.25-

1.46) and euthyroid (HR 1.28; CI 1.11-1.49) compared to controls (age and gender adjusted). Adding

Charlson’s comorbidity score and atrial fibrillation did not change the overall picture (hyperthyroid HR 1.27;

CI 1.18-1.38; euthyroid HR 1.24 CI 1.07-1.44).

Konklusion:

Radiation induces atherosclerosis, and the carotid arteries are exposed to substantial radiation during RAI

therapy, which could lead to increased cerebrovascular. We found an increased risk of cerebrovascular

events among all RAI treated. This risk was found both among hyperthyroid and euthyroid, pointing to the

possibility that RAI can induce clinically relevant atherosclerosis.

110

85. Associations between glycaemic deterioration and central haemodynamics in non-diabetic

individuals. The ADDITION-PRO study

Nanna B. Johansen 1,2, Signe S. Rasmussen 3, Niels Wiinberg 4, Dorte Vistisen 2, Marit E. Jørgensen 2,

Erling B. Pedersen 5, Torsten Lauritzen 6, Annelli Sandbæk 6, Daniel R. Witte 2,7

1 The Danish Diabetes Academy; 2 Steno Diabetes Center A/S, Gentofte, Denmark; 3 Department of

Cardiology, Nephrology and Endocrinology, Nordsjællands Hospital, Hillerød, Denmark; 4 Department of

Clinical Physiology, Frederiksberg Hospital, Frederiksberg, Denmark; 5 Department of Medical Research,

Holstebro Hospital and University of Aarhus, Holstebro, Denmark; 6 Department of Public Health, Section of

General Practice, Faculty of Health Sciences, Aarhus University, Aarhus, Denmark; 7 Centre de Recherche

Public de la Santé, Strassen, Luxembourg


Cross-sectional studies have shown that glycaemia is associated with increased levels of aortic stiffness–a

key marker of cardiovascular risk. Based on the hypothesis that higher diabetes risk is associated with

increased levels of central haemodynamics, we aimed to study the levels of aortic stiffness and central

blood pressure across groups at different levels of diabetes risk identified by a pragmatic stepwise

screening procedure in general practice, and to study the associations between central haemodynamics

and HbA1c and changes in HbA1c.

Metode:

A Danish population-based stepwise screening programme for diabetes included a diabetes risk score and

subsequent measurements of glycaemia and thereby identified groups of individuals at increasing levels of

diabetes risk. After 7.8 years of follow-up, 2,048 individuals underwent aortic stiffness assessment by

carotid-femoral pulse wave velocity (aPWV) and assessment of central blood pressure derived from

pressure wave forms at the radial artery. We compared differences in central haemodynamics at follow-up

between the diabetes risk groups defined at screening, and analysed the impact of HbA1c at screening and

change in HbA1c during follow-up on central haemodynamics adjusting for change in waist circumference

during follow-up and other relevant confounders.

Resultater:

At screening, median age was 59.0 years (IQR: (54.2;63.7) and median HbA1c was 5.7% (IQR: 5.4;6.0). At

follow-up, median aPWV was 8.0 m/s (IQR: 6.9;9.4) and median central systolic blood pressure was 132.7

mmHg (IQR: 121.3;144.3). Individuals with normal glucose tolerance despite a high diabetes risk score had

similar levels of aortic stiffness as individuals with a low diabetes risk score, whereas individuals with

impaired glucose regulation had higher levels of aortic stiffness. Per one %-point higher HbA1c at screening,

aPWV was 0.23 m/s (95% CI: 0.00;0.46) higher, central systolic blood pressure was -0.01mmHg (95% CI: -

2.05;2.03) lower, and central pulse pressure was 1.63 mmHg (95% CI: 0.60;2.66) higher. Per 0.1 %-point

annual increase in HbA1c, aPWV was 0.08 m/s (95% CI: -0.07;0.23) higher, central systolic blood pressure

was 0.49 mmHg (95% CI: -0.88;1.85) higher, and central pulse pressure was 0.35 mmHg (95% CI: -0.34;1.05)

higher.

Konklusion:

Aortic stiffness is elevated in high risk individuals with dysglycaemia, and higher levels of HbA1c is

associated with future higher levels of aortic stiffness but not with higher central systolic blood pressure.

However, the velocity of glycaemic deterioration over time does not affect central haemodynamics

independently of other metabolic risk factors.

111

86. Morning blood pressure surge is not associated with pulse wave velocity, cerebral white matter

lesions or urinary albumin excretion in patients with newly diagnosed type II diabetes

Lyhne J, Laugesen E, Høyem P, Christiansen JS, Knudsen ST, Hansen KW, Hansen TK, Poulsen PL.

Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Noerrebrogade, Denmark


Type ll diabetes patients are characterized by a significantly higher incidence of cardiovascular events

including stroke compared to non-diabetics. Both morning blood pressure surge (MBPS) and reduced

circadian variation in blood pressure have been introduced as risk factors for cerebro- and cardiovascular

events in hypertensive patients although data are not unequivocal. No studies have fully evaluated MBPS in

newly diagnosed type ll diabetes patients or studied the association to subclinical markers of end-organ

damage.

Metode:

Ambulatory blood pressure monitoring (ABPM) was performed in 100 patients with newly diagnosed type ll

diabetes and 100 age and sex matched controls. Five different versions of MBPS and systolic night-day

(SND) ratio were calculated. Markers of early end-organ damage were pulse wave velocity (PWV) white

matter lesions (WML) on brain MRI, and urinary albumin excretion (UAE).

Resultater:

No significant differences in MBPS (MS1: 27,5 vs. 24,6 mmHg; p=0,13), (MS2: 16,3 vs. 14,0 mmHg; p=0,20),

(MS3: 4,7 vs. 7,8 mmHg; p=0,11), (MS4: 16,0 vs. 13,6 mmHg; p=0,21), (MS5: 18,2 vs. 15,3 mmHg; p=0,07) or

SND-ratio (0,87 vs. 0,86; p=0,25) were found between diabetes patients and controls. 31,6 % of diabetes

patients vs. 24 % of controls were classified as non-dippers. None of the five MBPS or SND-ratio were

associated with PWV, UAE or WML independently of age, gender and 24-h systolic blood pressure.

Konklusion:

MBPS and SND-ratio were not associated with subclinical markers of end-organ damage in our cohort of

newly diagnosed type ll diabetes patients.

112

87. Ambulant 24 timers besemmelse af pulsbølgehastighed og aorta blodtryk: et pilot projekt

Christoffer Krogager, Niklas Rossen, Esben Laugesen, Søren Tang Knudsen, Per Løgstrup Poulsen, Klavs

Würgler Hansen

Diagnostisk Center, Regionshospitalet silkeborg og Medicinsk Endokrinologisk afd. Århus Sygehus


At vurdere anvendeligheden af Arteriograph24 udstyr til ambulant indirekte bestemmelse af

pulsbølgehastighed (PWV), central aorta systolisk blodtryk (Syaorta) og augmentation index (AIXaorta) hos

type 2 diabetes pt. samt angive reproducerbarhed af data. Desuden ønskes bestemmelse af

døgnvariationen af de angivne karstivhedsdata.

Metode:

22 pt. med type 2 diabetes fik med 14 dages interval foretaget 24 timers ambulant måling med

Arteriograph24. Udstyret ligner et alm. døgnblodtryksapparat. Der foretages oscillometrisk måling af det

brachiale blodtryk hver 20 minut. Umiddelbart efter en måling foretages automatisk reinsufflation af

overarmsmanchetten til et suprasystolisk niveau i ca 6 sekunder. Analyse af pulsbølge kurven i denne fase

danner baggrund for estimering af pulsbølgehastighed og central aorta blodtryksdata. En vellykket døgn

måling kræver mindst 14 enkeltmålinger i dagtiden og mindst 7 om natten.

Resultater:

21 pt. havde en døgnmåling der opfyldte kvalitets kriterierne ved mindst én af de to målinger. Blandt disse

var antallet af vellykkede enkelt målinger 29 om dagen (spændvidde 16-50) og 18 om natten (11-25). 13 pt.

havde to vellykkede døgnmålinger. Ved dobbeltbestemmelse var standard deviation af forskellen (SDD)

mellem to døgn målinger af PWV ±2,2 m/sec, ± 13,1 mmHg for Syaorta og ± 13,8 mmHg for det brachiale

systoliske BT. Syaorta var 6 mmHg lavere end det brachiale systoliske BT i dagtiden og 4 mmHg lavere om

natten (p<0,05). AIXaorta var numerisk lavere i dagtiden (0,23) end om natten (0,25: p=0,12). PWV om

natten var signifikant lavere end om dagen (9,1 vs 9,7 m/sec ±0,8: p< 0,01). Nat/dag ratio for PWV (94 %)

var significant højere end nat/dag ratio for det brachiale mean BT (89 %: p< 0,03) og der var ingen

korrelation mellem disse (r= 0,38, p=0,29).

Konklusion: Ambulant døgnmonitorering med Arteriograph24 er teknisk mulig til forskningsbrug om end

med en succesrate lavere end sædvanlig døgnmåling af brachialt BT. Reproducerbarheden er på niveau

med tidligere rapporter angående klinik målinger af PWV. Udstyret er følsomt for korrekt placering og

stramning af overarms manchetten. Tendensen til højere AIXaorta om natten skyldes formentlig lavere puls

om natten. PWV var 6 % lavere om natten end om dagen uden tydelig relation til reduktion af nat

blodtrykket.

113

88. Diabetes and stroke: Liraglutide is associated with a decreased risk of stroke in type 2 diabetes

mellitus. A nested case-control study

Jan Scheel-Thomsen, Jakob Starup-Linde, Michael Gejl, Soeren Gregersen, Peter Vestergaard

Aalborg Universitetshospital


Diabetes mellitus (DM) is associated with an increased risk of stroke. We investigated the effects of

antidiabetic drugs on stroke incidence in DM patients.

Metode:

We conducted a nested case-control study. Cases were DM patients who subsequently suffered from

stroke; controls were DM patients with no history of stroke. Using the Danish National Hospital Discharge

Register, we included DM patients with information on date of DM diagnosis, date of stroke, and

comorbidities. From the Central Region of Jutland, Denmark, medication use and biochemical parameters

(LDL, HDL, total cholesterol, HbA1c and creatinine) were collected. We used covariate logistic regression to

calculate the adjusted odds ratios.

Resultater:

16,396 DM patients were included, and of these 1,660 patients had information on biochemistry. Use of

insulin, biguanides, β-cell stimulating drugs, DPP-4 inhibitors and liraglutide decreased the risk of stroke. A

trend for a dose- and duration-response was present for liraglutide. Exenatide and pioglitazone had no

significant effect. Antihypertensive drugs showed the most pronounced effect, and no difference in

preventive effect between antidiabetic agents and statins were observed.

When results were adjusted for biochemistry, liraglutide was the only antidiabetic drug with a significant

reduction on the risk of stroke.

Konklusion:

We have shown an association between use of liraglutide and a reduced risk of stroke in type 2 DM

patients. The effect was not tied to patient biochemical values, e.g. cholesterol or glucose-control (HbA1c).

The decreased stroke risk may represent beneficial, pleiotropic effects beyond glucose-lowering.

114

89. Vitamin D and carotid intima media thickness in 416 Danish patients with type 2 diabetes mellitus

(T2D) at entry into the CIMT trial

K. Winckler1 , T. W. Boesgaard1, L. Tarnow1,6, H. Vestergaard2, T. Almdal7, L. Lundby-Christensen1, A.

Vaag3, S. Madsbad4, C. Gluud5,

1Clinical Research Unit, Steno Diabetes Center, Gentofte, Denmark


A number of studies indicate a high prevalence of vitamin D insufficiency in the general population, and

several epidemiological studies have reported an association between vitamin D insufficiency and risk of

cardiovascular disease (CVD). Low vitamin D status may have an impact on the degree of osteopenia,

osteoporosis and cardiovascular risk factors, including thickness of carotid intima media. The aim of the

present study was to investigate the association between vitamin D, risk factors for osteopenia and

osteoporosis, and carotid intima media thickness (carotid IMT) in the Copenhagen Insulin Metformin

Treatment Trial (CIMT).

Metode:

We investigated 416 patients with T2D included in the CIMT trial, recruited from 9 diabetes outpatient

clinics in the greater Copenhagen area. Inclusion criteria were age>30 years, HbA1C>7.5 % (>58 mmol/mol),

eGFR>60 ml/min and duration of T2D >1 year. Vitamin D, carotid IMT, bone mineral density (BMD),

trabecular bone structure (TBS) and anthropometric measures were determined at baseline. Vitamin D was

measured by immunoassay ECLIA and insufficiency was defined as 25(OH)D <50nmol/l and deficiency as

25(OH)D <25nmol/l. An ultrasound scan was performed to determine carotid IMT. BMD and TBS were

measured by Dual Energy X-ray Absorptiometry (DXA) (Hologic, Discovery A). Osteopenia was defined by

any T score (spine, neck and hip-neck) between -1 to -2.5 and osteoporosis as any T score<-2.5. BMD was

measured in (g/cm2).

Resultater:

A total of 416 patients (68% men), age 60 ± 9 years [mean ± SD], BMI (kg/m2) 32 ± 4 [mean ± SD], and

HbA1c 8.5 ± 1.0% [mean ± SD] were included. The prevalence of vitamin D insufficiency was 51% and 17%

was deficient. Patients had a carotid IMT of 0.8 mm ± 1.7 [mean ± SD] and 70 % had plaques. Vitamin D

levels correlated positively with carotid IMT (R = 0.1, P = 0.02, unadjusted and adjusted for gender and BMI)

(in men R = 0.04, P = 0.02). We found no correlation in relation to carotid IMT and TBS or BMD, and similar

no correlation between vitamin D and TBS or BMD. Konklusion:

Conclusion: A high prevalence of vitamin D insufficiency and deficiency as well as increased thickness of

carotid intima media, plaques and osteopenia was found in 416 Danish patients with T2D. We found a

paradoxical positive correlation between vitamin D and carotid IMT, and no correlation between vitamin D

status and measures of bone mineral contents.

115

90. Risk Stratification with Plasma-NT-proBNP and Coronary Calcium Score Predicts All-Cause Mortality in

Microalbuminuric Type 2 Diabetic Patients.

Bernt Johan Illum von Scholten, Henrik Reinhard, Peter Godsk Jørgensen, Simone Theilade, Peter Riis

Hansen, Niels Wiinberg, Andreas Kjær, Claus L Petersen, Kaj Winther, Hans-Henrik Parving, Jan Skov Jensen,

Peter K Jacobsen, Peter Rossing

Steno Diabetes Center


The burden of coronary artery disease (CAD) is significantly increased in type 2 diabetic patients and is

associated with mortality. An effective screening tool for subclinical CAD is needed to predict and prevent

cardiovascular mortality in these patients.

Metode:

Plasma-NT-proBNP, Agatston coronary calcium score (CCS) and echocardiography were performed in 200

asymptomatic type 2 diabetic patients with elevated urinary albumin excretion rate (>30mg/24 h) and

without prior history of CAD. Patients with P-NT-proBNP >45.2 ng/L and/or CCS ≥400 at baseline were

stratified as high risk patients for CAD and were further examined for significant CAD by myocardial

perfusion imaging and/or CT-angiography and/or coronary angiography. Following these investigations,

patients were stratified into 3 groups, low risk (n=67), high risk without CAD (n=63) and high risk with CAD

(n=70) and were followed prospectively.

After 5.3 years of follow-up, vital status was assessed in all subjects, and echocardiography was re-

performed in available patients (n=130) (65%).

Resultater:

At baseline, patients were 59±9 years, 152(76%) male, with eGFR: 96±26 ml/min/1.73m2 and diabetes

duration of 13±7 years.

Of 130 patients with follow-up echo-data available, 117 had normal (≥50%) left ventricular ejection fraction

(LVEF) at baseline. Of these, 2(5%) and 9(12%) patients with low vs. high risk had reduced LVEF (<50%) at

follow-up (p=0.324).

During follow-up, 22(11%) patients died from all-causes, of which 1(1%) low risk, 9(14%) high risk without

CAD and 12(17%) high risk with CAD (log rank p=0.012). In Cox regression analysis comparing low risk vs.

high risk no CAD patients, the latter had significantly higher mortality (p=0.041), as was the case for low risk

vs. high risk CAD patients (p=0.017). In Cox regression analysis comparing low risk vs. all high risk, the latter

had significantly higher mortality (HR: 8.7, p=0.047, adjusted for gender, age, HbA1c, cholesterol, systolic

blood pressure, smoking and creatinine). However, comparing the two high risk groups, mortality was

similar (p=0.5).

Konklusion:

Risk stratification with P-NT-proBNP and CCS predicts all-cause mortality in asymptomatic type 2 diabetes

patients with microalbuminuria and normal kidney function. Additional cardiovascular evaluation did not

improve risk prediction. Deterioration from normal to impaired LVEF was not significantly different

between groups although this may be a power issue.

116

Assessment of Central Blood Pressure in Patients with Type 2 Diabetes: A Comparison Between

Sphygmocor and Invasively Measured Values

E. LAUGESENa+e, N.B. ROSSENa+d, C.D. PETERSb, M. MÆNGc, E. EBBEHØJa, S.T. KNUDSENa, K.W. HANSENd,

H.E.BØTKERc, P.L. POULSENa

a) Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark, b)

Department of Renal Medicine, Aarhus University Hospital, Skejby, Denmark, c) Department of Cardiology,

Aarhus University Hospital, Skejby, Denmark, d) Department of Medicine, Diagnostic Center, Silkeborg

Regional Hospital, Denmark, e) The Danish Diabetes Academy


The SphygmoCor is used for non-invasive assessment of ascending aortic blood pressure (BP). However, the

validity of the SphygmoCor transfer function has not been tested in an exclusively type 2 diabetic patient

sample. Calibration with systolic (SBP) and diastolic (DBP) brachial BP has previously been associated with

substantial imprecision of central BP estimates. We hypothesized that different non-invasive calibration

strategies might improve the accuracy of the estimated ascending aortic BPs.

Metode:

In 34 patients with type 2 diabetes we estimated ascending aortic SBP and DBP using the SphygmoCor

device and compared these data with invasively recorded data. The validity of the transfer-function was

assessed by calibrating with invasively recorded DBP and mean BP (MBP). The influence of non-invasive

calibration strategies was assessed by calibrating with brachial oscillometric SBP+DBP vs DBP+MBP using a

form-factor (ff) of 0.33 and 0.40, respectively.

Resultater:

When calibrating with invasive BP, the difference between estimated and invasively measured ascending

aortic SBP and DBP was -2.3±5.6/1.0±0.9 mmHg. When calibrating with oscillometric brachial BPs, the

difference was -9.6±8.1/14.1±6.2mmHg (calibration with SBP and DBP), -8.3±11.7/13.9±6.1 mmHg (DBP

and MBP, ff 0.33) and 1.9±12.2/14.1±6.2, mmHg (DBP and MBP, ff 0.40), respectively. Calibration with the

average of 3 brachial BPs did not improve accuracy.

Konklusion:

The SphygmoCor transfer function seems valid in patients with type 2 diabetes. Non-invasive calibration

with DBP and MBP(ff 0.40) enables accurate estimation of mean ascending aortic SBP at the group level.

However, the wide limits of agreement indicate limited accuracy in the individual patient.

117

91. Environmentally-Induced Epigenetic Changes in Gametes – Does Our Lifestyle Affect the Next

Generation?

Ida Donkin1, Soetkin versteyhe1, Thais de Castro Barbosa2, Kui Quan1, Lars Ingerslev1, Juleen Zierath1, 2,

Romain Barrès1

1Section of Integrative Physiology, The Novo Nordisk Foundation Center for Basic Metabolic Research,

Faculty of Health Sciences, University of Copenhagen, Denmark 2Section of Integrative Physiology,

Department of Molecular medicine and Surgery, Karolinska Institutet


Type 2 Diabetes (T2D) is a complex metabolic disease known to be associated with obesity and sedentary

lifestyles. Although the inheritance of T2D is weak and non-genetic, epidemiological studies have

demonstrated a link between the lifestyle of ancestors and the prevalence of metabolic disorders. Several

studies in rodents have shown paternal diet to affect the metabolic phenotype as far as the second

generation, but the molecular carriers have still not been described. Here we hypothesize that obesity leads

to changes in the epigenetic pattern of spermatozoa and that these changes are transferred to the next

generation, potentially altering the metabolic phenotype of our offspring.

Metode:

Male rats (F0) fed either a high-fat diet (HFD) or a control diet were mated with control female rats. The

spermatozoa were collected from the F0 and the following generations (F1 + F2) were phenotyped for

metabolic changes. Concurrently, we isolated motile spermatozoa from cohorts of obese and lean young

men. Using deep sequencing we profiled the epigenome of spermatozoa: DNA methylation profile, small

non-coding RNAs (sncRNAs) expression and histone positioning was determined.

Resultater:

The F1 offspring of HFD fed male rats showed reduced body weight and decreased beta-cell mass at 3 days

of age compared to the offspring of control fathers. At 6 and 12 weeks of age both F1 and F2 male and

female offspring of HFD fed fathers showed glucose intolerance, suggesting a transgenerational effect. The

spermatozoa of the F0 generation fed a HFD showed several differentially expressed scnRNAs as compared

to the control F0 rats. In the human cohorts we found several differentially methylated regions and

differentially expressed sncRNAs between lean and obese.

Konklusion:

We provide evidence that paternal diet affects the metabolic phenotype of the subsequent 2 generations in

rats associated with an altered epigenetic profile of the spermatozoa, and we describe a difference in the

epigenome of spermatozoa from obese versus lean men. Collectively, our data reinforce the role of

environmental factors in the heritability of metabolic dysfunction and suggest that the gametic epigenome

is a carrier of such phenomenon.

118

92. Glucocorticoid-induced adrenal insufficiency in prednisolone treated patients and how it relates to

glucocorticoid dose and the duration of treatment

Stina Dinsen, Bo Baslund, Marianne Klose, Åse Krogh Rasmussen, Lennart Friis-Hansec, Linda Hilsted,

Henning Locht, Annette Hansen, Ulla Feldt-Rasmussen.

Department of Endocrinologya, Rheumatologyb, Clinical Biochemestryc, Rigshospitalet, Department of

Rheumatology Frederiksberg Hospitald and Gentofte Hospitale, Copenhagen University Hospital, Denmark


We aimed to assess the prevalence of glucocorticoid-induced adrenal insufficiency in prednisolone treated

patients, and its relation to glucocorticoid dose and duration of treatment.

Metode:

As part of a larger study 48 patients with rheumatoid arthritis (33 women, aged 34-85 years) treated with

mean prednisolone dose of 7.0mg (range 5-20mg), with a mean duration of treatment of 95 months (range:

6-360 months) had a 250μg Synacthen® test performed fasting, in the morning, after a mean prednisolone

pause of 47 hours (range: 36-60 hours). P-cortisol was measured before, 30 and 60 min after Synacthen®

injection.

Resultater:

Of the 48 patients 29 (60%) and 23 (48%), respectively, had an insufficient adrenal function using 550nmol/l

and 500nmol/l as cut-offs. An insufficient response was less frequently recorded in patients treated with

5mg/day than above (33% versus 72%; p=0.009) with 500nmol/l, but not with 550nmol/l cut-off (50%

versus 78%, p=0.06). P-cortisol correlated with prednisolone dose (30 min: r=-0.36, p=0.02), but not

duration of treatment (30 min: r=-0.06; p=0.7).

Konklusion:

Approximately half of the patients had suppressed adrenal function 47 hours after last prednisolone dose.

Depending on cut-off, an insufficient response tended to be less frequent in patients treated with 5mg, but

still occurred in 33-50% of those patients. Cortisol correlated with prednisolone dose, which, however, only

explained 13% of the correlation. Duration of treatment was not predictive for adrenal suppression. The

results indicate that a substantial number of patients in glucocorticoid therapy for rheumatoid arthritis

need particular awareness when considering withdrawal in order to avoid life-threatening adrenal

insufficiency.

119

93. Anthropometrics in Klinefelter syndrome and the influence of genetic and hypothalamic-pituitary-

gonadal markers

Simon Chang(1), Anne Skakkebæk(1), Anders Bojesen(2), Jens Michael Hertz(3), Arieh Cohen(4), David

Michael Hougaard(4), Mikkel Wallentin(5,6), Anders Degn Pedersen(7,8), John Rosendahl Østergaard(9),

Claus Højbjerg Gravholt(1,10)

(1)Department of Endocrinology and Internal Medicine (MEA), Aarhus University Hospital, 8000 Aarhus C,

Denmark, (2)Department of Clinical Genetics, Vejle Hospital, Sygehus Lillebaelt, 7100 Vejle, Denmark,

(3)Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark, (3)Section of

Neonatal Screening and Hormones, Department of Clinical Biochemistry, Immunology and Genetics, Statens

Serum Institute, (4)Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark,

(5)Center of Functionally Integrative Neuroscience, Aarhus University Hospital, 8000 Aarhus C, Denmark,

(6)Center for Semiotics, Aarhus University, 8000 Aarhus C, Denmark, 8200 Aarhus N, Denmark, (7)Vejleford

Rehabilitation Center,7140 Stouby, Denmark, (8)Department of Psychology and Behavioral Sciences, Aarhus

University, 8000 Aarhus, Denmark, (9)Centre for Rare Diseases, Department of Pediatrics, Aarhus University

Hospital, (10)Department of Molecular Medicine, Aarhus University Hospital, 8200 Aarhus N, Denmark.


The phenotype seen in Klinefelter syndrome, 47, XXY (KS) is highly diverse, which often may explain the

frequent occurrence of non-diagnosis. Here, we examine anthropometric data from KS males to better

describe the KS phenotype. Furthermore, we evaluate how genetic and hypothalamic-pituitary-gonadal

markers influence the anthropometric findings.

Metode:

We studied 73 KS males and 73 age- and educational-matches men, whereof 68% of the KS males were

treated with testosterone. Anthropometric measures were height, sitting height, arm span, length of arm,

length of hand and foot, biacromial and biiliac diameter, hip, waist, and head circumference. Also, second

to fourth digit ratio (2D:4D) was measured, as a surrogate marker of the androgen exposure during fetal

life. Genetic analysis was done to investigate parental origin of the supernumerary X-chromosome, skewed

X-chromosome inactivation and CAG-repeats for the androgen receptor (AR). Furthermore, blood tests,

including sex hormone analysis, were performed.

Resultater:

KS males were higher (p<0.001) with greater leg length (p<0.001) compared to controls. KS males had

longer arms (p<0.01) and greater arm span (p=0.045) compared to controls. 2D:4D was significantly

reduced in KS males compared to controls (p=0.02). KS males were found to be truncally obese, but with no

difference in BMI or total cholesterol compared to controls. KS males with a paternally derived

supernumerary X-chromosome (patX) had wider arm span (p=0.048) and greater waist circumference

(p=0.048) compared to KS males with maternally derived extra X-chromosomes. Arm span for patX KS

males exceeded height. In KS males a significant correlation was seen between AR CAG-repeat length and

arm length, arm span, leg length and HDL cholesterol (p=0.04, p=0.01, p=0.03 and p=0.04, respectively).

Konklusion:

Conclusion: We show that the specific anthropometric phenotype in KS is partly explained by genetic

markers such as parental origin of the supernumerary X-chromosome and AR CAG-repeat length.

Furthermore, we show that the 2D:4D digit ratio was reduced in KS indicating that the intrauterine milieu

of KS is at least partly hypogonadal, raising the possibility that some traits in KS are explained by this

hypogonadal milieu.

120

94. Copeptin in polycystic ovary syndrome

Signe Frøssing1, Mubeena Aziz3, Sven O. Skouby2, Caroline Kistorp1, Jens Faber1

1Department of Endocrinology, Herlev Universityhospital, Denmark 2 Department of Gynaecology and

Obstatrics, Herlev Universityhospital, Denmark 3 Department of Gynaecology and Obstatrics, Hillerød

Hospital, Denmark


Polycystic ovary syndrome (PCOS) is according to the Rotterdam criteria defined as at least 2 of the

following: oligomenoré, hyperandrogenism and a polycystic ovary. These criteria do not take in to account

PCOS’ association to the metabolic syndrome (MES) and ischaemic heart disease (IHD). Recently we have

grouped PCOS-patients into 4 phenotypes depending on normal/high BMI and normal/increased insulin

resistance (IR). We demonstrated that the PCOS-patients with high BMI and increased IR had a metabolic

phenotype with elevated hsCRP, PAI-1 and thrombin generation time, which are all associated with MES

and IHD.

Vasopressin stimulates water retention, mediate vasoconstriction and facilitate secretion of ATCH in

healthy. Copeptin is part of the precursor Vasopressin peptide and is released during processing. Copeptin

is stable and easy to measure, making it a surrogate marker for Vasopressin. Elevated levels of Copeptin

have been associated with IHD, diabetes, microalbinuria and it is hypothesized to be due to a central

stimulation due to low-grade inflammation. Our aim is to study Copeptin in PCOS.

Metode:

Cross sectional observation study. 98 women with PCOS according to the Rotterdam criteria from an

outpatient clinic were examined. Age 18-54, no medication the last 6 weeks and no diabetes. Copeptin was

measured using a commercial sandwich immunoassay from BRAHMS.

Resultater:

Copeptin was divided into tertiles and increasing levels were associated with increasing levels of C-peptide,

free testosterone and PAI-1.

Univariate linear regression analysis showed that age (β=-0,21; P=0,036), C-peptid(β=0,34; P=0,001), HOMA

(insulin) (β=0,21; P=0,041), free testosterone (β=0,25; P=0,012), SHBG (β=-0,27; P=0,007) and PAI-1

(β=0,27; P=0,008) correlate with concentrations of Copeptin.

Multivariate linear regression analysis showed that C-peptide and free testosterone were independently

associated. No correlation was found regarding the 4 phenotypes (normal/high BMI, normal/increased IR),

BMI, android fat, blood pressure, hsCRP, creatinin, hirsutism score, ovary volume, menstruation cycle or

cholesterol.

Konklusion:

Copeptin levels in these women with PCOS demonstrate a weak association to hyperandrogenism (free

testosterone), IR (C-peptide) and low-grade inflammation (PAI-1). The data are in agreement with the

emerging opinion that the Rotterdam criteria do not fully describe the polycystic ovary syndrome.

121

95. Determinants of non-alcoholic fatty liver disease in women with previous gestational diabetes

mellitus

Signe Foghsgaard1-3, Louise Vedtofte1, Camilla Andersen1, Emilie S. Andersen1, Lise L. Gluud1, Charlotte

Strandberg4, Thora Buhl5, Elisabeth R. Mathiesen6, Peter Damm7, Jens Svare8, Filip K. Knop1,2 and Tina

Vilsbøll1

1Diabetes Research Division, Department of Medicine, Gentofte Hospital, 2Department of Biomedical

Sciences, Panum Institute, 3NNF Center for Basic Metabolic Research, 4Department of Radiology; Gentofte

Hospital, 5Department of Nuclear Medicine; Gentofte Hospital, 6Center for Pregnant Women with Diabetes,

Department of Endocrinology, Rigshospitalet, 7Center for Pregnant Women with Diabetes, Department of

Obstetrics, Rigshospitalet, 8Department of Gynaecology and Obstetrics, Herlev Hospital; University of

Copenhagen, Copenhagen, Denmark


Previous gestational diabetes mellitus (GDM) has been reported to increase the risk of developing features

of the metabolic syndrome including type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). We

examined these features in obese, non-diabetic women with previous GDM.

Metode:

Based on a 75 g-oral glucose tolerance test (OGTT) women were classed as normal glucose tolerant (NGT)

or prediabetic (impaired fasting glucose and/or impaired glucose tolerance). Insulin resistance was assessed

by the homeostasis model assessment. Hepatic steatosis was evaluated ultrasonically, by liver blood tests,

and dual energy X-ray absorptiometry (DEXA) scan. The android-to-gynoid fat-ratio and total visceral fat

mass were calculated based on the DEXA scan. A questionnaire was used to evaluate alcohol consumption

habits. Predictors of NAFLD were analysed using logistic regression.

Resultater:

Fifty-six women were included. Eighteen women had NAFLD. Eighteen women were classed as NGT and 38

prediabetic. Univariable logistic regression analyses showed that glucose tolerance status (NGT or

prediabetes) did not predict NAFLD (p=0.63) whereas NAFLD was positively associated with BMI (p=0.004),

C-peptide (p=0.028), high-density lipoprotein (p=0.031), amount of visceral fat (p=0.008), the android-to-

gynoid fat-ratio (p=0.030), and plasma levels of alanine aminotransferase (p=0.011) and aspartate amino

transferase (p=0.026).

Konklusion:

NAFLD is prevalent in women with previous GDM regardless of their glucose tolerance and seems to be

associated with high BMI and C-peptide levels, android fat distribution and elevated liver enzymes in

plasma.

122

96. Prevalence of sleep apnea in Danish Type 1 Diabetes patients

Henriette Holst Hansen1, Lise Tarnow1,4, Ulrik Pedersen-Bjergaard1, Brynjulf Mortensen2, Michael Laub3

og Birger Thorsteinsson1,5

1Department of Cardiology, Nephrology and Endocrinology, Nordsjællands Hospital ? Hillerød, 2Steno

Diabetes Center,3Respiration Center East, 4Health, Aarhus University, 5Faculty of Health and Medical

Sciences, University of Copenhagen

Department of Cardiology, Nephrology and Endocrinology, Nordsjællands Hospital ? Hillerød


Obstructive sleep apnea (OSA) is a disorder associated with excessive daytime sleepiness, reduced quality

of life and increased cardiovascular morbidity and mortality. Previous studies have reported higher

prevalence of OSA in patients with Type 2 Diabetes compared to the background population (below 5%)?

partly due to obesity. A possible association between OSA and Type 1 Diabetes (T1D) has so far not been

investigated, and therefore the aim of this study is to describe the prevalence of OSA in a large, well-

characterized cohort of Danish T1D patients.

Metode:

A total of 52 T1D patients have so far participated in the study. The patients were examined for OSA with

the ApneaLink+, a home-sleep-diagnostic device. OSA was defined as an apnea-hypopnea index (AHI) equal

to or above 5 episodes/hour and was stratified as mild (AHI: 5-15), moderate (AHI: 15-30) and severe (AHI ≥

30). Symptoms of OSA were scored using the Epworth Sleepiness Score and the Berlin questionnaire.

Clinical data were collected on age, gender, duration of diabetes, BMI, and HbA1c.

Resultater:

Only 45% (n=22) of the examined patients had normal respiration during sleep. Thirty-nine percent of the

patients (n=19) had mild OSA, 6% (n=3) had moderate OSA and 4% (n=2) had severe OSA. Furthermore, 3

patients were already diagnosed with OSA, and another 3 patients showed signs of Cheyne-Stokes

respiration.

Patients with OSA were older (58.1±10.9 years (mean±SD)) than patients with normal nighttime breathing

(46.1±16.0 years) (p= 0.003), but were otherwise comparable with respect to gender (70% vs. 68% men),

duration of diabetes (23.9±13.8 vs. 21.6 ±12.0 years), BMI (25.4±2.8 vs. 25.0±3.2 kg/m2) and HbA1c

(7.6±0.8 vs. 7.9±0.8 %), respectively.

Patients with OSA were more likely to report observed apnea episodes (15% vs. 0%) and snoring (93% vs.

73%), but were not more tired during daytime (26% vs. 38%) in comparison with patients with normal

nighttime breathing.

Konklusion:

Our preliminary results indicate a high prevalence of especially mild OSA in Danish patients with T1D, even

in the absence of obesity. Our data also suggest that classical symptoms do not reliably identify patients

with OSA and Type 1 Diabetes.

123

97. Obstruktiv søvnapnø hos diabetes patienter henvist til søvnklinik.

Freja Eriksen1, Anne Roed Jacobsen1, Line Thorup2, Lykke Bennedsen2, Jonas Peter Yde Holm2, Klavs

Würgler Hansen1

Diagnostisk Center1, og Søvnfriklinikken2, Center for Planlagt Kirurgi, Regions Hospitalet Silkeborg


Formål: 1) At angive hyppigheden af kendt diabetes (DM) hos pt. med obstruktiv søvnapnø (OSA) der

tilbydes CPAP (continuous positive airway pressure) behandling 2) sammenligne kliniske data relateret til

OSA hos pt. med og uden kendt diabetes 3) angive andelen af patienter med persisterende brug af CPAP.

Metode:

Ved gennemgang af patient udfyldt spørgeskema og journal oplysninger er der etableret en database

omfattende alle pt. der er i perioden fra 1/1 2012 til 28/2 2013 (14 mdr.) er tilbudt CPAP behandling som

følge af nykonstateret OSA efter henvisning til en søvnklinik. Frafaldet af CPAP brugere angives ved Kaplan

Meir kurve.

Resultater:

Der er registreret i alt 711 pt. hvoraf 15 mangler oplysninger. Undersøgelsen baseres derfor på 696 pt,

heraf 60 (8,6 %) med og 636 pt. uden selvrapporteret diabetes. Der var overvægt af mænd (73 %) i begge

grupper. Frekvensen af antihypertensiv behandling (82 % vs. 36 %) og kardiovaskulær sygdom (33 % vs 5 %)

var signifikant højere hos DM pt. sammenlignet med ikke DM pt. DM pt. havde signifikant højere BMI (34,0

vs. 30,4 kg/m2, p< 0,001). Der var ingen forskel i Epworth træthedsscore (10,1 vs. 10,6) eller apnø-

hypopnø-index (AHI) (35,9 vs. 35,3). Let OSA (AHI 5-15) fandtes hos 340 pt heraf 26 med DM (8,2 %) og

moderat til svær OSA (AHI >15) fandtes hos 356 pt. hvoraf 34 med DM (9,6 %). Stort set alle pt. var henvist

fra egen læge (via egen otolog) eller fra neurologiske eller lungemedicinske hospitals afdelinger. Blandt DM

pt. var kun 5 pt. (8 %) henvist fra andre hospitals afdelinger eller ambulatorier. Brug af CPAP behandling

blev vurderet efter en median observations tid på 452 dage (spændvidde; 228 - 645 dage) efter apparatet

var udleveret. 88 % var persisterende brugere af CPAP behandling uanset DM status (figur).

Konklusion:

DM pt. med OSA har større kardiovaskulær komorbiditet og højere BMI men samme træthedsscore, AHI og

procentvis andel af pt. med persisterende brug af CPAP behandling sammenlignet med pt. uden kendt DM.

Hyppigheden af kendt DM blandt pt. med nykonstateret OSA var lavere end forventet hvilket formentlig

skyldes underdiagnosticering. Systematisk screening af pt. med nykonstateret OSA for DM kan foreslås. Det

ringe antal pt. henvist fra endokrinologiske ambulatorier vidner om beskedent focus på tilstanden.

124

98. The metabolic effects of lipopolysaccharide depend on intact pituitary stress hormone responses –

studies of glucose, lipid and amino acid metabolism in hypopituitary patients and healthy volunteers

Ermina Bach, Andreas B. Møller, Jens O. L. Jørgensen, Mikkel H. Vendelbo, Niels Jessen, Jonas F. Olesen,

Steen B. Pedersen, Niels Møller

Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark


In humans lipopolysaccharide (LPS/endotoxin) generates inflammatory responses and leads to insulin

resistance, lipolysis and protein breakdown; these metabolic events play a key role in the pathogenesis of

the metabolic syndrome, type 2 diabetes and cardiovascular disease, but it remains unclear whether they

are caused directly by LPS and subsequent cytokine release or depend on intact pituitary stress responses

triggering release of cortisol and growth hormone. We sought to define effects of LPS on glucose, protein

and lipid metabolism in hypopituitary patients (without hypothalamo-pituitary mediated stress hormone

release) and healthy controls in a randomized, placebo controlled, single-blinded design.

Metode:

We studied eight hypopituitary patients (HP) and eight age and gender matched healthy control subjects

(CTR) twice during 4-h basal and 2-h hyperinsulinemic euglycemic clamp conditions with muscle biopsies

and fat biopsies in each period during infusion with saline or LPS (0.06 ng/kg/h) for 6 h.

Resultater:

Overall LPS infusion significantly increased cortisol and GH levels in CTR but not in HP. LPS increased whole

body palmitate fluxes (3-fold) and decreased palmitate specific activity 40-50 % in CTR, but not in HP. Post

hoc testing revealed decreased G(0)/G(1) Switch Gene 2 (G0S2 – an inhibitor of lipolysis) adipose tissue

mRNA in CTR. LPS increased phenylalanine fluxes in both groups, but significantly more so in CTR. LPS

induced decreased insulin sensitivity and endogenous glucose production in HP with no difference between

groups. After LPS administration insulin levels were lower in both groups during the clamp. Intramyocellular

insulin signalling was unaltered in both groups, whereas phosphorylation of 4E-BP1 was increased in CTR

only.

Konklusion:

Our data confirm that LPS induces increased lipolysis and increased amino acid/protein fluxes in healthy

volunteers. In hypopituitary patients, however, there was no increase in lipolysis, less pronounced

increases in phenylalanine fluxes and cytokine levels and dampened intracellular G0S2 expression and 4E-

BP1 phosphorylation in fat and muscle. Thus in humans intact pituitary function and appropriate cortisol

and GH release is a crucial component of the metabolic response to LPS.

125

99. Incidence and late prognosis of Acromegaly in Denmark: Preliminary data

Jakob Dal1 , Ulla Feldt-Rasmussen2, Marianne Andersen3, Lars Ø. Kristensen4 ,Peter Laurberg5, Henrik Toft

Sørensen6, and Jens Otto L. Jørgensen1

Department of Endocrinology, Aarhus University Hospital1


Acromegaly is a rare disease caused by GH hypersecretion from a pituitary adenoma. However, accurate

estimates of incidence and prevalence are scarce and not based on nationwide populations. . It is well

known that surgical cure may normalize mortality and improve morbidity but similar data are not available

for patients receiving medical treatment.

Metode:

We first validated the ICD-8 and -10 diagnosis codes for acromegaly in The National Registry of Patients by

a systematic patient chart review of related diagnosis and pertinent clinical biochemistry. Data on the

entire acromegaly cohort were then obtained by individual patient chart review and by using several

national databases such as The Cancer Registry, The Registry of Cause of Death and The National Registry of

Patients.

Resultater:

The mean incidence rate of acromegaly from 1989 - 2010 were 3.8 cases /million/year (95% CI 3.6-4.1) with

a prevalence of 85 cases/million in 2010. The mean age at diagnosis was 47 years (CI 95% 46-48) with a sex

distribution on 49% males (CI 95% 45-53). We found a 1.4 (CI 95% 1.2-1.7) fold increased mortality among

patients with acromegaly compared to the background population. The impact of different treatment

modalities on mortality is under investigation.

Konklusion:

This nationwide study is the first to provide accurate estimates of incidence and prevalence rates of

acromegaly and to evaluate the impact of medical treatment as compared to surgery.

126

Deltagerliste

Agi Szocska Sanofi-Aventis

Agnethe Berglund Aarhus Universitetshospital

Aina Sætre Lihn Regionshospitalet Randers Aleksander Bill Hansen Odense Universitetshospital

Alin Andries Syddansk Universitet

Anders Ellekær Junker Gentofte Hopsital

Anders Herbild Sanofi-Aventis

Andreas Brønden Gentofte Hospital

Andreas Buch Møller Aarhus Universitetshospital Andreas James Thestrup Pedersen Odense Universitetshospital

Andreas Kaal Regionshospitalet Horsens

Anette Lykke Hansen MSD

Anil Mor Aarhus Universitetshospital

Anita Schmitz Vejle Sygehus

Anja Frederiksen Odense Universitetshospital

Ann Bech Thomsen Herlev Hospital

Ann Mosegaard Bak Aarhus Universitetshospital

Anna Pietraszek Aalborg Universitetshospital

Anne Arreskov Gentofte Hospital

Anne Bank Boisen Aarhus Universitetshospital

Anne Benedicte Juul Hillerød Hospital

Anne Krejbjerg Aalborg Universitetshospital

Anne Kristine Amstrup Aarhus Universitetshospital

Anne Lene Riis Regionshospitalet Horsens

Anne Rasmussen Steno Diabetes Center

Anne Sofie Korsholm Nielsen Aarhus Universitetshospital Anne Sofie Laulund Odense Universitetshospital

Anne-Dorthe Feldthusen Næstved Sygehus

Anne-Luise Thorsteinsson Hillerød Hospital

Annette Hansen Gentofte Hospital

Annette Mengel Aarhus Universitetshospital

Asger Lund Gentofte Hospital Ayse Dudu Dogan Sygehus Lillebælt

Benjamin Schnack Rasmussen Odense Universitetshospital

Bente Langdahl Aarhus Universitetshospital

Berit Maria Linde Sygehus Vendsyssel

Bernt Johan Illum von Scholten Steno Diabetes Center

Bettina Haar Havekrog Aalborg Universitetshospital

Bianca Hemmingsen Hillerød Hospital

Birger Thorsteinsson Hillerød Hospital

Birgitte Mumm Aarhus Universitetshospital

Birte Kristensen Rigshospitalet

127

Birte Nygaard Herlev Hospital

Bjarke J. Bruun Aarhus Universitetshospital Bjørn Richelsen Aarhus Universitetshospital

Bo Abrahamsen Glostrup Hospital

Camilla Andersen Gentofte Hospital

Camilla Sloth Østergaard Otsuka Pharma

Carl-Henrik Brogren Rigshospitalet

Caroline Brorsson Herlev Hospital Caroline Kistorp Herlev Hospital

Caroline Raun Hansen Bispebjerg Hospital

Carsten Dirksen Charlotte Berg Holt Aarhus Universitetshospital

Charlotte Ejersted Odense Universitetshospital

Charlotte Steffensen Aarhus Universitetshospital

Christian Kruse Aalborg Universitetshospital

Christian Selmer Herlev Hospital

Christoffer Hedetoft Christoffer Krogager Regionshospitalet Silkeborg

Christoffer Martinussen Hvidovre Hospital

Christophe Duret Novo Nordisk Claus H. Gravholt Aarhus Universitetshospital

Claus Juhl Sydvestjysk Sygehus

Claus Larsen Feltoft Herlev Hospital

Dan Hesse Frederiksberg Hospital

Diana Grove Regionshospitalet Silkeborg

Dorte Glintborg Odense Universitetshospital

Dorte Lindqvist Hansen Køge Sygehus

Dorte Worm Køge sygehus

Ebbe Eldrup Herlev Hospital

Eigil Husted Nielsen Aalborg Universitetshospital

Elisa Pouline Jensen Københavns Universitet

Elisabeth Hjøllund Regionshospital Randers

Elisabeth Svensson Aarhus Universitet

Ellen Grodum Fredericia Sygehus

Else Vestbo Aarhus Universitetshospital

Elsebeth Duun Gentofte Hospital

Emilie Balk-Møller København universitet Emilie Hein Petersen Steno Diabetes Center

Erik Kopperå Pfizer

Ermina Bach Aarhus Universitetshospital

Esben Laugesen Aarhus Universitetshospital

Esben Søndergaard Aarhus Universitetshospital

Eva Ebbehøj Aarhus Universitetshospital Eva hommel Steno Diabetes Center

Filip K. Knop Københavns Universitet

Finn Bennedbæk Herlev Hospital

Finn Edler von Eyben Center for Tobacco Control Research

Flemming Steen Nielsen Herlev Hospital

128

Frans Brandt Odense Universitetshospital

Frederik Persson Hillerød Hospital Gitte Bloch Rasmussen Aarhus Universitetshospital

Hanne Mari Skou Jørgensen Aarhus Universitetshospital

Hanne Mumm Odense Universitetshospital

Hanne Nygaard Sanofi-Aventis

Hanne Storm Regionshospitalet Silkeborg

Hanne Louise Kissow Københavns Universitet Hans Jørgen Gjessing Fredericia Sygehus

Heidi Storgaard Gentofte Hospital

Helga Holm Schultz Hillerød Hospital

Helle Brockstedt Aarhus Universitetshospital

Helle Ekkert Sabra Glostrup Hospital

Helle Harkjær Andersen Hvidovre hospital

Helle Thorsgaer Medtronic Danmark

Helle Zibrandtsen Aarhus Universitetshospital

Henning Rønne Sygehus Himmerland

Henriette Ejlsmark Knudsen Aarhus Universitetshospital

Henriette Holst Hansen Hillerød Hospital

Henrik Ancher Sørensen Holbæk Sygehus Henrik Billesø Maribo Medico

Henrik Ullits Andersen Steno Diabetes Center

Ida Donkin Københavns Universitet

Inge Bülow Pedersen Aalborg Universitetshospital

Jacob Stampe Frølich Odense Universitetshospital

Jakob Appel Østergaard Aarhus Universitet

Jakob Dal Aarhus Universitetshospital

Jakob Høgild Langdahl Sydvestjysk Sygehus

Jakob Starup Linde Aarhus Universitetshospital

Jan Erik Henriksen Jan Frystyk Aarhus Universitetshospital

Jan Scheel Thomsen Aalborg Universitetshospital

Jane Dahl Andersen Aarhus Universitetshospital

Jenna Rosenqvist Ibsen Aalborg Universitetshospital

Jenny Gadegaard Novo Nordisk

Jens Faber Herlev Hospital

Jens Meldgaard Bruun Regionshospitalet Randers Jens Møller Aarhus Universitetshospital

Jens Otto Jørgensen Aarhus Universitetshospital

Jens Pedersen Bispebjerg Hospital

Jens Peter Kroustrup Aalborg Universitetshospital

Jens Steen Nielsen Odense Universitetshospital

Jeppe Lerche la Cour Glostrup Hospital Jes Sloth Mathiesen Sydvestjysk Sygehus

Jesper Fleischer Aarhus Universitetshospital

Jesper Karmisholt Aalborg Universitetshospital

Jimmi Sloth Olsen Aarhus Universitetshospital

Joachim Størling Herlev Hospital

129

Joakim Andersson Viropharma

Joan Bach Nielsen Aarhus Universitetshospital Johanne Lyhne Aarhus Universitetshospital

Johanne Marie Holst Aarhus Universitetshospital

Jolanta Topolska Sygehus Sønderjylland

Jonatan Bagger Gentofte Hospital

Juliana Frohnert Hansen Endokrinologisk Laboratorium København

Julie Pildal Frederiksberg Hospital Julie Støy Aarhus Universitetshospital

Jørgen Rungby Rigshospitalet

Kamran Akram Steno Diabetes Center

Karen Bay Kønig Amager Hospital

Karen Boje Pedersen Herlev Hospital

Karen Fjeldborg Aarhus Universitetshospital

Karoline Schousboe Sygehus Lillebælt

Kathrine Ekström Hillerød Hospital

Katrhine Louise Jensen Rigshospitalet

Khanh Le MSD

Kim Brixen Odense Universitetshospital

Kirsten Alstrup Regionshospitalet Randers Kirsten Nyborg Rasmussen Aarhus Universitetshospital

Kirstine Nyvold Bojsen-Møller Hvidovre Hospital

Kirstine Stochholm Aarhus Universitetshospital

Kjeld Hasselström Regionshospitalet Herning

Klaus Levin Svendborg Sygehus

Klavs Würgler Hansen Regionshospitalet Silkeborg

Knud Yderstræde Odense Universitetshospital

Kristian Løkke Funck Jensen Aarhus Universitetshospital

Kristian Wraae Regionshospitalet Herning

Kristine Melgaard Michailidis Odense Universitetshospital

Lars Folkestad Odense Universitetshospital

Lars Mandrup MSD

Lars P. Sørensen Aarhus Universitetshospital

Lars Rejnmark Aarhus Universitetshospital

Lars Rolighed Aarhus Universitetshospital

Laszlo Hegedüs Odense Universitetshospital

Lena Sønder Snogdal Odense Universitetshospital Lene Hammer MSD

Lene Ring Madsen Aarhus Universitetshospital

Lene Ringholm Rigshospitalet

Lene Sundahl Mortensen Aarhus Universitetshospital

Lene von Fintel Sostack Odense Universitetshospital

Line Underbjerg Aarhus Universitetshospital Lisa Buus Aarhus Universitetshospital

Lisbet Kvorning Novo Nordisk

Lise Sofie Andersen Aarhus Universitetshospital

Lise Tarnow Nordsjællands Hospital

Liselotte Christiansen Gentofte Hospital

130

Liselotte fisker Aarhus Universitetshospital

Lissen Fruergaard Takeda Pharma Lone Elgetti Amgen

Lone Kvist Aarhus Universitetshospital

Lone Mann Nielsen Takeda Pharma

Lotte Holmbo Arentoft Aarhus Universitetshospital

Louise Bruun Thingsholm Aarhus Universitet

Louise Hansen Aalborg Universitetshospital Louise Lehmann Christensen Svendborg sygehus

Louise Tjelum Frederiksberg Hospital

Louise Vedtofte Gentofte Hospital

Louise Wamberg Sydvestjysk Sygehus

Louise Wulff Christensen Københavns Universitet

Luba Freja Michaelsson Herlev Hospital

Magda Andries Sygehus Lillebælt Fredericia

Maria Booth Nielsen Københavns Universitet

Maria Houborg Petersen Svendborg Sygehus

Maria Saur Svane Hvidovre Hospital

Marianne K Poulsen Aarhus Universitetshospital

Marianne Kleis Møller Regionshospitalet Horsens Marianne Klose Amager Hospital

Marianne Møller Brorson Endokrinologisk Laboratorium København

Marianne Thvilum Odense Universitetshospital

Marie Blicher Odense Universitetshospital

Marie Friis-Andersen Hvidovre Hospital

Marie Juul Ørnstrup Aarhus Universitetshospital

Marit Eika Jørgensen Steno Diabetes Center

Marius Carstensen Hospitalsenheden Horsens

Marlene Lunddal Krogh Aarhus Universitetshospital

Merete Skovdal Christiansen Gentofte Hospital

Mette Bjerre Aarhus Universitet

Mette Bohl Larsen Aarhus Universitetshospital

Mette Faurholdt Gude Regionshospitalet Silkeborg

Mette Sonne Steno Diabetes Center

Mette Søeby Regionshospitalet Silkeborg

Mette Zander Bispebjerg Hospital

Michael Røder Gentofte Hospital Michael Væggemose Aarhus Universitetshospital

Mikkel Holm Vendelbo Aarhus Universitetshospital

Minna Wittrup Steno Diabetes Center

Monika Botyre Aalborg Universitetshospital

Morten Frost Nielsen Kolding Sygehus

Morten Hansen Gentofte Hospital Morten Lindhardt Steno Diabetes Center

Morten Møller Poulsen Regionshospitalet Randers

Naja Laursen Takeda Pharma

Nanna Borup Johansen Steno Diabetes Center

Narges Safai Steno Diabetes Center

131

Neel Honoré Sanofi-Aventis

Niels Eiskjær Klinisk forskning Niklas Blach Rossen Aarhus Universitetshospital

Nikolaj Rittig Aarhus Universitetshospital

Nilani Ramshanker Aarhus Universitetshospital

Nils Bruun Jørgensen Amager Hospital

Nils Erik Magnusson Aarhus Universitetshospital

Palle Dahl Takeda Pharma Per Løgstrup Poulsen Aarhus Universitetshospital

Pernille Hermann Odense Universitetshospital

Pernille Holmager Herlev Hospital

Pernille Høyem Aarhus Universitetshospital

Pernille Kähler Rigshospitalet

Pernille Mensberg Gentofte Hospital

Pernille Wendelboe Larsen Otsuka Pharma

Peter Breining Aarhus Universitetshospital

Peter Dall Mark Peter Halkier Sygehus Thy-Mors

Peter Hejbroch Medtronic Danmark

Peter Kolind Brask-Thomsen Aarhus Universitetshospital Peter Laurberg Aalborg Universitetshospital

Peter Ravn MedImmune Ltd.

Peter Rossing Steno Diabetes Center

Peter Vestergaard Aalborg Universitetshospital

Pia Deichgræber Aarhus Universitet

Pia Eiken Hillerød Hospital

Rana bibi Aalborg Universitetshospital

Randi Ugleholdt Herlev Hospital

Rasmus Bo Jansen Bispebjerg Hospital

Regine Bergholdt Novo Nordisk

Rene Støving Odense Universitetshospital

Rikke Borg Rigshospitalet

Rikke Hjortebjerg Aarhus Universitetshospital

Rikke Lund Nielsen Sanofi-Aventis

Rikke Mette Agesen Hillerød Hospital

Rikke Reenberg Amgen

Rikke Viggers Aarhus Universitetshospital Rune Ehrenreich Kuhre Panum Instituttet

Sanne Fisker Aarhus Universitetshospital

Sascha Pilemann-Lyberg Steno Diabetes Center

Sevinch Brodersen Odense Universitetshospital

Signe Foghsgaard Gentofte Hospital

Signe Frøssing Herlev Hospital Signe Harring Østoft Gentofte Hospital

Signe Schmidt Hvidovre Hospital

Signe sætre Rasmussen Hillerød Hospital

Signe Toft Andersen Aarhus Universitetshospital

Sigrid Bjerge Gribsholt Aarhus Universitetshospital

132

Simon Chang Aarhus Universitetshospital

Simone Theilade Steno Diabetes Center Sine Knorr Aarhus Universitetshospital

Sisse Marie Schmidt Gentofte Hospital

Siv Lajlev Aarhus Universitetshospital

Sofie Haarbo Medtronic Danmark

Sophie Sejling Syddansk Universitet

Steen Andersen Nordsjællands Hospital Steen Bonnema Odense Universitetshospital

Stina Dinsen Rigshospitalet

Stine Aistrup Eriksen Aalborg Universitet

Stine Linding Andersen Aalborg Universitetshospital

Stinus Hansen Sydvestjysk Sygehus

Susanne Engberg Amager Hospital

Susanne Lerche Sygehus Lillebælt Fredericia

Susanne Sørensen Aarhus Universitetshospital

Søren Lund Søren Tang Knudsen Aarhus Universitetshospital

Sørensen Gregersen Aarhus Universitetshospital

Tanja Sikjær Aarhus Universitetshospital Thomas Almdal Gentofte Hospital

Thomas Dejgaard Steno Diabetes Center

Thomas H. Brix Odense Universitetshospital

Tina Hansen Barbisan Odense Universitetshospital

Tina Jorsal Hillerød Hospital

Tina Schou Andersen Aarhus Universitetshospital

Tina Vilsbøll Gentofte Hospital

Tina Zimmermann Belsing Freelance i Skandinavien

Tony Bill Hansen Svendborg Sygehus

Torben Harsløf Aarhus Universitetshospital

Torben Laursen Aarhus Universitetshospital

Torben Leo Nielsen Odense Universitetshospital

Torben Østergård Regionshospitalet Viborg

Tore Christiansen Danish Diabetes Academy

Trine Tang Christensen Aalborg Universitetshospital

Trine Welløv Boesgaard Novo Nordisk

Troels Bock Køge sygehus Troels Krarup Hansen Aarhus Universitetshospital

Ulla Bjerre-Christensen Steno Diabetes Center

Ulla Kampmann Aarhus Universitetshospital

Ulrich Rohde Gentofte Hospital

Ulrik Pedersen-Bjergaard Hospital Hillerød

Wajd Hassan Aarhus Universitetshospital Yasmin Hamid Bispebjerg Hospital

Zhulin Ma Aarhus Universitetshospital

Zuzana Vlachová Odense Universitetshospital

133

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DES Årsmøde 2014 - Dansk Endokrinologisk Selskab · Dansk Endokrinologisk Selskabs Årsmøde 2014 Hotel Helnan Marselis, Aarhus Fredag den 17. januar 2014 Registrering ... Gerrit