LETTERS - care.diabetesjournals.org · OBSERVATIONS Analysisofthe AgreementBetween theWorldHealth Organization Criteriaandthe NationalCholesterol EducationProgram-IIIDeﬁnitionofthe

OBSERVATIONS

Analysis of theAgreement Betweenthe World HealthOrganizationCriteria and theNational CholesterolEducation Program-III Definition of theMetabolic Syndrome

Results from a population-basedsurvey

Our objective was to evaluate the di-agnostic proficiency of the WorldHealth Organization (WHO) and

the National Cholesterol Education Pro-gram (NCEP)-III definitions (1,2) for themetabolic syndrome in a Mexican nation-wide, population-based survey. Details ofthe sampling procedures have been pre-viously described (3). The population wascomposed of 2,158 men and women aged20–69 years sampled after a 9- to 12-hfasting period. For the WHO criteria, in-sulin resistance was diagnosed if a non-diabetic case had fasting insulin concen-trations �126 pmol/l (21 �U/ml) (�75thpercentile in Mexican adults). The age-adjusted prevalence was 13.61% for theWHO criteria (n � 268) and 26.6% forthe NCEP-III definition (n � 574). Afterexcluding patients with diabetes, the prev-alence was 9.2 and 21.4%, respectively.The agreement between the definitionswas assessed in 1,969 subjects; 189 caseswere eliminated due to the lack of a urinesample.

The number of abnormal cases waslower using the WHO criteria. Only 237of the 545 subjects (43.4%) who fulfilledthe NCEP criteria were diagnosed as af-fected using the WHO definition. Just 16of 253 cases (6.3%) detected by the WHOdefinition did not fulfill the NCEP defini-tion. The agreement between the criteriawas moderate (� � 0.507). On the otherhand, the subjects diagnosed using theWHO recommendations had a worseprofile than the cases detected by theNCEP-III definition only—they had a

higher BMI and higher non-HDL choles-terol, triglyceride, and glucose concentra-tions. The demonstration of insulinresistance among the nondiabetic popu-lation caused the lack of agreement in 202of the 242 cases that fulfilled the NCEPdefinition but failed the WHO criteria.Other reasons for disparity were thehigher thresholds used by the WHO cri-teria; these differences explained the lackof agreement in 66 of the 152 cases withdiabetes.

In conclusion, the prevalence of themetabolic syndrome is influenced by theselection of the diagnostic criteria. TheWHO criteria identified a lower numberof cases than the NCEP-III definition.These differences were explained mainlyby the inclusion of abnormally high insu-lin concentrations as a diagnostic crite-rion. However, the presence of insulinresistance may help to identify patientsmore severely affected (4).

CARLOS A. AGUILAR-SALINAS, MD1

ROSALBA ROJAS, PHD2

FRANCISCO J. GOMEZ-PEREZ, MD1

VICTORIA VALLES, MD1

JUAN MANUEL RıOS-TORRES, MD1

AURORA FRANCO, PHD2

GUSTAVO OLAIZ, PHD2

JUAN A. RULL, MD1

JAIME SEPULVEDA, PHD2

From the 1Departamento de Endocrinologıa y Me-tabolismo del Instituto Nacional de Ciencias Medi-cas y Nutricion “Salvador Zubiran,” Mexico City,Mexico; and the 2Instituto Nacional de Salud Pu-blica, Cuernavaca, Morelos, Mexico.

Address correspondence to Carlos Alberto Agui-lar-Salinas, MD, Vasco de Quiroga 15, Mexico City14000, Mexico. E-mail: [email protected].

© 2003 by the American Diabetes Association.

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References1. Expert Panel on Detection, Evaluation,

and Treatment of High Blood Cholesterolin Adults: Executive Summary of TheThird Report of The National CholesterolEducation Program (NCEP) Expert Panelon Detection, Evaluation, and Treatmentof High Blood Cholesterol In Adults(Adult Treatment Panel III). JAMA 285:2486–2497, 2001

2. Alberti FGMM, Zimmet PZ: Definition,diagnosis and classification of diabetesmellitus and its complications. Part 1: di-agnosis and classification of diabetes mel-litus provisional report of a WHO con-sultation. Diabet Med 15:539–553, 1998

3. Aguilar-Salinas CA, Rojas R, Gomez-PerezFJ, Garcıa E, Valles V, Rıos-Torres JM,Franco A, Olaiz G, Sepulveda J, Rull JA:

Prevalence and characteristics of early-onset type 2 diabetes in Mexico. Am J Med113:569–574, 2002

4. Hanson R, Imperatore G, Bennett PH,Knowler W: Components of the “meta-bolic syndrome” and incidence of type 2diabetes. Diabetes 51:3120–3127, 2002

Complete Blockadeof the Renin-Angiotensin Systemin Patients WithAdvanced DiabeticNephropathy

W e read with interest the article byRossing et al. (1) in the January2002 issue of Diabetes Care. We

had previously assessed the effect of com-plete blockade of the renin-angiotensinsystem (RAS) in patients with advanceddiabetic nephropathy (type 2 diabetes)and severe proteinuria (2). To do so, westudied 10 patients on prior treatmentwith ACE inhibitors at recommendeddoses, to which 50 mg/day of Losartanwas added.

After 3 months of the combined ther-apy, urinary protein excretion decreasedfrom a mean of 6.9 (95% CI 4.3–9.6) to5.8 g/24 h (3–8.6) (P � 0.025) and, withthe exception of two patients, was re-duced in all cases. The proteinuria/urinary creatinine ratio also decreasedfrom 7.6 (4.2–11.05) to 6.0 g/g (3.2–8.7)(P � 0.02). In one patient in which pro-teinuria did not vary, the proteinuria/creatinine ratio also decreased, reflectinga possible error in the quantification ofthe patient’s proteinuria instead of a lackof response to the treatment. The glomer-ular filtration rate (GFR), calculated usingthe mean of creatinine and urea clearance,a measurement that avoids the overesti-mation that creatinine clearance producesin the GFR (3), decreased slightly from21.5 � 8.5 to 19.9 � 7.8 ml/min (P �0.158). An interesting decrease in totalcholesterol from 6.21 � 1.03 to 5.33 �1.27 mmol/l (P � 0.036) was observed.Total proteins, serum albumin, proteinintake, and mean arterial pressure (MAP)were not significantly modified. Only onepatient had hyperkaliemia (from 5.1 to7.2 mmol/l). No secondary effects wereseen in the other patients. At 12 months oftreatment, proteinuria decreased to 3.4

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g/24 h and the proteinuria/urinary creat-inine ratio to 3.6. GFR decreased by 0.83ml � min�1 � month�1 in the first 6months and only fell by 0.18 ml � min�1 �month�1 during the last 6 months. Twopatients received the combined treatmentfor �42 months. During the first 18months, proteinuria decreased by 74 and67% in each case; GFR fell by 0.5 and 1 ml� min�1 � month�1, respectively; and MAPdid not vary in the first case and decreasedfrom 123 to 101 mmHg in the second.Over the following 24 months, protein-uria was �1 g/24 h in both cases and GFRincreased in one patient by 2 ml/min anddid not vary in the other patient. In thisperiod, MAP and protein intake remainedunvaried.

The data of Rossing et al. confirm thatin the short term, complete blockade ofthe RAS system produces an antiprotein-uric effect and affords a greater renopro-tective effect since proteinuria is animportant risk factor for kidney diseaseprogression (4). Although our data canonly be considered as observational find-ings, they do allow us to intuit that thisrenoprotective effect, due to the dualblockade of the RAS, will be increasedwhen treatment is prolonged to mediumor long term. Moreover, the observed de-crease in total cholesterol levels wouldcontribute to reducing both the progres-sion of the nephropathy, since elevatedserum cholesterol levels act as an inde-pendent promoter of progression in dia-betic nephropathy (5), and the highcardiovascular risk seen in this type ofpatient.

JAVIER DEIRA, MD, PHD

HUGO DIAZ, MD

JESUS GRANDE, MD, PHD

From the Division of Nephrology, Internal Medi-cine, Hosptial Virgen de la Concha, Zamora, Spain.

Address correspondence to Dr. Javier Deira, Di-vision of Nephrology, Internal Medicine, HospitalVirgen de la Concha, Avenida de Requejo 35, 49022Zamora, Spain. E-mail: [email protected].


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References1. Rossing K, Christensen PK, Jensen BR,

Parving H-H: Dual blockade of the renin-angiotensin system in diabetic nephropa-thy. Diabetes Care 25:95–100, 2002

2. Deira J, Dıaz H, Gonzalez A, Grande J: Isthere a synergic antiproteinuric and reno-protective efect between angiotensin-con-verting-enzyme inhibitors and angiotensintype1 receptor antagonists in patientswith advanced diabetic nephropathy (Ab-

stract). J Hypertens 19 (Suppl. 2):S137,2001

3. Kasiske BL, Keane WF: Laboratory assess-ment of renal disease: clearance, urinaly-sis, and renal biopsy. In The Kidney. 5thed. Brener BM, Rector FC, Eds. Philadel-phia, WB Saunders, 1996, p. 1140

4. Remuzzi G: Nephropathic nature of pro-teinuria. Curr Opin Nephrol Hypertens8:655–663, 1999

5. Hovind P, Rossing P, Tarnow L, SmidtUM, Parving HH: Progression of diabeticnephropathy. Kidney Int 59:702–709, 2001

Effect of 2-WeekTreatment WithPirenzepine onFasting andPostprandial GlucoseConcentrations inIndividuals WithType 2 Diabetes

A cute cholinergic muscarinic block-ade with pirenzepine (PIR) inducesdose-related reductions in plasma

glucose (PG) and plasma insulin (PI) aftermixed meals in normal individuals and intype 2 diabetic and polycystic ovary syn-drome patients (1–2). Altogether, 24 pa-tients with type 2 diabetes (12 male and12 female) with a fasting plasma glucose�10 mmol/l were studied for the effectsof PIR (50 mg b.i.d.) given for 2 weeks onfasting and postprandial plasma glucoseand insulin concentrations. Patients onACE inhibitors or thiazide diuretics wereexcluded.

Oral hypoglycemics were stopped atleast 2 weeks before treating the patientswith either PIR or placebo in a random-ized, cross-over, double-blind fashionwith a 2-week washout period betweenthe two treatment arms. At the beginning(day 1) and end (day 14) of each treat-ment period, blood was sampled over12 h, during which time the patients re-ceived three standard meals. The sched-uling for blood sampling, meals, and PIRadministration is illustrated in Fig. 1. Theprimary outcome measure for the studywas the difference between PIR- and pla-cebo-treated fasting plasma glucose onday 14 of the study. Statistical analysiswas performed using the paired Student’st test.

There was a significant reduction inthe fasting PG levels on day 14 (PIR) com-

pared with day 14 (placebo) (mean reduc-tion � SD, 1.2 � 1.6 mmol/l, 95% CI0.5–1.9, P � 0.002 by paired Student’s ttest) (Fig. 1). There were trends for reduc-tion in the glucose area under the curveand highest postprandial peaks for day 14(PIR) compared with day 14 (placebo),but the results did not reach statistical sig-nificance. There was no significant differ-ence in fasting plasma insulin levels.

The mechanism through which PIRproduces its effect on PG is unknown.Possible hypotheses are the obliteration ofan increased hypothalamic cholinergictone responsible for increased 24-h growthhormone (GH) secretion, particularlysuppression of nocturnal GH secretion,which we and others (3,4) have previ-ously demonstrated. Another possibilityis the effect of PIR on gastrointestinal hor-mones through its anticholinergic effect,which may affect PG levels indirectly (5).

In conclusion, PIR caused a statisti-cally significant reduction in fasting PGlevels compared with placebo after 2weeks of therapy, but there was no corre-sponding increase in insulin levels. PIRmay be an effective drug in the treatmentof type 2 diabetes.

Acknowledgments— This study was sup-ported by a grant from Boehringer Ingelheim.

We are indebted to Drs. Mary Lewis andMark Lewis for their assistance with the insu-lin assay and Liz Gardner for her assistancewith statistical analysis.

BASIL G. ISSA, MD1

NICHOLA DAVIES, RGN1

KERENZA HOOD, PHD2

LAKDASA D.K.E. PREMAWARDHANA, MD3

JOHN R. PETERS, MD1

MAURICE F. SCANLON, MD1

From the 1Department of Endocrinology, UniversityHospital of Wales, Heath Park, Cardiff, U.K.; the2Department of Statistics, University Hospital ofWales, Heath Park, Cardiff, U.K.; and the 3Depart-ment of Medicine, Caerphilly Miners District Hos-pital, Caerphilly, Mid Glamorgan, U.K.

Address correspondence to Dr. Basil G. Issa, MD,FRCP, MRCP(I), Diabetes Centre, North Manches-ter General Hospital, Delaunays Road, Crumpsall,Manchester M8 5RB U.K. E-mail: [email protected].


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References1. Bevan JS, Ara J, Page MD, Scanlon MF,

Peters JR: Cholinergic blockade withpirenzepine induces dose-related reduc-

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tion in glucose and insulin responses to amixed meal in normal subjects and non-insulin dependent diabetics. Clin Endocri-nol 35:85–91, 1991

2. Premawardhana LDKE, Ismail IS, Riad-Fahmy D, Miell JP, Peters JR, Scanlon MF:Acute cholinergic blockade with low dosepirenzepine reduces the insulin and glucoseresponses to a mixed meal in obese womenwith the polycystic ovary syndrome. ClinEndocrinol 40:617–621, 1994

3. Page MD, Bevan JS, Dieguez C, Peters JR,Scanlon MF: Cholinergic blockade withpirenzepine improves carbohydrate toler-ance and abolishes the GH response tomeals in normal subjects. Clin Endocrinol30:519–524, 1989

4. Pietschmann P, Schernthaner G: The ef-fect of pirenzepine on growth hormoneand blood glucose levels in type I diabetesmellitus: a controlled study of patients onbasal bolus insulin treatment. Acta Endo-crinologica (Copenh) 117:315–319, 1988

5. El-Sabbagh HN, Bloom SR, Adrian TE,

Prinz RA, Baron JH, Welbourne RB: Theeffect of pirenzepine on meal-stimulatedgastrointestinal hormones. Scandinavian JGastroenterol 66:57–61, 1980

Improved InsulinSensitivity andMetabolic Control inType 2 DiabetesDoes Not InfluencePlasma Homocysteine

T ype 2 diabetes is characterized byboth insulin resistance and an in-creased cardiovascular mortality

(1). Elevated plasma total homocysteinelevels are an independent risk factor forcardiovascular disease (2). Also, in pa-tients with type 2 diabetes, elevatedplasma total homocysteine levels are asso-

ciated with an increased risk of cardiovas-cular disease and an increased mortality(3,4).

It is well known that insulin resis-tance is aggravated by chronic hypergly-cemia. This hyperglycemia-inducedinsulin resistance is reversed by treat-ment, resulting in a prolonged period ofeuglycemia (5).

Although in animal studies evidencewas found that hyperinsulinemia and/orinsulin resistance increased total homo-cysteine levels (6), in humans the relationbetween insulin resistance and total ho-mocysteine levels is unclear, in bothhealthy subjects (7–12) and patients withtype 2 diabetes (13–16). In patients withtype 2 diabetes, a positive association be-tween insulin resistance and total homo-cysteine levels was reported (13), but thisfinding was not reproduced (14). Fur-thermore, in patients with type 2 diabe-tes, a positive association between thedegree of metabolic control and total ho-mocysteine levels was reported (15,16).

We hypothesized that if insulin resis-tance is associated with elevated homo-cysteine levels, thereby providing anotherexplanation for the increased cardiovas-cular disease in type 2 diabetes, then ho-mocysteine levels will decrease afteramelioration of hyperglycemia-inducedinsulin resistance and associated meta-bolic abnormalities.

Here, we report the results of an in-tervention study (17). Eight obese type 2diabetic patients (aged 53 � 13 years,HbA1c 12.0 � 1.7%, BMI 38 � 5.8 kg/m2) with severe insulin resistance (subcu-taneous insulin dose, four-dose insulinregimen 1.92 � 0.66 units � kg�1 � day�1)were studied before and after a period of28 � 5 days of intravenous insulin treat-ment. Intravenous insulin treatment re-sulted in euglycemia. Before and afterintervention, insulin sensitivity was as-sessed by a hyperinsulinemic-euglycemicclamp. Fasting plasma total homocys-teine, HbA1c, and lipid concentrationswere measured on the days of the clamps.Also, 24-h urine creatinine excretion wasinvestigated before and after intervention.

Plasma total homocysteine levelswere measured with a high-performanceliquid chromatography method accord-ing to Fiskerstrand (18,19) with somemodifications. Because all variables werenormally distributed, statistical analysesof differences were performed by pairedStudent’s t test. P � 0.05 was considered

Figure 1—Day curve of plasma glucose (A) and insulin (B) concentrations after 14 days of PIR(50 mg b.i.d.) (F) and placebo (E). The vertical continuous lines represent the time when piren-zepine was administered and the interrupted lines represent the times at which breakfast, lunch,and dinner were given.

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significant. Results are given as themean � SD.

After a 4-week period of intravenousinsulin treatment resulting in an euglyce-mic period of 17 � 4 days, insulin sensi-tivity improved since body glucoseuptake, measured by clamp, increased(12.7 � 5.7 before vs. 22.4 � 8.8 �mol �kg�1 � min�1 after euglycemia, P �0.0005) and the intravenous insulin doserequired for achieving and maintainingeuglycemia decreased (1.7 � 0.9 beforevs. 1.1 � 0.6 units � kg�1 � day�1 aftereuglycemia, P � 0.005). Metabolic con-trol improved; HbA1c decreased substan-tially (12.0 � 1.7 before vs. 8.9 � 1.2%after euglycemia, P � 0.0001); total cho-lesterol decreased (5.40 � 1.09 before vs.4.50 � 1.10 mmol/l after euglycemia, P �0.05); and triglycerides tended to de-crease (4.34 � 3.32 before vs. 1.91 �0.69 mmol/l after euglycemia, P � 0.06).These results are described in detail else-where (17). Plasma total homocysteinelevels were similar before and after im-proved insulin sensitivity (total homocys-teine levels 8.5 � 2.4 before vs. 9.2 � 3.5�mol/l after euglycemia, P � 0.5). Urinecreatinine excretion was similar beforeand after euglycemia (15.0 � 4.8 beforevs. 12 � 4.3 �mol/24 h after euglycemia).

This intervention study shows thatdespite amelioration of hyperglycemia-induced insulin resistance and improvedmetabolic control, plasma total homocys-teine concentrations did not decrease.Homocysteine levels, measured in thesepatients with type 2 diabetes, were actu-ally within the normal range of healthysubjects (2).

Our study is the first interventionstudy to investigate the relation betweeninsulin resistance and plasma total homo-cysteine levels. To date only cross-sectional studies have been performed(13–15), which are more susceptible forconfounding by other metabolic factors.Also in contrast to previous reports(8,9,11,12,14,15), we studied insulinsensitivity by clamp, the gold standard.

We conclude that amelioration of hy-perglycemia-induced insulin resistancedoes not change plasma total homocys-teine levels. These data refute the hypoth-esis that homocysteine levels areinfluenced by insulin resistance and bythe degree of metabolic control, at least inthe patients we studied. Therefore, theseresults do not support elevated homocys-teine levels as an explanation for the link

between insulin resistance and the in-creased risk of cardiovascular disease intype 2 diabetes.

Acknowledgments— This study was sup-ported by a grant from the Dutch DiabetesFoundation. H.J.B. is an established investiga-tor of the Netherlands Heart Foundation(D97.021).

MARIE-JOSE J. POUWELS, MD1,2

MARTIN DEN HEIJER, MD, PHD1

HENK J. BLOM, PHD3

CEES J. TACK, MD, PHD1,2

AD R. HERMUS, MD, PHD1

From the 1Department of Endocrinology, UniversityMedical Center Nijmegen, the Netherlands; the 2De-partment of General Internal Medicine, UniversityMedical Center Nijmegen, the Netherlands; and the3Laboratory of Pediatrics and Neurology, UniversityMedical Center Nijmegen, the Netherlands.

Address correspondence to Marie-Jose Pouwels,MD, Division of General Internal Medicine, MedischSpectrum Twente, P.O. Box 50000, 7500 KA En-schede, The Netherlands. E-mail: [email protected].


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References1. Haffner SM, Lehto S, Ronnemaa T,

Pyorala K, Laakso M: Mortality from cor-onary heart disease in subjects with type 2diabetes and in nondiabetic subjects withand without prior myocardial infarction.N Engl J Med 339:229–234, 1998

2. Welch GN, Loscalzo J: Homocysteine andatherothrombosis.NEnglJMed338:1042–1050, 1998

3. Hoogeveen EK, Kostense PJ, Beks PJ,Mackaay AJC, Jakobs C, Bouter LM,Heine RJ, Stehouwer CD: Hyperhomocys-teinemia is associated with an increasedrisk of cardiovascular disease, especiallyin non-insulin-dependent diabetes melli-tus: a population-based study. ArteriosclerThromb Vasc Biol 18:133–138, 1998

4. Hoogeveen EK, Kostense PJ, Jakobs C,Dekker JM, Nijpels G, Heine RJ, BouterLM, Stehouwer CD: Hyperhomocysteine-mia increases risk of death, especially intype 2 diabetes: 5-year follow-up of thehoorn study. Circulation 101:1506–1511,2000

5. Rossetti L: Glucose toxicity. Clin InvestMed 18:255–260, 1995

6. Fonseca V, Dicker-Brown A, RanganathanS, Song W, Barnard RJ, Fink L, Kern PA:Effects of a high-fat-sucrose diet on en-zymes in homocysteine metabolism in therat. Metabolism 49:736–741, 2000

7. Giltay EJ, Hoogeveen EK, Elber JM,Gooren LJ, Asscheman H, Stehouwer CE:Insulin resistance is associated with ele-

vated plasma total homocysteine levels inhealthy, non-obese subjects. Atherosclero-sis 139:197–198, 1998

8. Meigs JB, Jacques PF, Selhub J, Singer DE,Nathan DM, Rifai N, D’Agostino RB Sr,Wilson PW: Fasting plasma homocys-teine levels in the insulin resistance syn-drome: the Framingham offspring study.Diabetes Care 24:1403–1410, 2001

9. De Pergola G, Pannacciulli n, Zamboni M,Minenna A, Brocco G, Sciaraffia M,Bosello, Giorgino R: Homocysteineplasma levels are independently associ-ated with insulin resistance in normalweight, overweight and obese pre-meno-pausal women. Diabetes Nutr Metab 14:253–258, 2001

10. Abbasi F, Facchini F, Humphreys MH,Reaven GM: Plasma homocysteine con-centrations in healthy volunteers are notrelated to differences in insulin-mediatedglucose disposal. Atherosclerosis 146:175–178, 1999

11. Bar-on H, Kidron M, Friedlander Y, Ben-Yehuda A, Selhub J, Rosenberg IH, Fried-man G: Plasma total homocysteine levelsin subjects with hyperinsulinemia. J InternMed 247:287–294, 2000

12. Godsland IF, Rosankiewicz JR, ProudlerAJ, Johnston DG: Plasma total homocys-teine concentrations are unrelated to in-sulin sensitivity and components of themetabolic syndrome in healthy men.J Clin Endocrinol Metab 86:719–723, 2001

13. Emoto M, Kanda H, Shoji T, Kawagishi T,Komatsu M, Mori K, Tahara H, IshimuraE, Inaba M, Okuno Y, Nishizawa Y: Im-pact of insulin resistance and nephropa-thy on homocysteine in type 2 diabetes.Diabetes Care 24:533–538, 2001

14. Buysschaert M, Dramais AS, WallemacqPE, Hermans MP: Hyperhomocysteine-mia in type 2 diabetes: relationship tomacroangiopathy, nephropathy, and in-sulin resistance. Diabetes Care 23:1816–1822, 2000

15. Drzewoski J, Czupryniak L, Chwatko G,Bald E: Total plasma homocysteine andinsulin levels in type 2 diabetic patientswith secondary failure to oral agents. Di-abetes Care 22:2097–2098, 1999

16. Chan NN: Homocysteine and insulin lev-els in type 2 diabetic patients (Letter). Di-abetes Care 23:1041, 2000

17. Pouwels MJ, Tack CJ, Hermus AR, Lutter-man JA: Treatment with intravenousinsulin followed by continuous subcuta-neous insulin infusion improves glycemiccontrol in severely resistant type 2 dia-betic patients. Diabet Med 20:76–79,2003

18. Fiskerstrand T, Refsum H, Kvalheim G,Ueland PM: Homocysteine and other thi-ols in plasma and urine: automated deter-mination and sample stability. Clin Chem39:263–271, 1993

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19. te Poele-Pothoff MT, van der Berg M,Franken DG, Boers GH, Jacobs C, deKroon IF, Eskes TK, Trijbels JM, Blom HJ:Three different methods for the determi-nation of total homocysteine in plasma.Ann Clin Biochem 32:218–220, 1995

The True OverallMortality ofUnselectedNephropathic Type 2Diabetic PatientsWith Mild toModerate RenalInsufficiency

D espite significant improvements intherapy over the last decade, theprognosis of nephropathic type 2

diabetic patients continues to be poor (1).In recent antihypertensive interventionstudies performed in type 2 diabetic pa-tients with overt nephropathy, the mean5-year mortality rate was �20%. In theirbesartan study published by Lewis et al.(2), the mean death rate after 54 monthsranged from 15 (irbesartan group) to16.3% (placebo group). Similar data wereobtained in the losartan study publishedby Brenner et al. (3). These results mightlead to false conclusions concerning theoverall mortality of all unselected type 2diabetic patients with overt nephropathy.In the irbesartan study, major excretioncriteria were congestive heart failure(New York Heart Association [NYHA]class III or worse) and cardiovascularevents within the last 3 months.

In accordance with the irbesartanstudy, in 1996 we recruited all nephro-pathic type 2 diabetic patients who weretreated at that time in our hospital and/orin the outpatient care unit and who ful-filled the inclusion criteria of the study(serum creatinine 1.0–3.0 mg/dl in fe-male and 1.3- 3.0 mg/dl in male patients,as well as protein excretion �1.0 g/24-hurine), without considering the usual ex-clusion criteria. We recruited 46 nephro-pathic type 2 diabetic patients (aged 61 �8 years, 26 women and 20 men, diabetesduration 17 � 4 years), and we prospec-tively studied their progression of diabeticnephropathy and the 5-year mortality rate.

Cardiovascular disease was present in43%, while 28% had heart failure (NYHA

class III and higher). Of patients, 36% hadexclusion criteria according to the irbe-sartan study. All patients underwent eval-uations in our outpatient unit (n � 24) orat the offices of their general physicians inat least 6-month intervals over an obser-vation period of 5 years. The followingparameters were routinely measured: cre-atinine in serum and 24-h urine, creati-nine clearance (calculated), protein in24-h urine, HbA1c, and blood pressure.The three end points of the study weredoubling of serum creatinine levels, end-stage renal disease, or death. Patients werealso divided into those with and withoutheart failure, and 5-year mortality rateswere assessed in both groups.

Serum creatinine had doubled in 37%of patients over 60 months, comparedwith 22% within 54 months in the irbe-sartan study. The percentage of patientswho reached end-stage renal disease was26% in our patients and 16.7% in theirbesartan study. During the period of ob-servation, mean HbA1c level in our pa-tients was 7.6 � 1.0%, while their meanblood pressure was 139 � 11/80 � 8mmHg. In the irbesartan study, the meanblood pressure at visits after baseline wassimilar, with 140/77 mmHg in the irbe-sartan group and 144/80 mmHg in theplacebo group.

The overall 5-year mortality of all ofour diabetic patients was 33%. Five-yearmortality rates were 57% in patients withheart failure (NYHA III or IV) and 22%(P � 0.05) in those without heart failure.In comparison with the data of the inter-vention studies, the mortality of our ne-phropathic type 2 diabetic patientswithout heart failure was similar to that ofthe selected patients in the irbesartanstudy. In contrast, survival was signifi-cantly lower in patients with heart failure,and as a consequence, the overall mortal-ity of all unselected type 2 diabetic pa-tients with overt nephropathy was alsohigher than that registered in the inter-vention studies. There were no significantdifferences at baseline visit in creatinineclearance (139 � 31 vs. 134 � 32 ml �min�1 � 1.73 m�2) and urinary protein(2.4 � 1.3 vs. 2.3 � 1.2 g/24 h) in thegroups with and without chronic heartfailure, respectively. The mean bloodpressure during the observation periodwas approximately the same in bothgroups (140 � 12 vs. 138 � 11 mmHg).Twenty-eight percent of the patients withand 25% of those without heart failure

reached end-stage renal disease. Our re-sults are in agreement with those of Short(4), who found, at a mean follow-up of5.3 years, a mortality rate of 37% in ne-phropathic type 2 diabetic patients com-pared with just 8% in a nonnephropathicgroup. Multivariate Cox regression anal-yses confirmed a fivefold excess risk forcardiovascular mortality in type 2 diabeticpatients with overt nephropathy. Angio-tensin II blockers have shown effectivecardiovascular protection in type 2 dia-betic patients (5).

In conclusion, the real mortality rateof all unselected type 2 diabetic patientswith overt nephropathy and mild-to-moderate renal insufficiency is muchhigher than the mortality of nephropathictype 2 diabetic patients selected for anti-hypertensive studies. The difference be-tween outcome in studies versus “real life”is mainly due to the fact that patients withheart failure are excluded from studies,but obviously present in a nonstudysituation.

GEORG BIESENBACH, MD

OTMAR JANKO, MD

From the 2nd Department of Medicine, GeneralHospital, Linz, Austria.

Address correspondence to Georg Biesenbach,MD, 2nd Department of Medicine, General Hospi-tal, Krankenhausstrasse 9, 4020 Linz, Austria. E-mail: [email protected].


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References1. Ismail N, Becker B, Strzelczyk P, Ritz E:

Renal disease and hypertension in non-insulin-dependent diabetes mellitus. Kid-ney Int 55:1–28, 1999

2. Lewis EJ, Hunsicker LG, Bain RP, ClarkeWR, Berl T, Pohl MA, Lewis JB, Ritz E,Atkins RC, Rhode R: Renoprotective effectof the angiotensin-receptor antagonistirbesartan in patients with nephropathydue to type 2 diabetes. N Engl J Med 345:851–860, 2001

3. Brenner BM, Cooper ME, Dick de Zeeuw,Keane WF, Mitch WE, Parving HH, Re-muzzi G, Snapinn SM, Zhang Z, ShahnazS, for the RENAAL Study Investigators:Effects of losartan on renal and cardiovas-cular outcomes in patients with type 2 di-abetes and nephropathy. N Engl J Med345:861–869, 2001

4. Short R: Natural history and prognosticfactors: nephropathy in type 2 diabetes. QJ Med 95:371–377, 2002

5. Deferrari G, Ravers M, Deferrari L, Vettor-etti S, Ratto E, Parodi D: Renal and cardio-

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vascular protection in type 2 diabetesmellitus: angiotensin II receptor blockers.J Am Soc Nephrol 13 (Suppl. 3):224–229,2002

HLA-DR-DQHaplotype in Rapid-Onset Type 1Diabetes inJapanese

T ype 1 diabetes is characterized bythe presence of insulitis and auto-antibodies, at least in the earlier

course of the disease. It is well known thatHLA locus confers strong genetic suscep-tibility to the disease. Imagawa et al. (1)described a unique subtype of type 1 di-abetes that shows a rapid and fulminantonset of the disease but lacks evidence ofinsulitis and autoantibodies. Althoughthe etiology of this unique subtype of type1 diabetes is unclear at present, Tanaka etal. (2) very recently reported that specificHLA-DQ genotypes may be associatedwith this subtype of type 1 diabetes. Here,we report clinical characteristics of sub-jects with type 1 diabetes of a rapid andfulminant onset who were collected fromthe registration of type 1 diabetes in ourinstitution.

We identified 19 type 1 diabetic sub-jects showing an acute and abrupt onsetof diabetes (duration of hyperglycemicsymptoms 6 � 3 days [mean � SD],range 1–10) accompanied by low HbA1clevels (6.8 � 0.9%, 5.4–8.2). The sub-jects consisted of 11 men and 8 womenaged 38 � 17 years (range 16–66) withBMI of 22.2 � 3.2 kg/m2 (17.1–27.7).Family history of diabetes (possibly type 2diabetes) was recorded in three subjects(16%). Among eight women, four mani-fested diabetes during gestation (n � 2) orjust after delivery (n � 2). History of pre-ceding upper respiratory infection wasnoted in nine subjects (47%). Despiteshort duration of subjective symptomsand low HbA1c levels, their initial concen-trations of plasma glucose was as high as34.1 � 13.2 mmol/l (range 13.6–72.4),indicating a fulminant onset of diabetes.In fact, 14 subjects showed diabetic keto-acidosis at their initial presentation (arte-rial pH 7.14 � 0.17, 6.80–7.34), and theremaining five had marked ketosis andhyperglycemia. GAD autoantibodies,

measured by commercial RIA kits (Cos-mic Corporation, Tokyo) (3), were nega-tive in 18 of the 19 subjects (�1.5 units/ml), but a single subject showed a weaklypositive level (5.6 units/ml). Insulinoma-associated protein 2 (IA2) autoantibodyand anti-thyroperoxidase and -thyroglob-ulin antibodies were negative in all sub-jects. Fasting serum level and urinaryexcretion of C-peptide were decreased to0.10 � 0.07 nmol/l (0–0.26) and 2.2 �2.1 �mol/day (0.2– 6.9), respectively,and they did not show any signs of remis-sion of insulin dependency during the ob-servation period.

As for HLA status, HLA-DRB1-DQB1genotypes were determined and com-pared with those in autoantibody (GADand/or IA2 autoantibodies)-positive sub-jects with significant type 1A diabetes(n � 87) derived from our registration.F requency o f HLA-DRB1*0405-DQB1*0401 haplotype in a homozygousmanner was significantly higher in therapid-onset group (5 of 19, 26%) than thetype 1A group (4 of 87, 5%, P � 0.009 byFisher’s exact probability). The frequencywas also far higher than that of nondia-betic Japanese subjects reported in the lit-erature (1 of 84, P � 0.001 [2] and 6 of157, P � 0.003 [4]). Frequency of othersusceptible haplotypes (DRB1*0405-DQB1*0401 in a heterozygous mannerand DRB1*0901-DQB1*0303 in a ho-mozygous manner) (4) did not differ be-tween the rapid-onset group and type 1Agroup (data not shown).

In our experience, homozygous HLA-DRB1*0405-DQB1*0401 haplotype con-fers genetic susceptibility to rapid-onsettype 1 diabetes in Japanese, consistentwith the recent report by Tanaka et al. (2).Frequency of GAD autoantibodies was ac-tually low in this subgroup of type 1 dia-betes (1,2), but a single subject showed apositive result at the onset of diabetes.There was also a case report in whichGAD autoantibodies turned positive 1year after the fulminant onset of type 1diabetes (5). Tanaka et al. (6) also dem-onstrated presence of insulitis in a case ofrapid-onset type 1 diabetes. Collectively,it is suggested that rapid-onset type 1 di-abetes could share autoimmune etiologywith type 1A diabetes (7). Of interest isthat half of the female patients developeddiabetes during or just after pregnancy.There have been many studies reportingaltered immune response during preg-nancy (8,9), and pregnancy is considered

to be a precipitating factor for type 1 dia-betes (10). We hypothesize that alteredimmune response to unknown stimulusmay be causative of rapid and aggressive-cell loss, together with the genetic sus-ceptibility, at least in part, determined byHLA-DR-DQ haplotypes.

TOMOATSU NAKAMURA, MD

SHOICHIRO NAGASAKA, MD

IKUYO KUSAKA, MD

TOSHIMITSU YATAGAI, MD

JIANMEI YANG, MD

SHUN ISHIBASHI, MD

From the Division of Endocrinology and Metabo-lism, Jichi Medical School, Tochigi, Japan.

Address correspondence to Shoichiro Nagasaka,MD, Division of Endocrinology and Metabolism, Ji-chi Medical School, Yakushiji 3311-1, Minami-kawachi, Tochigi 329-0498, Japan. E-mail:[email protected].


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References1. Imagawa A, Hanafusa T, Miyagawa J, Mat-

suzawa Y: A novel subtype of type 1 dia-betes mellitus characterized by a rapidonset and an absence of diabetes-relatedantibodies. N Engl J Med 342:301–307,2000

2. Tanaka S, Kobayashi T, Nakanishi K,Koyama R, Okubo M, Murase T, OdawaraM, Inoko H: Association of HLA-DQ ge-notype in autoantibody-negative and rap-id-onset type 1 diabetes. Diabetes Care 25:2302–2307, 2002

3. Akamine H, Komiya I, Shimabukuro T,Asawa T, Tanaka H, Yagi N, Taira T, Na-gata K, Arakaki K, Wakugami T, TakasuN, Powell MJ, Furmaniak J, Smith BR:High prevalence of GAD65 (and IA-2) an-tibodies in Japanese IDDM patients by anew immunoprecipitation assay based onrecombinant human GAD65. Diabet Med14:778–784, 1997

4. Kawabata Y, Ikegami H, Kawaguchi Y, Fu-jisawa T, Shintani M, Ono M, Nishino M,Uchigata Y, Lee I, Ogihara T: Asian-spe-cific HLA haplotypes reveal heterogeneityof the contribution of HLA-DR and -DQhaplotypes to susceptibility to type 1 dia-betes. Diabetes 51:545–551, 2002

5. Shimada A, Oikawa Y, Shigihara T, SendaT, Kodama K: A case of fulminant type 1diabetes with strong evidence of autoim-munity (Letter). Diabetes Care 25:1482–1483, 2002

6. Tanaka S, Kobayashi T, Momotsu T: Anovel subtype of type 1 diabetes mellitus.N Engl J Med 342:1835–1837, 2000

7. Lernmark A: Rapid-onset type 1 diabeteswith pancreatic excorine dysfunction.N Engl J Med 342:344–345, 2000

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8. Whitacre CC, Reingold SC, O’Looney PA:A gender gap in autoimmunity. Science283: 1277–1278

9. Elenkov IJ, Wilder RL, Bakalov VK, LinkAA, Dimitrov MA, Fisher S, Crane M,Kanik KS, Chrousos GP: IL-12, TNF-,and hormonal changes during late preg-nancy and early postpartum: implicationsfor autoimmune disease activity duringthese times. J Clin Endocrinol Metab 86:4933–4938, 2001

10. Buschard K, Buch I, Molsted-Pedersen L,Hougaad P, Kuhl C: Increased incidenceof true type 1 diabetes acquired duringpregnancy. BMJ 294:275–279, 1987

Sex, Diabetes, andStroke After CarotidEndarterectomy

While diabetes is associated withincreased risk of perioperativestroke among subjects who un-

dergo carotid endarterectomy (1–3),women and minorities have been gener-ally underrepresented in such trials (4).The North American Symptomatic Ca-rotid Endarterectomy Trial (NASCET)was a randomized study of 2,885 eligiblepatients with carotid stenosis �70% whoreceived either medical (n � 1,449) orsurgical therapy (n � 1,436 patients) (3).The median study age was 66 years, and93% of study subjects were white. Ap-proximately 30% of NASCET subjectswere female, and �22% had a history ofdiabetes, which was almost always type 2diabetes (3). The study showed that end-arterectomy safely and efficaciously re-duced the risk of stroke in symptomaticpatients with higher-grade carotid arterialstenosis when compared with medicaltherapy (3). Multivariate analysis indi-cated an increased risk of perioperativestroke in subjects with a history of diabe-tes (relative risk [RR] 2.0, 95% CI 1.2–3.1) (3). Because NASCET had a relativelyhigh proportion of both female and dia-betic subjects, we addressed the hypoth-esis that there would be differencesbetween diabetic men and women withrespect to the risk of peri- and postoper-ative complications. Subjects were subdi-vided by surgical or medical therapy andthen subdivided again by sex and diabeteshistory. End point data regarding strokesand deaths were collected.

Diabetic men had a significantly in-

creased risk of stroke or death 30 dayspostendarterectomy compared with non-diabetic men (RR 2.3, 95% CI 1.4–3.7),with no difference between diabetic andnondiabetic women (1.1, 0.5–2.4). Fur-thermore, diabetic men had a signifi-cantly increased risk of stroke 3 yearspostendarterectomy compared with non-diabetic men (RR 1.9, 95% CI 1.3–2.8),again with no difference between diabeticand nondiabetic women (1.0, 95% CI0.6–1.9). However, at 3 years postran-domization, diabetic men who receivedmedical treatment had no increased riskof stroke compared with nondiabetic men(RR 0.7, 0.5–1.1). In contrast, at 3 yearspostrandomization, diabetic women whoreceived medical treatment had a signifi-cantly increased risk of stroke comparedwith nondiabetic women (1.7, 1.1–2.8).

The results support the emerging im-pression of sex-related differences amongdiabetic subjects with respect to vasculardisease (5,6). Perioperative neurologicalmorbidity of carotid endarterectomy ismainly due to embolization at the time ofclamping or clamp release, ischemia dur-ing clamping of extracranial arteries, andintracerebral hemorrhage (7). There hasbeen a steady decrease in postoperativemorbidity among patients who undergocarotid endarterectomy as a result of bothimproved surgical technique and patientselection (7). Baseline clinical attributesare also helpful predictors of postopera-tive mortality and morbidity from stroke(3). Our analysis suggests that among di-abetic subjects who undergo carotid end-arterectomy, there may be sex-relateddifferences in postoperative neurologicalmorbidity. As with any post hoc subgroupanalysis, the results should be interpretedcautiously and must be replicated in otherstudies. However, if these findings areconfirmed, it might be appropriate toconsider sex and diabetes status in strate-gies to optimize the management of pa-tients with carotid disease (8).

ROBERT A. HEGELE, MD, FRCPC1

MICHAEL ELIASZIW, PHD2

MASSIMILIANO DE ANGELIS, MD3

From the 1Robarts Research Institute, London, On-tario, Canada; the 2Department of CommunityHealth Sciences, Faculty of Medicine, University ofCalgary, Calgary, Alberta, Canada; and the 3Depart-ment of Internal Medicine, Endocrinology and Me-tabolism Section, University of Perugia, Perugia, Italy.

Address correspondence to Dr. Robert Hegele,

Robarts Research Institute, London, Ontario N6A5K8, Canada. E-mail: [email protected].


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References1. Salenius JP, Harju E, Riekkinen H: Early

cerebral complications in carotid endar-terectomy: risk factors. J Cardiovasc Surg31:162–167, 1990

2. Akbari CM, Pomposelli FBJ, GibbonsGW, Campbell DR, Freeman DV, LoGerfoFW: Diabetes mellitus: a risk factor forcarotid endarterectomy? J Vasc Surg 25:1070–1075, 1997

3. Barnett HJ, Taylor DW, Eliasziw M, FoxAJ, Ferguson GG, Haynes RB, Rankin RN,Clagett GP, Hachinski VC, Sackett DL:Benefit of carotid endarterectomy in pa-tients with symptomatic moderate or severestenosis: North American SymptomaticCarotid Endarterectomy Trial Collabora-tors. N Engl J Med 339:1415–1425, 1998

4. Rigdon EE: Racial and sex differences inoutcome after carotid endarterectomy.Am Surg 64:527–530, 1998

5. Anderson KM, Odell PM, Wilson PW,Kannel WB: Cardiovascular disease riskprofiles. Am Heart J 121:293–298, 1991

6. Wilson PW: Diabetes mellitus and coro-nary heart disease. Am J Kidney Dis 32:S89–S100, 1998

7. Riles TS, Imparato AM, Jacobowitz GR,Lamparello PJ, Giangola G, Adelman MA,Landis R: The cause of perioperativestroke after carotid endarterectomy. J VascSurg 19:206–214, 1994

8. Barnett HJ, Meldrum HE, Eliasziw M,North American Symptomatic CarotidEndarterectomy Trial (NASCET) collabo-rators: The appropriate use of carotidendarterectomy. CMAJ 166:1169–1179,2002

The DiabetesEmpowerment Scale–Short Form (DES-SF)

In 2000 we developed the Diabetes Em-powerment Scale (DES) to measure thepsychosocial self-efficacy of people

with diabetes. The original questionnairecontained 37 items representing eightconceptual dimensions (i.e., assessing theneed for change, developing a plan, over-coming barriers, asking for support, sup-porting oneself, coping with emotion,motivating oneself, and making diabetescare choices appropriate for one’s priori-ties and circumstances). Using factoranalyses the questionnaire was reduced tothe current 28-item DES ( � 0.96) con-

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taining three subscales (1). The three sub-scales are: 1) managing the psychosocialaspects of diabetes with 9 items ( �0.93), 2) assessing dissatisfaction andreadiness to change with 9 items ( �0.81), and 3) setting and achieving goalswith 10 items ( � 0.91). In addition toproviding an overall assessment of dia-betes-related psychosocial self-efficacy,the three subscales of the DES allow for anexamination of its underlying components.

To allow for a brief overall assessmentof diabetes-related psychosocial self-efficacy, we developed an eight-item shortform of the DES (the DES-SF). TheDES-SF was created by choosing the itemfrom the remaining 28 items with highestitem to subscale correlation from each ofthe original eight conceptual domains.The reliability of the DES-SF using theoriginal dataset was � 0.85. We havesubsequently administered the DES-SF to229 subjects in a new study. The reliabil-ity of the DES-SF using the data from thenew sample was � 0.84. The contentvalidity of the DES-SF was supported inthe new study by the fact that bothDES-SF scores and HbA1c levels changedin a positive direction after the 229 sub-jects completed a 6-week problem-basedpatient education program (2). Thechange in DES-SF scores and HbA1c levelswere not correlated, suggesting that thesetwo measures vary independently.

These data provide preliminary evi-dence that the DES-SF is a valid and reli-able measure of overall diabetes-relatedpsychosocial self-efficacy. The DES andthe DES-SF, scoring information, andpermission to use them can be down-loaded from the Michigan Diabetes Re-search and Training Center web site at:www.med.umich.edu/mdrtc.

ROBERT M. ANDERSON, EDD1

JAMES T. FITZGERALD, PHD1

LARRY D. GRUPPEN, PHD1

MARTHA M. FUNNELL, MS, RN, CDE2

MARY S. OH, BS1

From the 1University of Michigan, DRTC, Depart-ment of Medical Education, Ann Arbor, Michigan;and the 2University of Michigan, Diabetes Researchand Training Center, Ann Arbor, Michigan.

Address correspondence to Robert M. Anderson,Department of Medical Education, G1100 TowsleyCenter, 1500 East Medical Center Dr., Ann Arbor,MI 48109-0201. E-mail: [email protected].


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References1. Anderson RM, Funnell MM, Fitzgerald JT,

Marrero DG: The diabetes empowermentscale: a measure of psychosocial self-effi-cacy. Diabetes Care 23:739–743, 2000

2. Anderson RM, Funnell MM, Nwankwo R,Gillard ML, Fitzgerald JT, Oh M: Eval-uation of a problem-based, culturallyspecific, patient education program forAfrican Americans with diabetes (Ab-stract). Diabetes 50 (Suppl. 2):A195, 2001

Increased OxidativeStress Is AssociatedWith ElevatedPlasma Levels ofAdrenomedullin inHypertensivePatients With Type 2Diabetes

P revious studies have demonstratedthat oxidative stress is associated notonly with hyperglycemia and hyper-

tension but also with the metabolic syn-drome and cadiovascular disease (1–3).

Adrenomedullin (AM) is a novel va-sorelaxant peptide isolated from humanpheochromocytoma (4,5). Oxidativestress enhances AM production from en-dothelium and vascular smooth musclecells in vitro (6,7). However, whether ox-idative stress is associated with circulatinglevels of AM in vivo is unknown. In thepresent study, we evaluated the relation-ship between the plasma levels of 8-epi-prostaglandinF2 (8-epi-PGF2;currently regarded as the most reliablemarker for the assessment of oxidativestress in humans) (8,9) and AM in normalsubjects and hypertensive patients withtype 2 diabetes.

This study comprised 17 hyperten-sive patients with type 2 diabetes (15 menand 2 women, age 47.3 � 3.0 years[mean � SE], BMI 23.2 � 0.8 kg/m2, fast-ing plasma glucose 8.2 � 0.5 mmol/l,HbA1c 9.9 � 0.5%, fasting serum insulin30.6 � 3.0 pmol/l, systolic blood pres-sure 150.2 � 3.4 mmHg, and diastolicblood pressure 76.5 � 2.2 mmHg) and18 normal subjects (17 men and 1women, age 43.0 � 1.9 years, BMI 23.8 �0.4 kg/m2, fasting plasma glucose 5.1 �0.2 mmol/l, fasting serum insulin 31.2 �

3.6 pmol/l, systolic blood pressure126.8 � 2.2 mmHg, and diastolic bloodpressure 79.8 � 1.6 mmHg). All subjectswere nonsmokers. Hypertensive patientswith type 2 diabetes were diagnosed at alocal clinic 3.0 � 0.2 years before the be-ginning of this study. All patients weretreated with diet (1,440–1,720 kcal/dayand sodium restriction 304 mmol/day)and exercise (walking 10,000 steps/day);none of them were receiving any kind ofdrug. Their blood glucose and blood pres-sure were in good control (HbA1c �6.5%,systolic blood pressure �140 mmHg, anddiastolic blood pressure �90 mmHg)during the initial several months. How-ever, thereafter the blood glucose andblood pressure of the patients graduallyincreased (HbA1c �8%, systolic bloodpressure �140 mmHg, and diastolicblood pressure �90 mmHg) because ofovereating and inactivity. They were re-ferred to our clinical department for con-trol of hyperglycemia and hypertension.None of them had evidence of micro- ormacroangiopathy. Informed consent wasobtained from all subjects before the be-ginning of the study. Plasma levels of free8-epi-PGF2 were measured using acommercially available enzyme immuno-assay kit (Cayman Chemical, Ann Arbor,MI). The detection limit of this assay was1.5 pg/ml, and the intra- and interassaycoefficients of variation were 7.5 and9.2%, respectively. AM in plasma sampleswas measured using a commercially avail-able immunoradiometric assay kit(Shionogi Pharmaceuticals, Osaka, Ja-pan). The detection limit of this assay was2 fmol/ml, and the intra- and interassaycoefficients of variation were 7.0 and6.9%. Serum insulin was measured usingan immunoradiometric assay kit (InsulinRiabead II kit; Dainabot, Tokyo). The in-tra- and interassay coefficients of varia-tion of the assay were 1.9 and 2.0%. Inaddition, we measured blood pressure insupine position after a 5-min rest.

Both plasma levels of 8-epi-PGF2and AM were significantly increased inhypertensive patients with type 2 diabetescompared with normal subjects (8-epi-PGF2 48.6 � 8.6 vs. 11.9 � 1.3 pg/ml,P � 0.05; AM 14.8 � 0.7 vs. 12.4 � 0.2fmol/ml, P � 0.02). The plasma levels of8-epi-PGF2 were proportionally corre-lated with AM (r � 0.696, P � 0.01) inonly hypertensive patients with type 2 di-abetes. Significant positive correlationswere observed between plasma levels of

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8-epi-PGF2 (r � 0.540, P � 0.05) orAM (r � 0.875, P � 0.001) and systolicblood pressure in patients with type 2 di-abetes.

This is the first report that demon-strated a relationship between oxidativestress and AM in vivo. The mechanism bywhich plasma levels of 8-epi-PGF2 cor-relate with AM and the cellular source ofAM remain unknown. Previous studieshave shown that oxidative stress stimu-lates secretion of AM from endotheliumand vascular smooth muscle cells and thatAM mRNA expression is increased by ac-tivation of the nuclear factor-�B pathway(6,7). Increased AM secretion from endo-thelium and vascular smooth muscle mayinfluence the plasma levels of AM. On theother hand, Shimosawa et al. (10) re-ported that endogenous AM may protectfrom organ damage by inhibiting oxida-tive stress production. Increased AM lev-els may compensate for oxidative stress–induced vasoconstriction and thus mayplay a protective role against organ injury.Adrenal medulla and pancreatic isletsmay also be a source of AM (4,11). Fur-ther study is needed to clarify the sourceof plasma AM and the mechanism of cor-relation between oxidative stress and AM.

In conclusion, there was a significantpositive correlation between increasedoxidative stress and elevated plasma lev-els of AM in hypertensive patients withtype 2 diabetes. Enhanced oxidative stressmay regulate the plasma levels of AM inhypertensive patients with type 2 diabetes.

AKIRA KATSUKI, MD1

YASUHIRO SUMIDA, MD1

HIDEKI URAKAWA, MD1

ESTEBAN C. GABAZZA, MD1

NORIKO MARUYAMA, MD1

KOHEI MORIOKA, MD1

NAGAKO KITAGAWA, MD1

YASUKO HORI, MD1

KANAME NAKATANI, MD2

YUTAKA YANO, MD1

YUKIHIKO ADACHI, MD1

From the 1Third Department of Internal Medicine,Mie University School of Medicine, Mie, Japan; andthe 2Department of Laboratory Medicine, Mie Uni-versity School of Medicine, Mie, Japan.

Address correspondence to A. Katsuki, MD,Third Department of Internal Medicine, Mie Univer-sity School of Medicine, 2-174 Edobashi, Tsu, Mie514-8507, Japan. E-mail: [email protected].


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References1. Ceriello A, Bortolotti N, Motz E, Crescen-

tini A, Lizzio S, Russo A, Tonutti L,Taboga C: Meal-generated oxidative stressin type 2 diabetic patients. Diabetes Care21:1529–1533, 1998

2. Yasunari K, Maeda K, Nakamura M, Yo-shikawa J: Oxidative stress is a possiblelink between blood pressure, blood glu-cose, and C-reacting protein. Hypertension39:777–780, 2002

3. Evans JL, Goldfine ID, Maddux BA, Grod-sky GM: Oxidative stress and stress-acti-vated signaling pathways: a unifyinghypothesis of type 2 diabetes. Endocr Rev23:599–622, 2002

4. Kitamura K, Kangawa K, Kawamoto M,Ichiki Y, Nakamura S, Matsuo H, Eto T:Adrenomedullin: a novel hypotensivepeptide isolated from human pheochro-mocytoma. Biochem Biophys Res Commun192:553–560, 1993

5. Kinoshita H, Kato K, Kuroki M, Naka-mura S, Kitamura K, Hisanaga S, Fuji-moto S, Eto T: Plasma adrenomedullinlevels in patients with diabetes (Letter).Diabetes Care 23:253–254, 2000

6. Chun T-H, Itoh H, Saito T, Yamahara K,Doi K, Mori Y, Ogawa Y, Yamashita J,Tanaka T, Inoue M, Masatsugu K, SawadaN, Fukunaga Y, Nakao K: Oxidative stressaugments secretion of endothelium-de-rived relaxing peptides, C-type natriureticpeptide and adrenomedullin. J Hypertens18:575–580, 2000

7. Ando K, Ito Y, Kumada M, Fujita T: Oxi-dative stress increases adrenomedullinmRNA levels in cultured rat vascularsmooth muscle cells. Hypertens Res 21:187–191, 1998

8. Sampson MJ, Gopaul N, Davies IR,Hughes DA, Carrier MJ: Plasma F2 iso-prostanes, direct evidence of increasedfree radical damage during acute hyper-glycemia in type 2 diabetes. Diabetes Care25:537–541, 2002

9. Gopaul NK, Manraj MD, Hebe A, KwaiYan SL, Johnston A, Carrier MJ, AnggardEE: Oxidative stress could precede endo-thelial dysfunction and insulin resistancein Indian Mauritians with impaired glucosemetabolism. Diabetologia 44:706–712, 2001

10. Shimosawa T, Shibagaki Y, Ishibashi K,Kitamura K, Kangawa K, Kato S, Ando K,Fujita T: Adrenomedullin, an endogenouspeptide, counteracts cardiovascular dam-age. Circulation 105:106–111, 2002

11. Katsuki A, Sumida Y, Gabazza EC, Mu-rashima S, Urakawa H, Morioka K, Kita-gawa N, Tanaka T, Araki-Sasaki R, Hori Y,Nakatani K, Yano Y, Adachi Y: Acute hyper-insulinemia is associated with increasedcirculating levels of adrenomedullin inpatients with type 2 diabetes mellitus. EurJ Endocrinol 147:71–75, 2002

Renin-AngiotensinSystem GenePolymorphisms andRetinopathy inChinese PatientsWith Type 2Diabetes

D iabetic eye disease is the leadingcause of new cases of blindness inmany developed countries, for

which macular edema and proliferativeretinopathy are major causes of loss of vi-sion (1). Genetic studies have previouslysuggested that diabetic retinopathy ispartly determined by genetic factors (2).Angiotensin II, produced locally withinthe retina, has potent hemodynamic andgrowth-promoting effects and stimulatesocular neovascularization (3,4). The pres-ence of retinopathy is associated with anactivated renin-angiotensin system (RAS)(5), and inhibition of the RAS signifi-cantly reduced the progression of reti-nopathy in nonhypertensive patients withtype 1 diabetes (6). The ACE gene inser-tion/deletion (I/D) polymorphism hasbeen reported to be associated with reti-nopathy in type 1 diabetic subjects, butthe findings are heterogeneous (7,8).Only limited data are available describingthe angiotensinogen (AGT) M235T andthe angiotensin II type 1 receptor (AT1R)A1166C polymorphisms and retinopathy(9,10).

In this study, we examined the asso-ciations between these three polymor-phisms and diabetic retinopathy in 827Chinese type 2 diabetic patients (based on1985 World Health Organization crite-ria). All subjects gave written informedconsent and were of Han Chinese origin.They were examined by the physicians orophthalmologists through dilated pupils.Retinopathy was considered to be presentif there was one or more areas of hemor-rhages, microaneurysms, cotton woolspots, and/or laser coagulation scars re-lated to diabetic retinopathy or history ofvitrectomy (11). The RAS genotype andallele frequencies were identified usingPCR/restriction fragment–length poly-morphism protocols (12) in 326 patientswith retinopathy and 501 diabetic pa-tients without retinopathy who werematched for age (59.8 � 11.4 vs. 60.4 �

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9.3 years), sex (44.2 female vs. 39.3%male), disease duration (6.3 [range 5.6–7.0] vs. 6.0 years [5.6–6.3]), and age ofonset of diabetes (53.2 � 9.7 vs. 51.9 �12.4 years). Of those with retinopathy,66.6% had nonproliferative, 8.3% pre-proliferative, and 8.9% proliferative dis-ease and 16.2% had advanced eye disease.Of the patients, 30.1% with retinopathyhad received laser therapy in at least oneeye, with 18.7, 29.2, 53.8, and 69.4% be-ing treated in the groups with increasingseverity of retinopathy.

The allele frequencies were 32.7 and32.1% for the ACE D allele, 16.1 and13.8% for the AGT M allele, and 4.6 and3.4% for the AT1R C allele in those with-out and with retinopathy, respectively.The genotype distributions for these genepolymorphisms are described in Table 1.No differences were identified in the ge-notype or allele frequencies between thegroups either for the dichotomous classi-fication of retinopathy or when the sever-ity of the retinopathy was graded.

The ACE D allele has been associatedwith increasing ACE levels (12). Subjectswith the angiotensinogen M235T poly-morphism TT genotype have increasedserum AGT levels, while the AT1R 1166Callele is associated with enhanced respon-siveness to angiotensin II (13). The ACEDD genotype was found to be associatedwith the presence of proliferative retinop-athy in a relatively small case-controlstudy of type 1 diabetic subjects (7). Inthe current study, the analysis compar-ing age-, sex-, and diabetes duration–matched subjects found no evidence ofassociations between the distribution ofgenotypes or alleles of these RAS genepolymorphisms and retinopathy. Ourdata support the majority of the literatureregarding the ACE I/D gene polymor-phism, which has reported no significantassociation with retinopathy in diabeticpatients (7,8).

G. NEIL THOMAS, PHD1

JULIAN A.J.H. CRITCHLEY, FRCP1

BRIAN TOMLINSON, FRCP1

VINCENT T.F. YEUNG, MD1

DENNIS LAM, MD2

CLIVE S. COCKRAM, FRCP1

JULIANA C.N. CHAN, FRCP1

From the 1Department of Medicine and Therapeu-tics, The Chinese University of Hong Kong, ThePrince of Wales Hospital, Shatin, Hong Kong; andthe 2Department of Ophthalmology and Visual Sci-ence, The Chinese University of Hong Kong, ThePrince of Wales Hospital, Shatin, Hong Kong.

Address correspondence to G. Neil Thomas, De-partment of Medicine and Therapeutics, The Princeof Wales Hospital, Shatin, Hong Kong. E-mail:[email protected].

J.A.J.H.C. is deceased.© 2003 by the American Diabetes Association.

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References1. Klein R, Klein BEK, Moss SE: Visual im-

pairment in diabetes. Ophthalmology 91:1–9, 1984

2. Leslie RD, Pyke DA: Diabetic retinopathyin identical twins. Diabetes 31:19–21, 1982

3. Fernandez LA, Twickler J, Mead A: Neo-vascularisation produced by angiotensinII. J Lab Clin Med 105:141–145, 1985

4. Danser AH, Derkx FH, Admiraal PJ, Dei-num J, de Jong PT, Schalekamp MA:Angiotensin levels in the eye. Invest Oph-thalmol Vis Sci 35:1008–1018, 1994

5. Migdalis IN, Iliopoulou V, Kalogeropou-lou K, Koutoulidis K, Samartzis M:Elevated serum levels of angiotensin-con-verting enzyme in patients with diabeticretinopathy. South Med J 83:425–427, 1990

6. Chaturvedi N, Sjolie A-K, Stephenson JM,Abrahamian H, Keipes M, Castellarin A,Rogulja-Pepeonik Z, Fuller J, the EUCLIDStudy Group: Effect of lisinopril on pro-gression of retinopathy in normotensivepeople with type 1 diabetes. Lancet 351:28–31, 1998

7. Rabensteiner D, Abrahamian H, IrsiglerK, Hermann KM, Kiener HP, Mayer G,Kaider A, Prager R: ACE gene polymor-phism and proliferative retinopathy in

type 1 diabetes: results of a case-controlstudy. Diabetes Care 22:1530–1535, 1999

8. Fujisawa T, Ikegami H, Kawaguchi Y,Hamada Y, Ueda H, Shintani M, FukudaM, Ogihara T: Meta-analysis of associa-tion of insertion/deletion polymorphismof angiotensin I-converting enzyme genewith diabetic nephropathy and retinopa-thy. Diabetologia 41:47–53, 1998

9. Tarnow L, Cambien F, Rossing P, NielsenFS, Hansen BV, Ricard S, Poirer O, Parv-ing HH: Angiotensin II type 1 receptorgene polymorphism and diabetic micro-angiopathy. Nephrol Dial Transplant 11:1019–1023, 1996

10. Staessen JA, Kuznetsova T, Wang JG,Emelianov D, Vlietinck R, Fagard R:M235T angiotensinogen gene polymor-phism and cardiovascular renal risk. J Hy-pertens 17:9–17, 1999

11. Ko GTC, Chan JCN, Lau MSW, CockramCS: Diabetic microangiopathic complica-tions in young Chinese diabetic patients: aclinic-based cross-sectional study. J Dia-betes Complications 13:300–306, 1999

12. Thomas GN, Critchley JAJH, TomlinsonB, Lee ZSK, Young RP, Chan JCN: Al-buminuria and the renin-angiotensinsystem gene polymorphisms in type 2diabetic and in normoglycaemic hyper-tensive Chinese. Clin Nephrol 55:7–15,2001

13. Peters J: Molecular basis of human hyper-tension: the role of angiotensin. BaillieresClin Endocrinol Metab 9:657–678, 1995

Prevalence of Type 1Diabetes–RelatedAutoantibodies inAdults With CeliacDisease

S tudies have shown a 4% prevalenceof celiac disease in type 1 diabeticpatients. Few data, however, are

available on the prevalence of type 1 dia-betes–related antibodies in patients withceliac disease, with studies being limitedby the recruitment of low numbers ofchildren only (1,2). We have assessedprevalence of type 1 diabetes–related au-toantibodies (islet cell antibody [ICA],GAD antibody [GADA], and antibodies tothe protein tyrosine phosphatase–relatedIA-2 [anti-IA2]) in a cohort of 378 nondi-abetic adults with celiac disease (89 un-treated and 289 treated with a gluten-freediet), aged 33.9 � 14.7 years (range15.7–81.3), who were cared for at ouroutpatient clinic. Known duration of glu-

Table 1—Genotype distributions for the ACE I/D, AGT M235T, and angiotensin type 1receptor A1166C gene polymorphisms in type 2 diabetic patients without and with retinopathy

GenotypesNo

retinopathyRetinopathy

(total) Nonproliferative

Advanced retinopathy(pre, proliferative,

advanced)

n 501 326 225 101ACE DD/ID/II 11.6/42.3/46.1 12.3/39.6/48.2 11.4/37.8/50.7 14.9/42.6/42.6AGT TT/MT/MM 69.7/28.5/1.7 74.2/24.0/1.8 75.0/23.8/1.2 77.0/20.7/2.3AT1R AC/AA 9.2/90.8 6.6/93.4 8.1/91.9 6.5/93.5

No significant differences were identified between the groups.

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ten withdrawal was �5 years in 146(48.2%), 5–9 years in 54 (17.8%), and�9 years in 103 (34.0%) patients. GADAswere measured by a radioligand assay us-ing human recombinant GAD 65 as anti-gen (Medipan Diagnostica, Selchow,Germany), ICAs by indirect immunoflu-orescence on frozen sections of humanblood group 0 pancreas with fluoresceinisothiocyanate-conjugated rabbit anti-bodies, and anti-IA2 by a radioligand as-say using highly purified humanrecombinant IA2 labeled with 125I (Medi-pan Diagnostica).

Of 289 treated nondiabetic patients,26 had type 1 diabetes–related autoanti-bodies, giving a prevalence of 9.0% (95%CI 6.7–12.3). All of them, however,showed no more than one marker positiv-ity (2.8% ICA, 3.1% GADA, 3.1% anti-IA2). Untreated celiac patients had asimilar prevalence (10.0%, P � 0.75). Inlinear regression analysis, levels of anti-IA2 were linearly associated with dura-tion of celiac disease ( � 0.002, P �0.05). In logistic regression analysis, du-ration of gluten withdrawal was indepen-dently associated with a prevalence oftype 1 diabetes–related autoantibodies.With respect to duration �5 years, a four-fold increased risk in patients with dura-tion �9 years was found (95% CI 1.51–10.6), even after adjustment for age, sex,presence of other autoimmune diseases,and compliance to diet. In a mean fol-low-up time of 3.0 � 1.3 years (range1.3–6.5), however, no incident case oftype 1 diabetes was diagnosed in eitherpatients with (79.0 person-years) or with-out (782.7 person-years) autoimmunemarkers.

In conclusion, this study shows thatprevalence of type 1 diabetes–related au-toantibodies in adults with celiac diseaseis high (9.0%), even after dietary glutenwithdrawal, and that it increases overtime but is associated with low risk of pro-gression to diabetes. These findings areconsistent with a role of common geneticsusceptibility of both diseases, such asfactors involved in intestinal permeabil-ity. Case-control studies show associationbetween various dietary factors and risk oftype 1 diabetes (3). Dietary gluten couldact as modifier rather than determinant oftype 1 diabetes, facilitating the progres-sion of other dietary factors to the laminapropria, where they activate the autoim-mune response against -cells.

GRAZIELLA BRUNO, MD

SILVIA PINACH, MD

SILVIA MARTINI, MD

MAURIZIO CASSADER, MD

GIANFRANCO PAGANO, MD

CARLA SATEGNA GUIDETTI, MD

From the Department of Internal Medicine, Univer-sity of Torino, Torino, Italy.

Address correspondence to Dr. Graziella Bruno,Department of Internal Medicine, Turin University,corso Dogliotti 14, I-10126 Torino, Italy. E-mail:[email protected].


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References1. Di Mario U, Anastasi E, Mariani P, Ballati

G, Perfetti R, Triglione P, Morellini M,Bonamico M: Diabetes-related autoanti-bodies do appear in children with coeliacdisease. Acta Paediatr 81:593–597, 1992

2. Galli-Tsinopoulou A, Nousia-ArvanitakisS, Dracoulacos D, Xefteri M, KaramouzisM: Autoantibodies predicting diabetesmellitus type 1 in celiac disease. Horm Res52:119–124, 1999

3. Dahlquist GG, Blom LG, Persson LA, Sad-strom AI, Wall SG: Dietary factors and therisk of developing insulin dependent dia-betes in childhood. BMJ 300:1302–1306,1990

Glycemic RelapseAfter an IntensiveOutpatientIntervention for Type2 Diabetes

The effectiveness of interventions thatreduce hyperglycemia in patientswith diabetes (1,2) is limited by the

tendency for glycemic relapse after the in-tervention ends. We sought to character-ize the occurrence of glycemic relapseafter initial improvement and to describepredictors of relapse.

Glycemic relapse was evaluated in265 consecutive patients with type 2 dia-betes who participated in a 3-month in-tensive outpatient intervention and werefollowed at least 1 year after completion ofthe intervention. Details of the interven-tion have been previously described (3).All had HbA1c �8% before the interven-tion and had achieved marginal glycemiccontrol (nadir HbA1c �8%) after the in-tervention. Glycemic relapse was definedas a subsequent HbA1c �8% and an ab-

solute increase of at least 1% above thepostintervention nadir HbA1c. All datawere analyzed using SAS 8.12 (SAS Insti-tute, Cary, NC).

The mean � SD age was 56 � 13.4years; 54% were women; 71% were Cau-casian; and 27% were African American.The mean duration of diabetes was 6.4 �8.4 years. Mean BMI was 32.2 � 8.6 kg/m2. The mean HbA1c before interven-tion was 10.1 � 1.7%. The mean HbA1cnadir after intervention was 6.8 � 0.7%.Twenty-five percent were receiving insu-lin therapy before the intervention, andan additional 25% initiated insulin duringthe program.

The cumulative incidence of relapseat 1 year was 25%. The initiation of insu-lin therapy during the intervention wasthe only identifiable independent predic-tor of relapse (hazard ratio 1.96, 95% CI1.02–3.74). Female sex, African-American race, duration of diabetes, lackof weight loss during the intervention pe-riod, and the levels of HbA1c before theintervention and at nadir after the inter-vention increased the risk of relapse inunivariate analysis, but these associationswere not statistically significant in multi-variate modeling. For those patients whorelapsed, the median time to relapse was 9months. Kaplan-Meier plots estimatedthat 50% of the population would relapseby 30.3 months.

Twenty-five percent of type 2 patientswho attained satisfactory glycemic con-trol after an intensive outpatient interven-tion relapsed within a year. Patients whoinitiated insulin therapy during the inter-vention had an almost double risk of re-lapse. Future studies should characterizesocial and behavioral variables as well asthe frequency and type of insulin in orderto better understand the relapse process.In the interim, this high-risk subgroupshould receive priority for continuation ofintensive care or other relapse preventivemeasures.

Acknowledgments— This study was sup-ported in part by NIDDK P60DK20593, theAmerican Diabetes Association, and the Rob-ert Wood Johnson Foundation.

TOM A. ELASY, MD, MPH1

ALAN L. GRABER, MD1

KATHLEEN WOLFF, RN, MSN2

ANNE BROWN, RN, MSN2

AYUMI SHINTANI, PHD1

Letters


From the 1Department of Medicine, Vanderbilt Uni-versity School of Medicine, Nashville, Tennessee;and 2Vanderbilt University School of Nursing,Nashville, Tennessee.

Address correspondence to Tom A. Elasy, S1121MCN, Department of Medicine, Vanderbilt Univer-sity School of Medicine, Nashville, TN 37232-2587.E-mail: [email protected].


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References1. The Diabetes Control and Complications

Trial Research Group: The effect of inten-sive treatment of diabetes on the develop-ment and progression of long-termcomplications in insulin-dependent dia-betes mellitus. N Engl J Med 329:977–986,1993

2. UK Prospective Diabetes Study (UKPDS)Group: Intensive blood-glucose controlwith sulphonylureas or insulin comparedwith conventional treatment and risk ofcomplications in patients with type 2 di-abetes (UKPDS 33). Lancet 352:837–853,1998

3. Graber AL, Elasy TA, Quinn D, Wolff K,Brown A: Improving glycemic control inadults with diabetes mellitus: shared re-sponsibility in primary care practices.South Med J 95:684–690, 2002

Gestational GlucoseIntolerance inMultiple Pregnancy

Twin pregnancies have been associ-ated with adverse obstetric and neo-natal outcomes. The incidence of

respiratory distress syndrome in the new-borns of multiple pregnancy patients isprobably related to the higher incidenceof preterm delivery. However, the com-plications of twin pregnancies are notlimited to infants; miscarriages, pre-eclampsia, anemia, placenta previa, poly-hydramnios, and premature rupture ofmembranes are more frequent than in sin-gleton pregnancy. There have been a fewreports that test the hypothesis that mul-tiple gestation could also be a risk factorfor gestational diabetes (1– 6). Thesestudies utilized various criteria for diag-nosing gestational diabetes (WorldHealth Organization [1], National Diabe-tes Data Group [2–4], and Carpenter andCoustan [7]) and did not report the per-centage of the positive glucose challengetest for each group.

To determine the prevalence of gesta-

tional diabetes (using the Carpenter andCoustan criteria) in singleton and twinpregnancies in a cohort population ofwomen who had had screening for ges-tational diabetes from January 1990 toJanuary 2000, we started a retrospec-tive study on 2,554 pregnant womenscreened for gestational diabetes in theDepartment of Obstetrics and Gynecol-ogy of our University Hospital. Of these,70 were multiple pregnancies. A 50-g oralglucose challenge test was performed be-tween 24 and 28 weeks’ gestation, and a1-h value �135 mg/dl was consideredpositive and followed by a 100-g oral glu-cose tolerance test. The results were inter-preted according to the Carpenter andCoustan threshold values (95, 180, 155,and 140 mg/dl) at fasting and after 1, 2,and 3 h, respectively. If two thresholdswere met or exceeded, then the diagnosisof gestational diabetes was made. Age, fa-milial or personal anamnestic factors, par-ity, and BMI at first visit, all consideredrisk factors for GDM, were recorded inour database. A positive glucose challengetest occurred in 520 of 2,554 pregnantwomen (20.3%). The test was positive in22 of 70 (31.4%) multiple pregnanciesand 498 of 2,484 (20.0%) singleton preg-nancies (P � 0.029). The rates of GDMwere 80 of 2,484 (3.6%) in singleton and4 of 70 (5.7%) in twin pregnancies (P �0.416). No statistically significant differ-ences exist for the maternal risk factors forGDM between the two groups.

The decreased insulin sensitivity inpregnancy may be modified by severalfactors, such as diet, BMI, maternal age,and the placental mass, all of which mayplay a role affecting -cell function andsensitivity to insulin. It has been sug-gested that in multiple pregnancies withtwo placentas or one that is larger, theincidence of gestational diabetes may beincreased (3,4,6). Our data show that inour Sicilian population, twin pregnancycannot be considered a proven risk factorfor gestational diabetes. In fact, the differ-ences (3.6 vs. 5.7%) are not statisticallydifferent. Our data showed that one-thirdof twin pregnancies (22 of 70, 31.4%)manifest a positive glucose challenge test,as compared with 20% of singleton preg-nancies (498 of 2,484). It seems possiblethat with a larger sample size, the differ-ence in incidence of gestational diabetesmight have been statistically significant,although of questionable clinical signifi-

cance. Another hypothesis could be thatthe greater relative elevation of anti-insulin placental hormone levels in a twingestation may precipitate a mild degree ofglucose intolerance in a woman whowould have been normal with a singletonpregnancy. If this were the case, the im-pact of such a mild degree of glucose in-tolerance remains undetermined.

Acknowledgments— The authors thankProf. D.R. Coustan (Brown University, Provi-dence, RI) for critical reading of the manu-script.

FRANCESCO CORRADO, MD

FRANCESCO CAPUTO, MD

GRAZIELLA FACCIOLA, MD

ALFREDO MANCUSO, MD

From the Department of Obstetrics and Gynecol-ogy, University of Messina, Messina, Italy.

Address correspondence to F. Corrado, MD, De-partment of Obstetrics and Gynecology, PoliclinicoUniversitario “G. Martino” 98100, Messina, Italy. E-mail: [email protected].


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References1. Wein P, Warwick MM, Beisher NA: Ges-

tational diabetes in twin pregnancy: prev-alence and long-term implications. AustNZ J Obstet Gynecol 32:325–327, 1992

2. Henderson CE, Scarpelli S, La Rosa D, Di-von MY: Assessing the risk of gestationaldiabetes in twin gestation. J Natl Med As-soc 87:757–758, 1995

3. Roach VJ, Lau TK, Wilson D, Rogers MS:The incidence of gestational diabetes inmultiple pregnancy. Aust NZ J Obstet Gy-necol 38:56–57, 1998

4. Schwartz DB, Daoud Y, Zazula P, GoyertG, Bronsteen R, Wright D, Copes J: Ges-tational diabetes mellitus: metabolic andblood glucose parameters in singletonversus twin pregnancies. Am J Obstet Gy-necol 181:912–914, 1999

5. Egeland GM, Irgens LM: Is multiple birthpregnancy a risk factor for gestational di-abetes? (Letter). Am J Obstet Gynecol 185:1275–1276, 2001

6. Sivan E, Maman E, Homko CJ, Lipitz S,Cohen S, Schiff E: Impact of fetal reduc-tion on the incidence of gestational diabe-tes. Obstet Gynecol 99:91–94, 2002

7. Carpenter MW, Coustan DR: Criteria forscreening test for gestational diabetes.Am J Obstet Gynecol 144:768–773, 1982

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Cytokine MilieuTends TowardInflammation inType 2 Diabetes

I t has been postulated that type 2 dia-betes is a manifestation of the inflam-matory host response (1). Increased

inflammatory activity is believed to playa critical role in development of athero-genesis and to predispose establishedatherosclerotic plaques to rupture (2). In-terleukin (IL)-8 is a potent chemoattractant(chemokine) and induces recruitment ofneutrophils and T-cells into the subendo-thelial space, as well as adhesion of mono-cytes to endothelium (3). IL-18 is a potentproinflammatory cytokine reported toplay a role in plaque destabilization and topredict cardiovascular death in patientswith coronary artery disease (4). Adi-ponectin is an adipocyte-derived plasmaprotein (adipokine) that accumulates inthe injured artery and has potential anti-atherogenic properties; male patientswith hypoadiponectinemia present a two-fold increase in coronary artery diseaseprevalence (5).

We studied 30 patients (age 42 � 4years, BMI 26.9 � 1.2 kg/m2, and HbA1c7.2 � 0.6% [mean � SD]) with newlydiagnosed type 2 diabetes (within 6months of diagnosis) without hyperten-sion or evidence of vascular complica-tions treated only by diet. Thirty healthysubjects, matched for age, sex, and bodyweight, served as the control group. Noneof the subjects (diabetic and nondiabetic)were taking any drugs. Serum samples forIL-8, IL-18, and adiponectin were storedat �80°C and measured in duplicate us-ing enzyme-linked immunosorbent kits.All samples for a given patient were ana-lyzed in the same series.

Circulating levels of IL-8 and -18 con-centrations were higher in diabetic pa-tients (13.7 � 2.8 and 205 � 39 pg/ml,respectively) than in control subjects(8.7 � 1.9 and 120 � 25 pg/ml, P �0.05–0.001), while circulating adiponec-tin levels were lower (4.9 � 1.2 vs. 7.1 �1.9 �g/ml, P � 0.01). There was a signif-icant correlation between fasting glucoseand IL-8 levels in diabetic patients (r �0.31, P � 0.05); adiponectin concentra-tions were negatively correlated with fast-ing insulin levels (r � �0.43, P � 0.01).

Our study shows that circulating IL-8

concentrations are significantly higherand adiponectin levels are significantlylower in type 2 diabetic patients thanmatched control subjects. Previous stud-ies reported similar findings (6,7). To ourknowledge, this is the first demonstrationthat circulating IL-18 concentrations areincreased in type 2 diabetic patients, ascompared with age-, sex-, and bodyweight–matched nondiabetic subjects. Ina prospective study of 1,229 subjects, in-cluding one-sixth of diabetic patients,with documented coronary artery dis-ease, serum IL-18 concentration wasidentified as a strong independent predic-tor of future cardiovascular events (5).The correlation we found between IL-18and glucose levels in diabetic patients andthe evidence that acute hyperglycemiamay increase circulating IL-18 levels inhealthy subjects and IGT patients (8) sug-gest a role for this cytokine in plaque de-stabilization associated with stresshyperglycemia (9).

KATHERINE ESPOSITO, MD

FRANCESCO NAPPO, MD, PHD

FRANCESCO GIUGLIANO

CARMEN DI PALO

MYRIAM CIOTOLA

MICHELANGELA BARBIERI, MD

GIUSEPPE PAOLISSO, MD

DARIO GIUGLIANO, MD, PHD

From the Department of Geriatrics and MetabolicDiseases, Second University of Naples, Naples, Italy.

Address correspondence to Katherine Esposito,MD, Dipartimento di Geriatria e Malattie del Me-tabolismo, Policlinico Universitario, Piazza L. Mira-glia,80138Napoli,Italy.E-mail:[email protected].


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References1. Pickup JC, Mattock MB, Chusney GD,

Burt D: NIDDM as a disease of the in-nate immune system: association ofacute-phase reactants and interleukin-6withmetabolic syndrome. Diabetologia 40:1286–1292, 1997

2. Libby P, Ridker PM, Maseri A: Inflamma-tion and atherosclerosis. Circulation 105:1135–1143, 2002

3. Gerzten RE, Garcia-Zepeda EA, Limm YC,Yoshida M, Ding HA, Gimbrone Jr MA,Luster AD, Luscinskas FW, RosenzweigA: MCP-1 and IL-8 trigger firm adhesionof monocytes to vascular endotheliumunder flow conditions. Nature 398:718–723, 1999

4. Blankenberg S, Tiret L, Bickel C, Peetz D,Cambien F, Meyer J, Rupprecth HJ: Inter-

leukin-18 is a strong predictor of cardio-vascular death in stable and unstableangina. Circulation 106:24–30, 2002

5. Kumada M, Kihara S, Sumitsuji S,Kawamoto T, Matsumoto S, Ouchi N,Arita Y, Okamoto Y, Shimomura I,Hiraoka H, Nakamura T, Funahashi T,Matsuzawa Y, the Osaka CAD StudyGroup: Association of hypoadiponectine-mia with coronary artery disease in man.Arterioscler Thromb Vasc Biol 23:85–89, 2003

6. Zozulinska D, Majchrzak A, Sobieska M,Wiktorowicz K, Wierusz-Wysocka B:Serum interleukin-8 levels is increasedin diabetic patients. Diabetologia 42:117–123, 1999

7. Weyer C, Funahashi T, Tanaka S, Hotta K,Matsuzawa Y, Pratley RE, Tataranni PA:Hypoadiponectinemia in obesity and type2 diabetes: close association with insulinresistance and hyperinsulinemia. J ClinEndocrinol Metab 86:1930–1935, 2001

8. Esposito K, Nappo F, Marfella R, Giugli-ano G, Giugliano F, Ciotola M, QuagliaroL, Ceriello A, Giugliano D: Inflammatorycytokine concentrations are acutely in-creased by hyperglycemia in humans: roleof oxidative stress. Circulation 106:2067–2072, 2002

9. Capes SE, Hunt D, Malberg K, GersteinHC: Stress hyperglycemia and increasedrisk of death after myocardial infarction inpatients with and without diabetes: a sys-temic overview. Lancet 355:773–778, 2000

LipoproteinAbnormalities inHuman GeneticCD36 DeficiencyAssociated WithInsulin Resistanceand Abnormal FattyAcid Metabolism

CD36 is an 88-kDa membranous pro-tein with multiple relevant functionthat is widely expressed in human

tissues (1). Because we and others (2)found human genetic deficiency of thismolecule, we have elucidated the molec-ular bases and pathophysiology. We havereported that the human deficiency maybe associated with insulin resistance (3)and abnormal dynamics of long-chainfatty acid (LCFA) (4). The aim of thepresent study was to further characterizelipid and lipoprotein metabolism in thehuman genetic CD36 deficiency, espe-cially focusing on postprandial responses.

Letters


Seven Japanese patients with type ICD36 deficiency (cases 1–7) were sub-jected. They were divided into the follow-ing two groups: group A, two youngerpatients we have recently identified (cases1 and 2); and group B, patients �50 yearsof age (cases 3–7, reported in our previ-ous paper [3]). For the analysis of eachgroup, aged-matched healthy and nono-bese volunteers were subjected as controlsubjects (Table 1). First, we confirmedthat insulin resistance was also present inthe two younger patients (group A).

At the fasting state, “midbands,”which imply the accumulation of rem-nant lipoproteins, were observed in groupB but not in group A. Preparative ultra-centrifugation confirmed an increase inintermediate-density lipoprotein choles-terol in the all of the CD36-deficient sub-jects in group B compared with thecontrol subjects. The oral fat loading testdemonstrated that the patients in group Bpresented postprandial hyperlipidemiawith the accumulation of small intestine–derived lipids. Whereas the patients ingroup A did not show apparent abnor-malities, though they did have insulinresistance.

The present study indicated that thismonogenic disorder with the abnormalmetabolism in LCFA and insulin resis-tance may cause the phenotypic expres-sion of hyperlipidemia at both fasting andpostprandial states. These data also sug-gest that the clinical manifestation is af-fected by the acquired factors, such asaging and dietary contents. We believe

that human genetic CD36 deficiency maybe a monogenic form of “metabolic syn-drome.” Further studies to elucidate mo-lecular mechanism for the phenotypicexpression in CD36-deficient states areunder way in our laboratories.

Acknowledgments— This work was sup-ported by grants-in-aid to K.H. (no.13671191) and S.Y. (nos. 11557055 and10671070) from the Ministry of Education,Science, Sports, and Culture of Japan.

We gratefully thank Natsu Iwamoto, SonoeShima, and Atsuko Ohya for the skillful tech-nical assistance.

TAKAHIRO KUWASAKO, MD1

KEN-ICHI HIRANO, MD, PHD1

NAOHIKO SAKAI, MD, PHD1

MASATO ISHIGAMI, MD, PHD1

HISATOYO HIRAOKA, MD, PHD1

MOHAMED JANABI YAKUB, MD, PHD1

KEIKO YAMAUCHI-TAKIHARA, MD, PHD2

SHIZUYA YAMASHITA, MD, PHD1

YUJI MATSUZAWA, MD, PHD1

From the 1Department of Internal Medicine andMolecular Science, Graduate School of Medicine,Osaka University, Osaka, Japan; and the 2Depart-ment of Molecular Medicine, Graduate School ofMedicine, Osaka University, Osaka, Japan.

Address correspondence to Ken-ichi Hirano,MD, PhD, Department of Internal Medicine and Mo-lecular Science, Graduate School of Medicine, B5,Osaka University, 2-2 Yamadaoka, Suita, Osaka565-0871, Japan. E-mail: [email protected].


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References1. Febbraio M, Hajjar DP, Silverstein RL:

CD36: a class B scavenger receptor in-

volved in angiogenesis, atherosclerosis,inflammation, and lipid metabolism.J Clin Invest 108:785–791, 2001

2. Yamamoto N, Ikeda H, Tandon NN, Her-man J, Tomiyama Y, Mitani T, SekiguchiS, Lipsky R, Kralisz U, Jamieson GA: Aplatelet membrane glycoprotein (GP) de-ficiency in healthy blood donors: Naka,platelet lack detectable GP IV(CD36).Blood 76:1698–1703, 1990

3. Miyaoka K, Kuwasako T, Hirano K,Nozaki S, Yamashita S, Matsuzawa Y:CD36 deficiency associated with insulinresistance. Lancet 357:686–687, 2001

4. Yoshizumi T, Nozaki S, Fukuchi K, Ya-masaki K, Fukuchi T, Maruyama T, To-miyama Y, Yamashita S, Nishimura T,Matsuzawa Y: Pharmacokinetics andmetabolism of iodine-123-BMIPP fattyacid analogue in normal and CD36-defi-cient subjects. J Nucl Med 41:1134–1138,2000

The RelationBetween PhysicalActivity andMetabolic Control inType 2 DiabetesWith <20 Years ofEvolution

Obesity and reduced levels of physi-cal activity are directly associatedwith the insulin resistance that

characterizes type 2 diabetes (1,2). Phys-ical activity is one of the cornerstones oftype 2 diabetes management (3). Few

Table 1—Lipid and lipoprotein abnormalities at fasting and postprandial states in human genetic CD36 deficiency

Group A Group B

Case 1 Case 2 Control (n � 4) Case 3 Case 4 Case 5 Case 6 Case 7 Control (n � 8)

Age (years)/sex (M/F) 34/M 32/M 33 � 2 (4M) 58/M 65/F 54/F 54/F 54/M 55 � 10 (3M/5F)BMI (kg/m2) 22.9 32.0 22.4 � 1.0 26.2 22.2 32.8 17.3 24.9 22.7 � 2.3WBGU (mg � kg�1 � min�1)* 7.8 2.8 9.1 � 0.5 2.67† 7.09† 5.49† 4.85† 5.29† 8.6 � 0.5†Fasting state

Total cholesterol (mmol/l) 4.20 5.01 4.78 � 0.38 5.81 6.18 5.97 5.45 5.84 5.10 � 0.69Triglyceride (mmol/l) 0.78 1.23 1.00 � 0.17 2.73 1.43 1.77 1.28 3.41 1.20 � 0.38Midband in PAG disc

electrophoresis‡� � � � � � �

IDL cholelsterol (mmol/l)§ ND ND 0.48 0.38 0.29 0.34 0.22 0.11 � 0.03Postprandial state�

AUC-TG (mmol/l 6 h) 5.3 8.8 8.8 � 0.7 20.6 13.4 14.0 14.0 26.8 10.0 � 2.9AUC-Apo B48 (AU/ml 6 h)** 223 268 329 � 107 866 671 941 551 541 360 � 120

Data are means � SD unless otherwise indicated. apo, apolipoprotein; AUC, area under the curve; PAG, polyacrylamide gel; WBGU, mean whole-body glucoseuptake. *Insulin resistance was determined by euglycemic clamp technique (ref. 3); †part of data from cases 3–7 were described previously (Ref. 3); ‡lipoproteinswere analyzed by PAG electrophotesis. §IDL was separated by preparative ultracentrifugation (1.019 � d � 1.063 g/ml); �postprandial hyperlipidemia was analyzedby the oral fat loading test with fat cream containing 30 g fat/m2 body surface area; TG and apo B48 levels were measured at 0, 2, 4, and 6 h after loading, and AUCswere calculated; **serum apo B48 levels were measured by the enzyme-linked immunosorbent assay we have developed.

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large studies have assessed the impact ofintensity and quality of exercise on meta-bolic control in these patients, and theinfluence of age on the metabolic re-sponse to physical activity is still contro-versial (4). We conducted the Interventionon Key Cardiovascular Risk Factors inType 2 Diabetes National Study (KAREN),a country-based case-control study nestedin a survey of 1,485 consecutive type 2diabetic patients treated by 208 endocri-nologists across Spain to assess the impactof physical activity on metabolic control.Patient risk factors, history characteris-tics, medication and diet compliance, gly-cemia, fasting HbA1c, and lipids weredetermined.

Patient characteristics are presentedin Table 1 by quartile of physical activity.After adjustment for age, sex, triglycer-ides, BMI, and diet compliance, patientsin the lowest quartile of physical activityhad an OR of 1.52 and a 95% CI of 1.11–2.08 for having an HbA1c �7.5%. TheORs for patients �65 years of age and inthe lowest quartile of physical activitywere 1.55 (95% CI 1.04–2.31) comparedwith the fourth, 1.64 (1.09–2.47) withthe third, and 1.84 (1.22–2.75) with thesecond quartile. Patients �65 years of ageand in the lowest quartile of physical ac-tivity had a similar adjusted risk com-

pared with the rest of quartiles (OR 1.14,95% CI 0.70–1.85; 1.38, 0.84–2.26, and0.87, 0.53–1.43, respectively). A signifi-cant reduction of 0.2% (95% CI �0.36 to�0.04) in HbA1c was observed for pa-tients expending �50 kcal/day versus thefirst quartile; the reduction for patients�65 years of age was 0.27% (�0.49 to–0.06), but for patients �65 there was nosignificant difference.

These results suggest that physical ac-tivity produces better glycemic controland improved cardiovascular risk profilein diabetic patients, particularly in those�65 years of age.

PEDRO DE PABLOS-VELASCO, MD, PHD1

WILFREDO RICART, MD, PHD2

SUSANA MONEREO, MD3

BASILIO MORENO, MD, PHD4

JAUME MARRUGAT, MD, PHD, FESC5

ON BEHALF OF THE KAREN INVESTIGATORS

From the 1Department of Endocrinology, HospitalDoctor Negrın, Las Palmas de Gran Canaria, Spain;the 2Department of Endocrinology, Hospital Trueta,Gerona, Spain; the 3Department of Endocrinology,Hospital Getafe, Madrid, Spain; the 4Department ofEndocrinology, Hospital Gregorio Maranon, Ma-drid, Spain; and the 5Unit of Lipid and Cardiovas-cular Epidemiology, Institut Municipal d’InvestigacioMedica (IMIM) and Universitat Autonoma Schoolof Medicine, Barcelona, Spain.

Address correspondence to Dr. Jaume Marrugat,

Lipid and Cardiovascular Epidemiology Unit, Insti-tut Municipal d’Investigacio Medica (IMIM), CarrerDr. Aiguader, 80, E-08003 Barcelona, Spain. E-mail:[email protected].


AppendixThe KAREN Investigators comprise 208Spanish endocrinologists who work inprimary outpatient diabetes clinics of theNational Health Service.

The KAREN investigators are as fol-lows: Abellan T, Acha FJ, Acosta D, Agui-lar M, Aguillo E, Albero R, Alcaraz M,Alvarez JA, Alvarez P, Alvarez J, AndiaVM, Aranda S, Arranz A, Arribas LD, Ar-teaga R, Asensio C, Ayala C, Ballester E,Barril R, Becerra A, Blanco B, Blay V, BotasP, Brito MA, Bruscas M, Bueno J, Burgo R,Cabezas J, Calderon D, Calero M, Calvo F,Cancer E, Carrasco R, Casal F, Castano G,Castro JC, Cepero D, Cervello G, ChenaJA, Conget I, Corrales JJ, Costilla E, CovesMJ, Darıas R, de la Cuesta C, de Pablos P,Dıaz C, Diez A, Domınguez JR, Duran S,Duran M, Elviro R, Enrıquez L, EscaladaFJ, Escobar L, Esmatges E, Espiga J, Es-topinan V, Ezquerra R, Famades A, Fer-nandez JI, Fernandez M, Fernandez JM,Fernandez F, Fernandez T, Fernandez JA,Fernandez J, Flandez B, Flaquert P, FraileAL, Fraile J, Freijanes J, Galvez A, Garcıa

Table 1—Demographic, comorbidity, lifestyle, biochemical, and somatometric characteristics by physical activity levels (quartiles) of type 2diabetic patients who participated in the KAREN study

�51 kcal/day 51–148 kcal/day 149–264 kcal/day �264 kcal/day P

n 368 373 375 369Age (years) 62 � 10 61 � 10 61 � 9 61 � 10 NSWomen (%) 49.6 45.3 54.4 69.6 �0.001Time with diabetes (years) 10.3 � 6.4 9.9 � 6.3 10.1 � 6.4 10.3 � 6.2 NSHypertension (%) 51.8 58.3 50.7 46.3 0.017Current smokers (%)* 19.4 18.9 19.0 16.0 NSSystolic BP (mmHg) 140 � 17 139 � 17 139 � 16 139 � 19 NSDiastolic BP (mmHg) 80 � 10 79 � 9 79 � 10 78 � 11 NSBMI (kg/m2) 28.8 � 3.4 28.5 � 3.5 28.1 � 3.3 28.3 � 3.3 0.035Coronary heart disease (%)† 17.9 14.4 18.0 14.0 NSCerebrovascular disease (%)‡ 8.5 6.4 6.6 5.1 NSGlycemia (mg/dl) 9.5 � 3.2 9.1 � 2.9 9.1 � 3.0 8.8 � 2.7 �0.001HbA1c (%)* 7.9 � 1.6 7.6 � 1.4 7.6 � 1.4 7.4 � 1.0 �0.001Total cholesterol (mmol/l) 5.3 � 1.0 5.4 � 1.0 5.2 � 1.0 5.1 � 1.0 �0.001HDL cholesterol (mmol/l) 1.2 � 0.3 1.3 � 0.3 1.2 � 0.3 1.3 � 0.4 0.014LDL cholesterol (mmol/l) 3.4 � 0.9 3.4 � 0.9 3.2 � 34.7 3.3 � 0.9 NSTriglycerides (mmol/l) 1.9 � 1.8 1.7 � 0.9 1.7 � 1.1 1.5 � 0.9 �0.001Creatinine (�mol/l) 91.9 � 31.8 85.7 � 24.7 86.6 � 26.5 88.4 � 19.4 0.035Good diet compliance (%) 37.1 35.1 49.2 52.2 �0.001Daily alcohol consumption (g) 12.9 � 12.8 12.5 � 12.3 12.8 � 13.3 12.5 � 12.3 NS

Data are means � SD and %. *Smokers of at least one cigarette per day in average; †myocardial infarction or angina; ‡transient ischemic attack or stroke.

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JA, Garcıa A, Garcıa C, Garcıa G, Garcıa I,Garcıa J, Garcıa M, Garcia-Hierro V, Gar-gallo MA, Gentil AC, Gil A, Gilsanz A,Gimenez G, Gippini A, Girbes AJ, GodayA, Godoy DV, Goena M, Goicolea I, Go-mez F, Gonzalez A, Gonzalez JM, Gonza-lez O, Goni F, Guerrero E, Hernandez C,Hernandez A, Hernandez JA, HernandezC, Hernandez A, Hernandez C, Iglesias P,Ikobalceta P, Illan F, Inigo P, Iriarte A,Irigoyen L, Jaunsolo MA, Lain T, Levy I,Llorente I, Lopez AJ, Lopez de la Torre M,Lopez-Guzman A, Losada F, Luna R, Ma-canas G, Macia C, Maldonado JA, MangasMA, Manzanares JM, Maravall FJ, MarcoA, Marco AL, Marin M, Martın T, MartınA, Martınez MP, Martınez FJ, MartınezMA, Matia P, Mato JA, Megia A, Menen-dez E, Meoro A, Merino JF, Mesa J,Mezquita P, Micalo T, Miralles JM, MolinaMJ, Monereo S, Morales MJ, Moreno A,Moreno C, Mories T, Munoz L, Munoz M,Munoz A, Muros T, Nubiola A, Oleaga A,Olivan B, Palacios N, Palomares R, PazosF, Pena E, Penafiel FJ, Pereyra F, Perez A,Pesquera C, Picon MJ, Piedrola G, PinedoR, Pinies J, Pizarro E, Prieto J, Puig M,Puigdevall V, Pumar A, Recas I, Recio JM,Reverter J, Ricart W, Rius F, Rivas M,Rosell R, Rubio JA, Ruiz JM, Sagarra E,Sales J, Salinas I, Sanchez C, Sanchez JC,Santiago P, Santiago L, Sastre J, Segura P,Simo R, Simon I, Solache I, Soriano J, SotoA, Suarez-Lledo E, Surruca L, Tebar FJ,Tenes T, Todolı J, Tofe S, Tolosa M, Tor-ras R, Torres A, Vadillo V, Velasco JL,Vences LF, Vendrell JJ, Vicente A, Vidal JI,Villa M, Villar A, Zurro J.

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References1. Everhart JE, Pettitt DJ, Bennett PH,

Knowler WC: Duration of obesity in-creases the incidence of NIDDM. Diabetes41:235–240, 1992

2. American Diabetes Association: Diabetesmellitus and exercise (Position State-ment). Diabetes Care 25 (Suppl. 1):S64–S68, 2002

3. Harding AH, Williams DE, Hennings SH,Mitchell J, Wareham NJ: Is the associationbetween dietary fat intake and insulin re-sistance modified by physical activity?Metabolism 50:1186–1192, 2001

4. Boule NG, Haddad E, Kenny GP, WellsGA, Sigal RJ: Effects of exercise on glycemiccontrol and body mass in type 2 diabetesmellitus: a meta-analysis of controlledclinical trials. JAMA 286: 1218–1227,2001

Education andMortality in Type 2Diabetes

A dults with diabetes tend to havehigher age-adjusted mortality rates(1,2). Evidence from Britain (3)

suggests that mortality in diabetic adultsis inversely related to socioeconomic sta-tus. The importance of self-care andblood glucose control in adults with dia-betes suggests that education may be animportant factor in long-term health out-comes, a hypothesis that is also consistentwith evidence in the health economics lit-erature that education increases the effi-ciency of investment in health (4,5). Thespecific hypothesis tested here is thatmortality in adults with diabetes is in-versely related to education.

The data are taken from the NationalHealth Interview Survey (NHIS) of 1989,including its diabetes supplement, withmortality status taken from the NHISMultiple Cause of Death Public Use DataFile, including deaths from 1989 to 1995.The statistical analysis is applied to thoseadults who self-reported that they hadbeen diagnosed with diabetes, excludingthose with apparent type 1 diabetes (ageof onset �30 years, with insulin depen-dence, and a BMI �27.2 kg/m2 for menand �26.9 for women). The resultingsample includes 2,387 adults with type 2diabetes having an average age of 61.8years.

Logistic regression analysis is used toexplore the relation between mortalityand educational attainment, family in-come (greater than or less than $20,000per year in 1989), age, sex, marital status,race, and duration of diabetes. The statis-tical analysis is carried out with the svy-logit procedure in STATA software,version 7 (STATA, College Station, TX),using the NHIS sampling weights.

The primary finding is that mortalityis inversely related to education for dia-betic adults (OR [95% CI] 0.61 [0.40–0.93] for college graduation or higher and0.78 [0.61–0.99] for high school gradu-ation or higher). Mortality is not signifi-cantly related to family income, maritalstatus, or race, but age, male sex, and du-ration of diabetes have the expected pos-itive and statistically significant associationswith mortality. The finding that educa-tion reduces the mortality risk of diabeticadults is consistent with the predictions

from health investment theory that edu-cation increases the efficiency of healthinvestment. Education may also be a fac-tor in the relatively poor health status andoutcomes of adults with diabetes (6).

Acknowledgments— The author thanksPhilip Jacobs for comments, Glenn Harrisonfor generous help with the data, and PaulaVeiga for expert research assistance. Any re-maining errors are mine.

RONALD P. WILDER, PHD

From the Department of Economics, Moore Schoolof Business, University of South Carolina, Colum-bia, South Carolina.

Address correspondence to Ronald P. Wilder,PhD, Department of Economics, Moore School ofBusiness, University of South Carolina, Columbia,SC 29208. E-mail: [email protected].


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References1. Geiss LS, Herman WH, Smith PJ: Mortal-

ity in non-insulin dependent diabetes. InDiabetes in America. 2nd ed. NationalDiabetes Data Group, National Institutesof Health, National Institute of Diabetesand Digestive and Kidney Diseases, 1995(NIH Publ. no. 95-1468)

2. Gu K, Cowie CC, Harris MI: Mortality inadults with and without diabetes in a na-tional cohort of the U.S. population,1971–1993. Diabetes Care 21:1138–1145, 1998

3. Roper NA, Bilous RW, Kelly WF, UnwinNC, Connolly VM: Excess mortality in apopulation with diabetes and the impactof material deprivation: longitudinal,population based study. BMJ 322:1389–1393, 2001

4. Grossman M, Kaestner R: Effects of edu-cation on health. In The Social Benefits ofEducation. Behrman J, Stacey N, Eds. AnnArbor, MI, University of Michigan Press,1997

5. Kahn ME: Education’s role in explainingdiabetic health investment differentials.Econ Educ Rev 17:257–266, 1998

6. Harris MI: Health care and health statusand outcomes for patients with type 2 di-abetes. Diabetes Care 23:854–758, 2000

StressHyperglycemia,Inflammation, andCardiovascular Events

One-third of all individuals with hy-perglycemia admitted to an urbangeneral hospital do not have a pre-

vious diagnosis of diabetes; in these pa-

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tients, hyperglycemia is a risk factor foradverse outcomes during acute illness (1).For example, in patients presenting withacute myocardial infarction, glucose val-ues in excess of 6.1–8.0 mmol/l were as-sociated with a threefold increase inmortality and a higher risk of heart failure(2). Control of hyperglycemia with inten-sive insulin therapy during acute illnessresults in marked improvements of clini-cal outcomes (3).

Dandona et al. (4) put forward aworking hypothesis linking in a feedbackloop of glucose (and possibly other nutri-ents), insulin, and inflammation. Accord-ing to this paradigm, hyperglycemia has aproinflammatory action that is normallyrestrained by the anti-inflammatory effectof insulin secreted in response to thatstimulus. A likely corollary of this para-digm is that the proinflammatory effectsof acute (stress) hyperglycemia may beimplicated in the poor prognosis of hos-pitalized patients with or without diabe-tes (particularly death, disability afteracute cardiovascular events, and infec-tions). We have demonstrated that circu-lating levels of some proinflammatorycytokines are regulated by glucose levelsin humans (5). Acute hyperglycemia(�15 mmol/l) induced by glucose clamp-ing in normal subjects and lasting 5 hdetermines a significant increase of inter-leukin (IL)-6, IL-18, and tumor necrosisfactor- (TNF-) circulating levels. Theseeffects were more sustained in patientswith impaired glucose tolerance, as wellas following consecutive pulses of intra-venous glucose, and were annulled byglutathione, implicating an oxidativemechanism. Interestingly enough, thesecytokines have been implicated in insulinresistance (TNF- and IL-6), atheroscle-rotic plaque destabilization (IL-18), andfuture cardiovascular events (IL-6, IL-18,and TNF-). So, an increased oxidativestress may be a likely mechanism linkingstress hyperglycemia to cardiovascularevents via an increased cytokine production.

Free fatty acids (FFAs) also induceproinflammatory changes. During illness,stress increases the concentration ofcounterregulatory hormones (mainly glu-cagon, an epinephrine). Given this back-ground, it is plausible that in the presenceof high concentrations of both glucoseand FFA, inflammation is more promi-nent. We tested this hypothesis by givingtype 2 diabetic patients two differentmeals: a high-carbohydrate meal (high

glucose levels) and a high-fat meal (highglucose plus high FFA levels). In the lattercondition, the serum concentrations ofcytokines (TNF- and IL-6) and adhesionmolecules (intracellular adhesion mole-cule-1 and vascular cell adhesion mole-cule-1) were at the highest level (6).

In conclusion, high circulating con-centrations of glucose and FFAs may ex-plain, at least in part, the oxidative andinflammatory derangements during acuteillness; insulin may exert its anti-inflam-matory action by ameliorating glucoseand lipid parameters. However, any addi-tional anti-inflammatory effect insulinmay have of its own is welcome. The im-portance is to recognize that treatment ofeven trivial hyperglycemia during acuteillness is fundamental to improve sur-vival. Because insulin is the best choice tonormalize glucose control during stress,accepting the premise will inevitablybring increased insulin use in intensivecare units.

KATHERINE ESPOSITO, MD

RAFFAELE MARFELLA, MD, PHD

DARIO GIUGLIANO, MD, PHD

From the Department of Geriatrics and MetabolicDiseases, Cardiovascular Research Center, SecondUniversity of Naples, Naples, Italy.

Address correspondence to Dario Giugliano, MD,PhD, Department of Geriatrics and Metabolic Dis-eases, Policlinico della Seconda Universita diNapoli, Piazza L. Miraglia, 80138 Naples, Italy.Email: [email protected].


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References1. Umpierrez GE, Isaacs SD, Bazargan N,

You X, Thaler LM, Kitabchi AE: Hy-perglycemia: an independent marker ofin-hospital mortality in patients withundiagnosed diabetes. J Clin EndocrinolMetab 87:978–982, 2002

2. Capes SE, Hunt D, Malmberg K, Pathak P,Gerstein HC: Stress hyperglycemia andincreased risk of death after myocardialinfarction in patients with and without di-abetes: a systematic overview. Lancet 355:773–778, 2000

3. Van den berghe G, Wouters P, Weekers F,Verwaest C, Bruyninckx F, Schetz M,Vlasselaers D, Ferdinande P, Lauwers P,Bouillon R: Intensive insulin therapy incritically ill patients. N Engl J Med 345:1359–1367, 2001

4. Dandona P, Aljada A, Bandyopadhyay A:The potential therapeutic role of insulin inacute myocardial infarction in patientsadmitted to intensive care and in thosewith unspecified hyperglycemia. Diabetes

Care 26:516–519, 20035. Esposito K, Nappo F, Marfella R, Giugli-

ano G, Giugliano F, Ciotola M, QuagliaroL, Ceriello A, Giugliano D: Inflammatorycytokine concentrations are acutely in-creased by hyperglycemia in humans: roleof oxidative stress. Circulation 106:2067–2072, 2002

6. Nappo F, Esposito K, Cioffi M, GiuglianoG, Molinari AM, Paolisso G, Marfella R,Giugliano D: Postprandial endothelial ac-tivation in healthy subjects and in type 2diabetic patients: role of fat and carbohy-drate meals. J Am Coll Cardiol 39:1145–1150, 2002

Laughter Loweredthe Increase inPostprandial BloodGlucose

N egative emotions such as anxiety,fear, and sorrow are known to befactors that elevate the blood glu-

cose level (1). Conversely, positive emo-tions such as laughter have been reportedto modify the levels of neuroendocrinefactors involved in negative emotions(2,3) and to modulate immune function(3,4). However, there have been no stud-ies on the effects of laughter on blood glu-cose level. The purpose of this study wasto clarify changes in the blood glucoselevel after laughing episodes in patientswith diabetes.

A 2-day experiment was performed in19 patients with type 2 diabetes not re-ceiving insulin therapy (16 men and 3women, age 63.4 � 1.3 years, BMI23.5 � 0.7 kg/m2, HbA1c, 7.2 � 0.1%[means � SE]) and 5 healthy subjects(2 men and 3 women, age 53.6 � 3.5years, BMI 24.3 � 1.6 kg/m2, HbA1c4.8 � 0.1% [means � SE]). On both ex-perimental days, they consumed the same500-kcal meal (79.9 g carbohydrate,21.0 g protein, 7.8 g fat, and 1.0 g fiber).On the first day, they attended a monot-onous lecture (40 min) without humor-ous content. On the second day, as partof an audience of 1,000 people attend-ing MANZAI (a Japanese cross-talk com-edy) (40 min) in a civic hall, the subjectslaughed. Blood glucose was measuredfrom the fingertip by enzyme colorimet-ric assay using a blood glucose self-measurement apparatus. The subjectsestimated their laughter level on a scale of

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0–5, and most of them considered thatthey laughed well (level 4 or 5). Self-monitoring of blood glucose was per-formed before food intake (fasting bloodglucose [FBG]) and 2 h after the meal wasstarted (2-h postprandial blood glucose[PPBG]).

The results are presented as means �SE. In the patients, the mean 2-h PPBGwas 6.8 � 0.7 mmol/l higher than theFBG after the lecture and 4.3 � 0.8mmol/l higher after the comedy show.The difference in the mean increase be-tween the lecture and comedy show was2.5 � 0.7 mmol/l (P � 0.005). In thehealthy subjects, the mean increases were2.0 � 0.7 and 1.2 � 0.4 mmol/l after thelecture and comedy show, respectively,and the difference was 0.8 � 0.5 mmol/l(P � 0.138).

These results suggest a significantsuppression of the increase in 2-h PPBGby comedy show in patients with diabe-tes, suggesting that laughter amelioratesthe postprandial glucose excursion in thepresence of insufficient insulin action.This favorable effect of laughter may in-clude the acceleration of glucose utiliza-tion by the muscle motion during thecomedy show. However, it is possible thatpositive emotions such as laughter actedon the neuroendocrine system and sup-pressed the elevation of blood glucoselevel.

In conclusion, the present study elu-cidates the inhibitory effect of laughter onthe increase in PPBG and suggests the im-portance of daily opportunities for laugh-ter in patients with diabetes.

KEIKO HAYASHI, RN, PHD1

TAKASHI HAYASHI, BAG2

SHIZUKO IWANAGA, RN3

KOICHI KAWAI, MD, PHD3

HITOSHI ISHII, MD, PHD4

SHIN’ICHI SHOJI, MD, PHD5

KAZUO MURAKAMI, PHD2

From the 1Institute of Community Medicine, Uni-versity of Tsukuba, Tsukuba, Ibaraki, Japan; the2Foundation for Advancement of International Sci-ence, Bio-Laboratory, Tsukuba, Ibaraki, Japan; the3Tsukuba Diabetes Center, Kawai Clinic, Tsukuba,Ibaraki, Japan; the 4Department of Endocrinology,Tenri Hospital, Tenri, Nara, Japan; and the 5Instituteof Clinical Medicine, University of Tsukuba,Tsukuba, Ibaraki, Japan.

Address correspondence to Keiko Hayashi, RN,PhD, 1-1-1, Tennoudai, Tsukuba, Ibaraki, 305-8577, Japan. E-mail: [email protected].


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References1. Surwit RS, Schneider MS: Role of stress in

the etiology and treatment of diabetesmellitus. Psychosom Med 55:380 –393,1993

2. Berk LS, Tan SA, Fry WF, Napier BJ,Lee JW, Hubbard RW, Lewis JE, EbyWC:Neuroendocrine and stress hormonechanges during mirthful laughter. Am JMed Sci 298:390–396, 1989

3. Berk LS, Tan SA, Napier BJ, Eby WC: Eu-stress of mirthful laughter modifies natu-ral killer cell activity (Abstract). Clin Res37:115, 1989

4. Takahashi K, Iwase M, Yamashita K, Tat-sumoto Y, Ue H, Kuratsune H, Shimizu A,Takeda M: The elevation of natural killercell activity induced by laughter in a cross-over designed study. Int J Mol Med 8:645–650, 2001

Differential Levelsof �-GlutamylTransferase Activityand ApolipoproteinCIII in Men on EitherStatin or FibrateTherapy

H igh triglycerides and low HDL cho-lesterol are frequently associatedwith insulin resistance. Statins are

potent hypocholesterolemic drugs, whilefibrates are better at reducing triglycer-ides and enhancing HDL. However, littleis known of their effects on other param-eters potentially associated with insulinresistance, such as �-glutamyl transferase(GGT) (1) and apolipoprotein CIII (2).

In this cross-sectional study, we haveanalyzed the biochemical profiles of 500men from Southwestern France as a func-tion of their hypolipidemic therapy.Comparison between untreated (n �361) and fibrate (n � 50)- and statin (n �89)-treated subjects revealed no differ-ence in their levels of total, LDL, and HDLcholesterol, apo B, apo AI, and apo E, afteradjustment for age, BMI, alcohol intake,smoking, and physical activity. This sug-gests that both therapies are equally effec-tive at normalizing classic lipid variables.

By contrast, apo CIII was higher in thestatin group (34.3 � 13.9 mg/l) than inboth the fibrate (26.7 � 10.3, P � 0.01)and nontreated (28.7 � 10.9 mg/l, P �0.001) groups after adjustment for con-

founders, including triglycerides. Similardifferences were found for Lp B:CIII, amarker measuring apo CIII associatedwith apo B. These observations might in-dicate an additional beneficial effect of fi-brates, considering that Lp B:CIII hasbeen described as an independent predic-tor of coronary events, better than triglyc-erides (3).

Most interesting, GGT was two timeslower for fibrates (36.7 � 24.4 units/l)than for the two other groups (67.1 �71.3 units/l for statins, P � 0.01 and58.1 � 51.7 units/l in nontreated sub-jects, P � 0.01), taking into considerationpotential confounders, including alcoholintake and triglycerides. GGT is often el-evated in obese subjects and has been as-sociated with steatosis, which could bedue to increased effects of insulin in theliver and could contribute to the develop-ment of systemic insulin resistance andhyperinsulinemia in obesity. GGT was re-ported as one of the independent predic-tors of the metabolic syndrome and type 2diabetes (1,4). Moreover, GGT was de-tected in atheromatous plaques and hasbeen shown to promote LDL oxidation byhydrolyzing glutathione into more potentiron reductants (5). Thus, fibrates mayprove effective in the treatment of dyslip-idemic diabetic or obese patients, sincethey should improve the hepatic sufferinginduced by the triglyceride load and alsolimit the potential proatherogenic effectsof GGT.

Acknowledgments— This study was sup-ported by Laboratoires Fournier.

LAURENCE MABILE, PHD1,2

JEAN-BERNARD RUIDAVETS, MD1

JOSETTE FAUVEL, PHD3

BERTRAND PERRET, MD2

JEAN FERRIERES, MD, FESC1

From the 1Departement d’Epidemiologie, InsermU558, Faculte de Medecine, Toulouse, France; 2In-serm U563, CHU Toulouse, France; and the 3Labo-ratoire de Biochimie III, CHU Toulouse, France.

Address correspondence to Prof. Jean Ferrieres,Inserm U558, Faculte de Medecine, 37 allees JulesGuesde, 31 073, Toulouse Cedex 03, France. E-mail: [email protected].


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References1. Rantala AO, Lilja M, Kauma H, Savolainen

MJ, Reunanen A, Kesaniemi YA: Gamma-glutamyl transpeptidase and the meta-

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bolic syndrome. J Intern Med 248:230–238, 2000

2. Dallongeville J, Meirhaeghe A, Cottel D,Fruchart JC, Amouyel P, Helbecque N:Polymorphisms in the insulin response el-ement of APOC-III gene promoter influ-ence the correlation between insulin andtriglyceride-rich lipoproteins in humans.Int J Obes Relat Metab Disord 25:1012–1017, 2001

3. Sacks FM, Alaupovic P, Moye LA, ColeTG, Sussex B, Stampfer MJ, Pfeffer MA,Braunwald E: VLDL, apolipoproteins B,CIII, and E, and risk of recurrent coro-nary events in the Cholesterol and Recur-rent Events (CARE) trial. Circulation 102:1886–1892, 2000

4. Perry IJ, Wannamethee SG, Shaper AG:Prospective study of serum gamma-glu-tamyltransferase and risk of NIDDM. Di-abetes Care 21:732–737, 1998

5. Paolicchi A, Minotti G, Tonarelli P, Tongi-ani R, De Cesare D, Mezzetti A, DominiciS, Comporti M, Pompella A: Gamma-glu-tamyl transpeptidase-dependent iron re-duction and LDL oxidation: a potentialmechanism in atherosclerosis. J InvestigMed 47:151–160, 1999

COMMENTS ANDRESPONSES

IGF-1 andMacrovascularComplications ofDiabetes

Alternative interpretations ofrecently published data

The hypothesis of a detrimental rolefor IGF-1 and other growth factorsin the development of vascular dis-

ease (1) has not been consistently sup-ported by recent studies (2,3). Newevidence suggests that cellular senescence(4) and impaired vascular endothelialproliferation, adhesion, and incorpora-tion play a pivotal role in the developmentof macrovascular disease (5). Indeed, re-cent data on large numbers suggest thathigher IGF-1 bioavailability may protectagainst the onset of ischemic heart disease(6,7) and glucose intolerance (8) and, intype 2 diabetic patients, may offer im-proved metabolic control and preventvascular complications (9,10). Other po-tential beneficial actions of IGF-1 in car-

diovascular physiology include increasednitric oxide synthesis and K� channelopening (11,12), and this may explain theimpaired small-vessel function associatedwith low IGF-1 levels in patients with car-diovascular syndrome X (12). By counter-acting oxidized LDL-induced cytotoxicityand vascular smooth muscle cell apopto-sis, IGF-1 may protect against plaque in-stability and rupture (2). In patients withacute myocardial infarction, markedly re-duced IGF-1 values are associated with aworse outcome (13,14), and recent datasuggest that intramyocardial (15,16) orvascular (17) gene delivery of growth fac-tors can improve symptoms and exercisecapacity in patients with coronary or pe-ripheral vascular disease.

We were therefore surprised by tworecent studies proposing IGF-1 as a me-diator of harmful vascular effects (18,19).The authors found an inverse associationbetween IGF binding protein (IGFBP)-1and carotid intimal-medial thickness (r ��0.135, P � 0.041) (18), macrovasculardisease (19), and hypertension (19) in pa-tients with type 2 diabetes. IGFBP-1 is aminor component of the system ofIGFBPs 1– 6, first discovered in the1990s, and regulated by a complex groupof proteases and phosphatases (20). AsIGFBP-1 is generally assumed to inhibitIGF-1 bioavailability (21), the authorsconclude that IGF-1 exerted harmful vas-cular effect (18,19).

We propose two different interpreta-tions of the above data, not necessarilyexclusive. First, the reduced IGFBP-1concentration observed in situations ofvascular disease (18,19) could result fromactivation of a compensatory mechanismleading to higher IGF-1 bioavailability.This interpretation is confirmed by thefinding in hypertensive patients of higherIGF-1 levels than in control subjects (22),and of a positive association amongIGF-1, insulin sensitivity, and preservedvasodilator capacity (23,24). Indeed, inthese patients, IGF-1 was the main inde-pendent predictor of both coronary re-serve and insulin sensitivity (23). Second,alternatively or additionally, one shouldconsider that the interaction betweenIGF-1 and its binding proteins is com-plex. An adequate serum amount of totalIGFBP-1 is essential for IGF-1’s biologicalactivity (8,25), independently of its phos-phorilation status. Moreover, overexpres-sion of IGFBP-1 attenuates IGF-1’sgrowth-promoting actions in vitro but en-

hances them in vivo (26). Thus, a thresh-old concentration of IGFBP-1 mightenhance, rather than impair, IGF-1’s bio-activity through a partial agonism-likeaction.

Because IGFBPs have been character-ized only recently and their physiology inhumans is not completely understood, wethink further studies are needed to betterunderstand the true value of the IGF-1/IGFBP axis in promoting or protectingagainst vascular complications.

ELENA CONTI, MD1

DARIO PITOCCO, MD2

ETTORE CAPOLUONGO, BSC, PHD3

CECILIA ZUPPI, MD3

GIOVANNI GHIRLANDA, MD2

FILIPPO CREA, MD, FESC, FACC1

FELICITA ANDREOTTI, MD, PHD, FESC1

From the 1Department of Cardiology, Catholic Uni-versity, Rome, Italy; the 2Department of Diabetolo-gia, Catholic University, Rome, Italy; and the3Department of Hormonal Chemistry, Rome, Italy.

Address correspondence to Elena Conti, MD, In-stitute of Cardiology, Catholic University, Via Todi60, 00181 Rome. E-mail: [email protected].


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References1. Grant MB, Wargovich TJ, Ellis EA, Cabal-

lero S, Mansour M, Pepine CJ: Localiza-tion of insulin-like growth factor 1 andinhibition of coronary smooth muscle cellgrowth by somatostatin analogues in hu-man coronary smooth muscle cells: a po-tential treatment for restenosis? Circulation89:1511–1517, 1994

2. Frystyk J, Ledet T, Moller N, Flyvbjerg A,Orskov H: Cardiovascular disease and in-sulin-like growth factor 1. Circulation106:893–895, 2002

3. Janssen JA, Lamberts SWJ: The role ofIGF-1 in the development of cardiovascu-lar disease in type 2 diabetes mellitus: isprevention possible? Eur J Endocrinol 146:467–477, 2002

4. Erusalimsky JD, Fenton M: Further invivo evidence that cellular senescence isimplicated in vascular pathophysiology(Letters). Circulation 106:e144, 2002

5. Tepper OM, Galiano RD, Capla JM, KalkaC, Gagne PJ, Jacobowitz GR, Levine JP,Gurtner GC: Human endothelial progen-itor cells from type II diabetics exhibitimpaired proliferation, adhesion, and in-corporation into vascular structures. Cir-culation 106:2781–2786, 2002

6. Juul A, Scheike T, Davidsen M, Gyllen-borg J, Jorgensen T: Low serum insulin-like growth factor 1 is associated withincreased risk of ischemic heart disease: a

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population-based case control study. Cir-culation 106:939–944, 2002

7. Conti E, Crea F, Andreotti F: IGF-1 andrisk of ischemic heart disease. Circulation.In press

8. Sandhu MS, Heald AH, Gibson JM,Cruickshank JK, Dunger DB, WarehamNJ: Circulating concentrations of insulin-like growth factor-1 and development ofglucose intolerance: a prospective obser-vational study. Lancet 359:1740–1745,2002

9. Garay-Sevilla ME, Nava LE, Malacara JM,Wrobel K, Perez U: Advance glycosylationend products (AGEs), insulin-like growthfactor-1 (IGF-1) and IGF binding pro-tein-3 (IGFBP-3) in patients with type 2diabetes mellitus. Diabetes Metab Res Rev16:106–113, 2000

10. Janssen JAMIL, Lamberts SWJ: Circulat-ing IGF-1 and its protective role in thepathogenesis of diabetic angiopathy. Clin-ical Endocrinology 52:1–9, 2000

11. Muniyappa R, Walsh MF, Rangi JS, ZayasRM, Standley PR, Ram JL: Insulin-likegrowth factor 1 increases vascular smoothmuscle nitric oxide production. Life Sci-ence 61:925–931, 1997

12. Conti E, Andreotti F, Sestito A, Riccardi P,Menini E, Crea F, Maseri A, Lanza GA:Markedly reduced insulin-like growthfactor-1 associated with insulin resistancein syndrome X patients. Am J Cardiol 89:973–975, 2002

13. Conti E, Andreotti F, Sciahbasi A, Ric-cardi P, Marra G, Menini E, Ghirlanda G,Maseri A: Markedly reduced insulin-likegrowth factor-1 in the acute phase ofmyocardial infarction. J Am Coll Cardiol38:26–32, 2001

14. Friberg L, Werner S, Eggertsen G, AhnveS: Growth hormone and insulin-likegrowth factor-1 in acute myocardial in-farction. Eur Heart J 21:1547–1554, 2000

15. Stewart DJ, on behalf of the REVASCStudy Investigators: A phase 2, random-ized, multicenter, 26-week study to assessthe efficacy and safety of BIOBYPASS(AdGVVEGF121,10) delivered throughminimally invasive surgery versus maxi-mum medical treatment in patients withsevere angina, advanced coronary arterydisease, and no options for revasculariza-tion (Abstract). Circulation 106:2986, 2002

16. Losordo DW, Kawamoto A: Biological re-vascularization and the interventionalmolecular cardiologist: bypass for thenext generation. Circulation 106:3002–3005, 2002

17. Vale PR, Isner JM, Rosenfield K: Thera-peutic angiogenesis in critical limb andmyocardial ischemia. J Interv Cardiol 14:511–528, 2001

18. Leinonen ES, Salonen JT, Salonen RM,Koistinen RA, Leinonen PJ, Sarna SS,Taskinen MR: Reduced IGFBP-1 is asso-

ciated with thickening of the carotid wallin type 2 diabetes. Diabetes Care 25:1807–1812, 2002

19. Heald AH, Siddals KW, Fraser W, TaylorW, Kaushal K, Morris J, Young RJ, WhiteA, Gibson JM: Low circulating levels ofinsulin-like growth factor binding pro-tein-1 (IGFBP-1) are closely associatedwith the presence of macrovascular dis-ease and hypertension in type 2 diabetes.Diabetes 51:2629–2636, 2002

20. Baxter RC: Insulin-like growth factor(IGF)-binding proteins: interactions withIGFs and intrinsic bioactivities. Am J PhysiolEndocrinol Metab 278:E967–E976, 2000

21. Schneider MR, Lahm H, Wu M, HoeflichA, Wolf E: Transgenic mouse models forstudying the functions of insulin-likegrowth factors. FASEB J 14:629–640, 2000

22. Galderisi M, Vitale G, Lupoli G, BarbieriM, Varricchio G, Carella C, de Divitiis O,Paolisso G: Inverse association betweenfree insulin-like growth factor-1 and iso-volumic relaxation in arterial systemic hy-pertension. Hypertension 38:240–245, 2001

23. Galderisi M, Caso P, Cicala S, De SimoneL, Barbieri M, Vitale G, de Divitiis O, Pa-olisso G: Positive association between cir-culating free insulin-like growth factor-1levels and coronary flow reserve in arterialsystemic hypertension. Am J Hypertens15:766–772, 2002

24. Laviades C, Gil MJ, Monreal I, GonzalezA, Diez J: Tissue availability of insulin-likegrowth factor I is inversely related to in-sulin resistance in essential hypertension:effects of angiotensin converting enzymeinhibition. J Hypertens 16:863–870, 1998

25. Shinobe M, Sanaka T, Nihei H, NobuhiroS: IGF-1/IGFBP-1 as an index for discrim-ination between responder and nonre-sponder to recombinant human growthhormone in malnourished uremic pa-tients on hemodialysis. Nephron 77:29–36, 1997

26. Modric T, Rajkumar K, Murphy LJ: Thy-roid gland function and growth in IGFbinding protein-1 transgenic mice. Eur JEndocrinol 141:149–159, 1999

IGF BindingProtein-1 andCarotid Intima-Media Thickness inType 2 DiabetesResponse to Conti et al.

W e thank Conti et al. (1) for theirinterest in our recent article (2)and the editor for the opportu-

nity to further discuss the role of the IGFsystem in atherosclerosis.

We found an inverse relation betweenIGF binding protein-1 (IGFBP-1) and ca-rotid intima-media thickness (IMT) intype 2 diabetic patients. In the linear re-gression model for diabetic subjects withcardiovascular disease (CVD), IGFBP-1was one of the main determinants of IMT(standardized coefficient � �0.353,P � 0.027) together with age, Apo B, andpulse pressure; other determinants werediabetes duration, smoking, BMI, sex,and lipoprotein [Lp(a)]. This model ex-plained 57.3% of maximum IMT varia-tion. IGFBP-1 also remained in the linearregression model for IMT in subjectswithout CVD. Our cross-sectional studysetting does not allow the interpretationto which extent these associations arecausal. In agreement with previous data(3), IGFBP-1 concentration was inverselyrelated to insulin resistance examined byhomeostasis model assessment.

On the contrary, after adjusting forconfounders, we found no association be-tween total IGF-I and either IMT or pres-ence of CVD. This indicates the relationbetween IGFBP-1 and IMT to be indepen-dent of IGF-I. Our results underlineIGFBP-1 as a marker of insulin resistanceand the metabolic syndrome, but thiscannot be extrapolated to reflect an IGF-Ieffect on the vasculature. Similarly, Healdet al. (4) demonstrated an inverse corre-lation between IGFBP-1, but not IGF-I,and clinical cardiovascular disease in type2 diabetic subjects.

Another finding was the positive cor-relation of total IGF-I with LDL choles-terol and Lp(a) and IGFBP-3 with LDLcholesterol, Lp(a), total cholesterol, andApo B after controlling for age, sex, BMI,and diabetes duration. Thus, in hyper-cholesterolemic diabetic patients the IGFaxis seems to be activated.

The relation of the IGF system to CVDis complex and awaits a conclusive an-swer after over 1,000 published articles(5). Therefore, we agree with Conti et al.that further research is needed to under-stand the entire picture.

EEVA S. LEINONEN, MD1

PEKKA J. LEINONEN, MD, PHD2

MARJA-RIITTA TASKINEN, MD, PHD1

From the 1Department of Internal Medicine, Hel-sinki University Central Hospital, Helsinki, Finland;and the 2Department of Obstetrics and Gynecology,Helsinki University Central Hospital, Helsinki, Fin-land.

Address correspondence to Professor Marja-

Letters


Riitta Taskinen, Helsinki University Hospital, Bio-medicum, Haartmaninkatu 8, P.O. Box 700, 00029Helsinki, Finland. E-mail: [email protected].


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References1. Conti E, Pitocco D, Capoluongo E, Zuppi

C, Ghirlanda G, Crea F, Andreotti F:IGF-1 and macrovascular complicationsof diabetes: alternative interpretations ofrecently published data (Letter). DiabetesCare 26:1653–1654, 2003

2. Leinonen ES, Salonen JT, Salonen RM,Koistinen RA, Leinonen PJ, Sarna SS,Taskinen MR: Reduced IGFBP-1 is asso-ciated with thickening of the carotid wallin type 2 diabetes. Diabetes Care 25:1807–1812, 2002

3. Mohamed-Ali V, Pinkney JH, Panahloo A,Cwyfan-Hughes S, Holly JM, Yudkin JS:Insulin-like growth factor binding pro-tein-1 in NIDDM: relationship with theinsulin resistance syndrome. Clin Endocri-nol (Oxf) 50:221–228, 1999

4. Heald AH, Siddals KW, Fraser W, TaylorW, Kaushal K, Morris J, Young RJ, WhiteA, Gibson JM: Low circulating levels ofIGF binding protein-1 are closely associ-ated with the presence of macrovasculardisease and hypertension in type 2 diabe-tes. Diabetes 51:2629–2636, 2002

5. Frystyk J, Ledet T, Møller N, Flyvbjerg A,Ørskov H: Cardiovascular disease and in-sulin-like growth factor I. Circulation 106:893–895, 2002

Metformin in Type 1Diabetes

Is this a good or bad idea?

The article by Meyer et al. (1) revivesa debate regarding the appropriate-ness of metformin use for people

with type 1 diabetes. Given the potentialfor coexisting lactic acidosis and diabeticketoacidosis, how can one justify its use?Indeed, there was little reason to expect abenefit in patients who were studied:nonobese type 1 diabetic subjects withHbA1c �9.0% who were taking �0.7units � kg insulin�1 � day�1. A modestaverage reduction of daily insulin require-ments, 4.3 units, as compared with an in-crease of 1.7 units for placebo, does notseem to be worth the trade-off of in-creased risk for severe hypoglycemia (19events in metformin group vs. 8 events inplacebo group). There was no differentialeffect in terms of HbA1c. Only 7 of 31

patients (23%) treated with metformin re-sponded in terms of a significant (20%)reduction in insulin requirement. Fur-thermore, it is likely that the incidence ofhypoglycemia would be much greater ifmore aggressive metabolic targets ofHbA1c had been applied. Despite the fail-ure to observe diabetic ketoacidosis, thelimited number and short period of ob-servation does not permit the conclusionthat metformin is safe in ketosis-prone di-abetic subjects.

We have seen a number of type 1diabetic patients who have received met-formin prescriptions by other practitio-ners. It appears that these prescriptionswere given because of a failure to identifylatent autoimmune diabetes in adults orbecause the physician believed that thepotential for insulin dose reduction andlipid improvement justified a putativesmall risk for diabetic ketoacidosis andlactic acidosis. The temptation to pre-scribe metformin is increased because ofthe high prevalence of metabolic syn-drome among U.S. adults (2). Indeed, thediagnosis of metabolic syndrome can fre-quently be made in the type 1 diabeticpopulation. For example, using BMI as amarker for metabolic syndrome, we ob-served an average BMI of 27 kg/m2 in 343consecutive subjects with type 1 diabetes;this means that our average type 1 dia-betic patient is overweight. A BMI �30kg/m2, sufficient to diagnosis obesity, wasobserved in 89 of 343 subjects (26%).Seven of our type 1 diabetic patients had aBMI �41 kg/m2. Of these severely obesesubjects, two were receiving metformintherapy as well as insulin.

The results of the study by Meyer etal. suggest that a small subset of type 1diabetic patients benefit in terms of insu-lin dose reduction when metformin isadded to insulin. Questions about long-term safety and efficacy in this patientpopulation remain unanswered. There-fore, when is it reasonable and defensibleto prescribe metformin in type 1 diabetes?We suggest that metformin should beavoided unless the following criteria aremet: 1) insulin resistence is clearly inter-fering with satisfactory glucose controldespite lifestyle interventions; 2) the riskof diabetic ketoacidosis is minimized byan intensive program of insulin, self-monitoring of blood glucose, urine ke-tone measurement if blood glucoseexceeds 300 mg/dl, and regular medicalsupervision; 3) the patient receives coun-

seling so that he or she understands thepotential risk for lactic acidosis; and 4)efficacy is frequently evaluated to justifycontinued use of metformin.

J. DAVID FAICHNEY, MD, FACP

PHILIP W. TATE, MD

From the Center for Diabetes and Endocrinology,Saint Mary’s Mercy Medical Center, Grand Rapids,Michigan.

Address correspondence to J. David Faichney,Center for Diabetes and Endocrinology, Saint Mary’sMercy Medical Center, 300 Lafayette SE, Suite 2045,Grand Rapids, MI 49503. E-mail: [email protected].


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References1. Meyer L, Bohme P, Delbachian I, Lehert P,

Cugnardey N, Drouin P, Guerci B: Thebenefits of metfomin therapy during con-tinuous subcutaneous insulin infusiontreatment of type 1 diabetic patients. Di-abetes Care 25:2153–2158, 2002

2. Ford ES, Giles WH, Dietz WH: Prevalenceof the metabolic syndrome among USadults: findings of the third NationalHealth and Nutrition Examination Sur-vey. JAMA 287:356–359, 2002

Metformin andInsulin in Type 1Diabetes

The first step

T he insulin-sparing effect of met-formin and its positive effect on glu-cose metabolism is now well

documented in insulin-treated type 2 di-abetic patients, although the mechanismsof these effects are not overly clear (1). Ininsulin-treated type 1 diabetic patients,the use of metformin has only been as-sessed in a few studies and, surprisingly,the same insulin-sparing effect has beenfound despite some methodological diffi-culties. However, the clinical interest ofmetformin in the treatment of type 1 dia-betes has remained questionable. For thefirst time, we have shown in a randomizeddouble-blind trial that metformin has aninsulin-sparing effect in type 1 diabeticpatients (even if the studied populationwas not clinically insulin resistant) (2).

The selected patients were C-peptidenegative after intravenous glucagon injec-tion and were not identified as having

Letters


metabolic syndrome. The patients weremoderately overweight (BMI close to 25kg/m2), and their daily insulin needs werenot greater than that seen for other type 1diabetic patients. The insulin-sparing ef-fect of metformin was obtained for basalinsulin needs but not for prandial needs.Although no definitive explanation couldbe given, it is now clear that the use ofmetformin may be appropriate for sometype 1 diabetic patients.

Our study was designed to assess theinsulin-sparing effect of metformin in in-sulin-treated type 1 diabetic patients, andthis end was achieved. However, it wasnot designed to give clinical or biologicalcriteria of indications associated withmetformin use and insulin. We found thata subset of patients had a reduction of atleast 20% in insulin requirements withstable and satisfactory glucose control,but a backward logistic regression did notallow prediction criteria of a good re-sponse to be defined. Thus, an expandedstudy using selection criteria identified inour previous study coupled with a largerrange of BMI or bodyweight and a largerrange of daily insulin doses in selectedpatients must be performed to determinetherapeutic indications of this association

We believe that metformin use couldbe beneficial in type 1 diabetic patientswho are overweight or obese, are receiv-ing large doses of insulin, and have anHbA1c �8%. The use of metformin couldbe very useful in these patients but mustbe carried out under clinical and biologi-cal supervision to avoid complicationssuch as lactic acidosis, which remains ex-ceptional in our experience of type 1 andin type 2 diabetic patients.

LAURENT MEYER, MD

BRUNO GUERCI, MD, PHD

From the Service de Diabetologie, MaladiesMetaboliques & Maladies de la Nutrition, CIC-INSERM, Hopital Jeanne d’Arc, Centre Hospitalo-Universitaire de Nancy, Toul Cedex, France.

Address correspondence to Laurent Meyer, Ser-vice de Diabetologie, Maladies Metaboliques & Mal-adies de la Nutrition, CIC-INSERM, Hopital Jeanned’Arc, Centre Hospitalo-Universitaire de Nancy,B.P. 303, 54201 Toul Cedex, France. E-mail:[email protected].


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References1. Wulffele MG, Kooy A, Lehert P, Bets D,

Ogterop JC, Borger van der Burg B,Donker AJ, Stehouwer CD: Combination

of insulin and metformin in the treatmentof type 2 diabetes. Diabetes Care 25:2133–2140, 2002

2. Meyer L, Bohme P, Delbachian I, Lehert P,Cugnardey N, Drouin P, Guerci B: Thebenefits of metformin therapy duringcontinuous subcutaneous insulin infu-sion treatment of type 1 diabetic patients.Diabetes Care 25:2153–2158, 2002

Prospective Relationof C-Reactive ProteinWith Type 2Diabetes

Response to Han et al.

W e read with great interest the ar-ticle by Han et al., which was re-cently published in Diabetes Care

(1). The authors studied the associationbetween baseline levels of C-reactive pro-tein (CRP) and the 6-year incidence of themetabolic syndrome and type 2 diabetesin Mexican subjects. They found an oddsratio (OR) of 4.1 (95% CI 2.1–8.0) fordeveloping the metabolic syndrome andan OR of 5.4 (2.2–13.4) for incident type2 diabetes among women in the highestcompared with the lowest tertile of CRP.ORs were adjusted for age, smoking,physical activity, and alcohol intake. Inmen, no such association was found. Ad-ditional adjustment for BMI slightly low-ered the ORs; adjustment for waist-to-hipratio (WHR) did not.

We have studied baseline CRP levelsand their relation to incident type 2 dia-betes in an age-, sex-, and glucose-stratified sample of the Hoorn Study, apopulation-based cohort study of glucosetolerance among Caucasian people (2).The study methods and follow-up dura-

tion are closely similar to the Mexico CityDiabetes Study (MCDS) described by Hanet al., except that our subjects were �15years older at baseline. Glucose tolerancestatus was assessed by a 75-g oral glucosetolerance test at baseline and after 6.4years of follow-up. CRP was measured inplasma by high-sensitive enzyme-linkedimmunosorbent assay, while informationwas available on BMI, WHR, smoking,and physical activity. Of the 140 men and139 women who had follow-up measure-ments and were free of diabetes at base-line, 17.8% of the men and 20.9% of thewomen developed diabetes. In contrast tothe findings of Han et al., we did not ob-serve an association between baselineCRP levels and incident diabetes inwomen, while in men we found an OR of3.0 (95% CI 1.0–9.3) in the highest com-pared with the lowest tertile of CRP, afteradjustment for age (Table 1). Further ad-justment for BMI, smoking, or physicalactivity did not materially change theseresults, while adding WHR to the modelsubstantially lowered the OR in men.Thus, in the Hoorn Study, CRP is not avery strong determinant of the develop-ment of type 2 diabetes, in contrast toWHR and impaired glucose metabolism(3). We realize that our study sample of279 subjects is much smaller than thestudy presented by Han et al. (n � 1,244).The relationship in men, however, wasstrong, whereas in the MCDS it wasstrong only in women. In the previousprospective study by Barzilay et al. (4) anOR of 2.0 (1.4–2.9) was found when ex-treme quartiles of CRP were compared.They did not analyze men and women orblack and white subjects separately.Pradhan et al. (5) found an OR of 4.2(1.5–12.0) in women. Both studies didnot take WHR into account. Ethnicity

Table 1—Relative risk associated with high C-reactive protein (second and third tertile com-pared with the first tertile) for developing type 2 diabetes after 6.4 years of follow-up in theHoorn Study

Model

Men Women

2nd tertile 3rd tertile 2nd tertile 3rd tertile

1 Age 1.4 (0.4–4.8) 3.0 (1.0–9.3) 0.7 (0.3–2.1) 1.1 (0.4–3.0)2 Model 1 � BMI 1.4 (0.4–4.8) 3.0 (1.0–9.3) 0.6 (0.2–1.8) 0.9 (0.3–2.5)3 Model 1 � WHR 1.4 (0.4–4.8) 1.9 (0.6–6.4) 0.6 (0.2–1.7) 0.9 (0.3–2.5)4 Model 1 � smoking 1.3 (0.4–4.7) 2.9 (0.9–9.2) 0.7 (0.3–2.1) 1.2 (0.4–3.2)5 Model 1 � physical activity 1.4 (0.4–4.7) 3.0 (1.0–9.3) 0.7 (0.3–2.1) 1.1 (0.4–3.0)

Data are OR (95% CI).

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may also play an important role in ex-plaining the inconsistent results.

In conclusion, we suggest caution inthe interpretation of the results because ofinconsistent findings, in particular be-tween sexes. It is unclear why inflamma-tion would be important in the patho-genesis of type 2 diabetes only in womenor only in men.

MARIEKE B. SNIJDER, MSC1

JACQUELINE M. DEKKER, PHD1

MARJOLEIN VISSER, PHD1

COEN D.A. STEHOUWER, MD, PHD1,2

JOHN S. YUDKIN, MD1,3

LEX M. BOUTER, PHD1

ROBERT J. HEINE, MD, PHD1,4

GIEL NIJPELS, MD, PHD1

JACOB C. SEIDELL, PHD1,5

From the 1Institute for Research in Extramural Med-icine, VU University Medical Center, Amsterdam,the Netherlands; the 2Department of Internal Med-icine, VU University Medical Center, Amsterdam,the Netherlands; the 3Department of Medicine, Di-abetes and Cardiovascular Disease Academic Unit,University College London Medical School, Lon-don, U.K.; the 4Department of Endocrinology, VUUniversity Medical Center, Amsterdam, the Nether-lands; and the 5Department of Nutrition and Health,Faculty of Earth and Life Sciences, Vrije Universiteit,Amsterdam, the Netherlands.

Address correspondence to Marieke B. Snijder,MSC, Institute for Research in Extramural Medicine,VU University Medical Center, Van der Boechorst-straat 7, 1081 BT Amsterdam, The Netherlands. E-mail: [email protected].


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References1. Han TS, Sattar N, Williams K, Gonzalez-

Villalpando C, Lean ME, Haffner SM: Pro-spective study of C-reactive protein inrelation to the development of diabetesand metabolic syndrome in the MexicoCity Diabetes Study. Diabetes Care 25:2016–2021, 2002

2. Mooy JM, Grootenhuis PA, de Vries H,Valkenburg HA, Bouter LM, Kostense PJ,Heine RJ: Prevalence and determinants ofglucose intolerance in a Dutch Caucasianpopulation: the Hoorn Study. DiabetesCare 18:1270–1273, 1995

3. de Vegt F, Dekker JM, Jager A, HienkensE, Kostense PJ, Stehouwer CD, Nijpels G,Bouter LM, Heine RJ: Relation of impairedfasting and postload glucose with incidenttype 2 diabetes in a Dutch population: theHoorn Study. JAMA 285:2109–2113, 2001

4. Barzilay JI, Abraham L, Heckbert SR,Cushman M, Kuller LH, Resnick HE,Tracy RP: The relation of markers of in-flammation to the development of glucosedisorders in the elderly: the Cardiovas-

cular Health Study. Diabetes 50:2384 –2389, 2001

5. Pradhan AD, Manson JE, Rifai N, BuringJE, Ridker PM: C-reactive protein, inter-leukin 6, and risk of developing type 2 dia-betes mellitus. JAMA 286:327–334, 2001

Prospective Relationof C-Reactive ProteinWith Type 2 Diabetes

Response to Snijder et al.

W e thank Snijder et al. (1) for theirinterest in our article (2) and forsharing their data relating C-re-

active protein (CRP) to the risk of diabetesdevelopment in the Hoorn Study. Wereadily agree that it is unclear why inflam-mation might be more important to thepathogenesis of type 2 diabetes in womencompared with men or indeed vice versa.We have reanalyzed our CRP data usingthe same covariates as Snijder et al. andessentially our results are unchanged—the relation between CRP and diabetes re-mains strong in women, even afterinclusion of waist-to-hip ratio (WHR),but is absent in men (Table 1). Interest-ingly, on reanalysis of similarly relevantdata from the Insulin Resistance Athero-sclerosis Study (IRAS) (3), a study of sim-ilar size to the Mexico City Diabetes Study(MCDS), the relation between baselineCRP and diabetes development was alsostronger in women compared with menusing the same covariate adjustments(data not shown). Moreover, in both theMCDS and IRAS, adjustment for BMI at-

tenuated the link between CRP and dia-betes more so than WHR.

One possibility of the divergent re-sults could be the younger baseline age(�46 years) in MCDS in comparison tothat of the Hoorn study (�61 years). Inthis respect it is important to consider theadditional potential confounding influ-ence of hormonal replacement therapy(HRT) in women. HRT use increases CRPconcentrations in women (4), but para-doxically recent data from the Heart andEstrogen/Progestin Replacement Studysuggest that HRT reduces risk of diabetesdevelopment by 35% (5). In MCDS, only4% of women were on HRT at baselineand hormonal use did not confound thelink between CRP and diabetes. However,because of higher age, a potentially muchhigher proportion of women in the HoornStudy may have been on HRT at baseline,which could thus disguise any potentialassociation between CRP and diabetesrisk.

We acknowledge that our inability tofind an association between CRP and di-abetes risk in men may simply be due to alack of power. A recent relevant study (6)from the West of Scotland Coronary Pre-vention Study (WOSCOPS) group thatincluded 127 new cases (predominantlyCaucasian) of diabetes reported a strongassociation between baseline CRP and di-abetes risk independent of BMI, bloodpressure, smoking, and fasting lipids andglucose concentrations. Alternatively andas Snijder et al. suggest, ethnicity may alsoplay a role in explaining inconsistentresults.

Clearly, further studies are needed toexamine the relation between inflamma-

Table 1—ORs (with 95% CIs) associated with high C-reactive protein (second and third tertilecompared to first tertile) for developing type 2 diabetes after 6.5 years of follow-up in theMexico City Diabetes Study

Model

Men(35 incident cases/n � 460)

Women(54 incident cases/n � 672)

Second tertile(0.91–1.64 ng/ml)

Third tertile(�1.64 ng/ml)

Second tertile(1.24–2.16 ng/ml)

Third tertile(�2.16 ng/ml)

1 Age 0.7 (0.3–1.7) 1.0 (0.5–2.3) 3.1 (1.2–7.9)* 5.7 (2.3–13.9)†2 Model 1 � BMI 0.6 (0.2–1.4) 0.8 (0.4–1.9) 2.2 (0.9–5.8)* 3.1 (1.2–8.1)*3 Model 1 � WHR 0.6 (0.2–1.5) 0.9 (0.4–2.1) 3.0 (1.2–7.7)* 5.4 (2.2–13.3)†4 Model 1 � smoking 0.7 (0.3–1.7) 1.0 (0.5–2.3) 3.1 (1.2–8.0)* 5.7 (2.3–14.1)†5 Model 1 � physical

activity0.7 (0.3–1.6) 0.9 (0.4–2.0) 2.7 (1.0–7.1)* 5.3 (2.2–13.2)†

The main effect of gender is significant (P � 0.05) for each model. Gender-CRP tertile interaction: *P � 0.05,†P � 0.01.

Letters


tory markers and diabetes risk. It wouldbe useful if such studies were to reportassociations separately in men andwomen in order to enable identification ofany potential gender differences.

NAVEED SATTAR, MD, PHD1

KEN WILLIAMS, MS2

THANG S. HAN, MD, PHD3

CLICERIO GONZALEZ-VILLALPANDO, MD4

MICHAEL E.J. LEAN, MD, FRCP5

STEVEN M. HAFFNER, MD, MPH2

From the 1University Department of PathologicalBiochemistry, Glasgow Royal Infirmary, GlasgowU.K.; the 2Department of Medicine #7873, Univer-sity of Texas Health Science Center at San Antonio,San Antonio, Texas; 3Addenbrooke’s Hospital,Cambridge University Medical School, Cambridge,U.K.; the 4Center de Estudios in Diabetes, MexicoCity, Mexico; and the 5University Department ofHuman Nutrition, Glasgow Royal Infirmary, Glas-gow, U.K.

Address correspondence to Steven M. Haffner,MD, Department of Medicine #7873, University ofTexas Health Science Center at San Antonio, SanAntonio, TX 78229-3900. E-mail: [email protected].


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References1. Snijder MB, Dekker JM, Visser JM, Ste-

houwer CDA, Yudkin JS, Bouter LM,Heine RJ, Nijpels G, Seidell JC: Prospec-tive relation of C-reactive protein withtype 2 diabetes (Letter). Diabetes Care 26:1656–1657, 2003

2. Han TS, Sattar N, Williams K, Gonzalez-Villalpando C, Lean ME, Haffner SM: Pro-spective study of C-reactive protein inrelation to the development of diabetesand metabolic syndrome in the MexicoCity Diabetes Study. Diabetes Care 25:2016–2021, 2002

3. Festa A, D’Agostino R Jr, Tracy RP,Haffner SM: Elevated levels of acute-phase proteins and plasminogen activatorinhibitor-1 predict the development oftype 2 diabetes: the insulin resistance ath-erosclerosis study. Diabetes 51:1131–1137, 2002

4. Manning PJ, Sutherland WH, Allum AR,de Jong SA, Jones SD: Effect of hormonereplacement therapy on inflammation-sensitive proteins in post-menopausalwomen with type 2 diabetes. Diabet Med19:847–852, 2002

5. Kanaya AM, Herrington D, Vittinghoff E,Lin F, Grady D, Bittner V, Cauley JA, Bar-rett-Connor E: Glycemic effects of post-menopausal hormone therapy: the Heartand Estrogen/progestin ReplacementStudy: a randomized, double-blind, pla-cebo-controlled trial. Ann Intern Med 138:1–9, 2003

6. Freeman DJ, Norrie J, Caslake MJ, Gaw A,Ford I, Lowe GD, O’Reilly DS, Packard CJ,Sattar N: C-reactive protein is an indepen-dent predictor of risk for the developmentof diabetes in the West of Scotland Coro-nary Prevention Study. Diabetes 51:1596–600, 2002

A MultivariateLogistic RegressionEquation to Screenfor Diabetes

Response to Tabaei and Herman

W e read the article by Tabaei andHerman (1) in the November2002 issue of Diabetes Care with

great interest and feel that it covers anexciting and vital area of diabetes re-search. We applaud the authors’ attemptsto improve current standards of diabetesscreening and the journal’s willingness topublish important new findings in thefield. However, when we reviewed the ar-ticle, we found the results difficult to re-produce, especially as there were nonumerical examples provided in the text.Using the precise formula given in the ar-ticle, our calculations produced negativeprobability values. We would thereforelike to take this opportunity to point out asource of possible error in the equationand clarify the logistic regression model.

The logistic regression model and the“logit” model can be written as:

ln P/�1 � P)] � 0 � iXi � e (2)

where X � 0 � iXi are the coefficients(parameters) for the linear predictor andXi represents the values of the explanatoryvariables (we have assumed that these co-efficients have been correctly estimated inthe article); ln is the natural logarithm,logexp, where exp � 2.71828. . . ; P is theprobability that the event “previously un-diagnosed diabetes” occurs; P/(1 � P) isthe “odds ratio”; and ln[P/(1 � P)] is thelog odds ratio, or “logit.”

In contrast to the simple linear prob-ability model (Y � a � bX � e), the logitdistribution constrains the estimatedprobabilities to lie between 0 and 1. Forinstance, the estimated probability is:

P � [exp(0 � iXi)]/[1 � exp(0 � iXi)]

or

P � 1/[1 � exp (�0 � iXi)]

For a 45-year-old man with a BMI of29 kg/m2, a plasma glucose level of 125mg/dl, and a postprandial time of 3 h, theprobability calculated with the publishedformula would be P � �0.0555 (i.e. P �0). This result does not match the require-ment for probabilities to lie between 0 and1. For the same case, but with the cor-rected formula, the probability of beingpreviously undiagnosed for diabetes isP � 0.04996.

Details of the calculation with theformula published in the article:

P � 1/[1 � exp(�X)]

X � �10.0382 � 0.0331*(age � 45years) � 0.0308*(plasma glucose � 125mg/dl) � 0.25*(postprandial time � 3 h)� 0.562*(sex � 0) � 0.0346*(BMI � 29kg/m2). X � �2.9453 and P � 1/[1 �exp(�X)] � 1/(1 � exp(2.9453) � 1/(1 �19.01636644) � 1/�18.01636644. P ��0.0555.

Details of the calculation with thecorrected formula:

P � 1/[1 � exp(�X)]

X � �2.9453; P � 1/[1 � exp(�X)] �1/ (1 � exp[2 .9453]) � 1/ (1 �19.01636644) � 1/20.01636644; P �0.04996.

Therefore, we would suggest that thefollowing equations should be used:

X � �10.0382 � 0.0331*(age) � 0.0308*

(plasma glucose) � 0.25* (postprandial

time) � 0.562 (if female) � 0.0346* (BMI)

and P � 1/[1 � exp(�X)]

We hope these comments serve toclarify this logistic regression equation toscreen for diabetes and, in conjunctionwith the valuable work of our colleaguesDrs. Tabaei and Herman, help expand theknowledge base in this key area of diabe-tes research.

STEPHANE ROZE, MSC

ANDREW J. PALMER, BSC, MBBS

WILLIAM J. VALENTINE, PHD

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From the Center for Outcomes Research (CORE),Basel, Switzerland.

Address correspondence to Stephane Roze,CORE: Center for Outcomes Research, St. Johanns-Ring 139, 4056 Basel, Switzerland. E-mail: [email protected].


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References1. Tabaei BP, Herman WH: A multivariate

logistic regression equation to screen fordiabetes. Diabetes Care 25:1999–2003,2002

2. Hosmer D, Lemeshow S: Applied LogisticRegression. New York, Wiley, 1989

A MultivariateLogistic RegressionEquation to Screenfor Diabetes

Response to Roze, Palmer, andValentine

W e would like to thank Roze,Palmer, and Valentine (1) fortheir careful reading of our arti-

cle (2) entitled “A multivariate logisticregression to screen for diabetes: develop-ment and validation.” The estimatedprobability formula for the logistic regres-sion model was indeed misprinted with aminus sign. The correct estimated proba-bility formula is:

P � 1/(1 � e�x), where x ��10.0382 � [0.0331 (age in years) �0.0308 (random plasma glucose in mg/dl) � 0.2500 (postprandial time assessedas 0 to 8� hours) � 0.5620 (if female) �0.0346 (BMI)].

BAHMAN P. TABAEI, MPH1

WILLIAM H. HERMAN, MD, MPH1,2

From the 1Department of Internal Medicine, Uni-versity of Michigan Health System, Ann Arbor,Michigan; and the 2Department of Epidemiology,University of Michigan Health System, Ann Arbor,Michigan.

Address correspondence to William H. Herman,MD, MPH, University of Michigan Health System,Division of Endocrinology and Metabolism, 1500East Medical Center Dr., 3920 Taubman Center,Ann Arbor, MI 48109-0354. E-mail: [email protected].


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References1. Roze S, Palmer AJ, Valentine WJ: A mul-

tivariate logistic regression equation toscreen for diabetes (Letter). Diabetes Care26:1658–1659, 2003

2. Tabael BP, Herman WH: A multivariatelogistic regression equation to screen fordiabetes. Diabetes Care 25:1999–2003,2002

�2-AdrenergicReceptorPolymorphism andObesity in Type 2DiabetesResponse to van Tilburg et al.

W e read with interest the observa-tion letter by van Tilburg et al.(1) reporting that the Glu27Gln

polymorphism of the 2-adrenergic re-ceptor (B2ADR) has no important effecton BMI, metabolic control, or plasma lip-ids. However, the authors did not men-tion the physical activity and diet regimenin their study. B2ADR is a major lipolyticreceptor in human adipocytes, activatedby catecholamines especially during aweight reduction regimen. Meirhaeghe etal. (2) reported that B2ADR Glu27Glnpolymorphism is significantly associatedwith obesity in individuals who do nothave regular physical activity, while noeffect of such polymorphism is found inthose who do have physical activity, andsuggested that obese individuals withB2ADR Glu27Gln genotype may benefitfrom physical activity to reduce their bodyweight. We also demonstrated the same as-sociation between another B2ADR poly-morphism (Arg16Gly) and obesity inindividuals treated with a combined low-energy diet and exercise regimen (3). There-fore, the authors should have furtherdivided the subjects according to the degreeof their physical activity and analyzed thedata, because body weight and body fat ormetabolic control are influenced by physi-cal activity and dietary changes, especiallyin individuals with such polymorphisms.

KEIJI YOSHIOKA, MD1

TOSHIHIDE YOSHIDA, MD2

TOSHIKAZU YOSHIKAWA, MD2

From the 1Department of Diabetes and Endocrinol-ogy, Matsushita Memorial Hospital, Moriguchi,

Osaka, Japan; and the 2Department of Diabetes, En-docrinology, and Metabolism, Kyoto PrefecturalUniversity of Medicine, Koyto, Japan.

Address correspondence to Keiji Yoshioka. De-partment of Diabetes and Endocrinology, Matsushi-ta Memorial Hospital, 5-55, Sotojma-cho, Moriguchi,Osaka, Japan. E-mail: [email protected].


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References1. van Tilburg JH, Wijmenga C, van Bakel H,

Rozeman L, Pearson PL, van Haeften TW:Relationship of 2-adrenergic receptorpolymorphism with obesity in type 2diabetes (Letter). Diabetes Care 26:251–252, 2003

2. Meirhaeghe A, Helbecque N, Cottel D,Amouyel P: 2-adrenoceptor gene poly-morphism, body weight, and physical ac-tivity. Lancet 353:896, 1999

3. Sakane N, Yoshida T, Umekawa T, Ko-gure A, Kondo M: 2-adrenoceptor genepolymorphism and obesity. Lancet 353:1976, 1999

�2-AdrenergicReceptorPolymorphism andObesity in Type 2DiabetesResponse to Yoshioka, Yoshida,and Yoshikawa

W e recently reported that ourgroup (n � 502) of type 2 dia-betic subjects did not reveal sta-

tistically significant differences in BMIwith respect to the three groups of carriersof 2-adrenergic receptor polymor-phisms (1). Meirhaghe et al. (1) reportthat in men not participating in physicalactivity, Gln27Gln carriers had a higherBMI than the Glu27 (combined heterozy-gous and homozygous) carriers (27.2 �0.4 vs. 25.2 � 0.3 kg/m2), while no effecton BMI was found in the men not partic-ipating in physical activity.

We have not collected data on thephysical activity of our subjects. How-ever, taking into account that our subjectshad a mean age of 61 � 9 years (roughly10 years older than the subjects reportedby Meirhaghe et al.), we suspect that thevast majority of them do not participate inmuch physical activity. In any case, theirphysical activity is presumably less thanthat of the subjects studied by Meirhagheet al. Much to our surprise, we actually

Letters


find the opposite, which is a lower (andnot a higher!) BMI (27.2 � 3.8) in theGln27Gln carriers compared with theothers (27.9 � 4.4 for Gln27Glu and28.2 � 4.0 kg/m2 for Glu27Glu), al-though the differences did not attain sta-tistical significance. These findings weresimilar for men and women when takentogether or separately.

Obviously, there are two major differ-ences between these two studies. The sub-jects in our study (2) had type 2 diabetesand were considerably older. Whetherthese two differences explain the diver-gent findings of the study of Meirhaghe etal. and our study is uncertain. However,the suggestion by van Tilburg et al. that, ifanything, the BMI was lower (and nothigher) in the Gln27Gln27 group might

point to a chance finding in the studies byMeirhaghe et al. As for the observationsregarding the Arg16Gly polymorphism,we have not studied this polymorphismsin our group of subjects.

It has become more and more clearthat association studies of a particularpolymorphism with a certain physiologi-cal parameter are often hard to replicate;this necessitates the need to perform rep-lication studies before a finding can beregarded as truly positive.

JONATHAN H. VAN TILBURG, PHD1

CISCA WIJMENGA, PHD1

TIMON W. VAN HAEFTEN, MD2

From the 1Department of Biomedical Genetics, Uni-versity Medical Center, Utrecht, the Netherlands;

and the 2Department of Internal Medicine, Univer-sity Medical Center, Utrecht, the Netherlands.

Address correspondence to Timon W. vanHaeften, MD, Department of Internal Medicine, G02.228, University Medical Center, P.O. Box 85500,3508 GA Utrecht, The Netherlands. E-mail: [email protected].


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References1. van Tilburg JH, Wijmenga C, van Bakel H,

Rozeman L, Pearson PL, van Haeften TW:Relationship of 2-adrenergic receptorpolymorphism with obesity in type 2diabetes (Letter). Diabetes Care 26:251–252, 2003

2. Meirhaghe A, Helbecque N, Cottel D,Amouyel P: B2-adrenoceptor gene poly-morphism, body weight, and physical ac-tivity. Lancet 353:896, 1999

Letters


Documents

LETTERS - care.diabetesjournals.org · OBSERVATIONS Analysisofthe AgreementBetween theWorldHealth Organization Criteriaandthe NationalCholesterol EducationProgram-IIIDeﬁnitionofthe