Upload
meagan-gobel
View
215
Download
0
Tags:
Embed Size (px)
Citation preview
Are all Type 2 Diabetes Created the Same?: How Better Understanding Leads to Efficient
Management
Osama Hamdy, MD, PhD, FACEMedical Director Joslin Obesity Clinical Program
Director of Inpatient Diabetes ProgramJoslin Diabetes Center
Harvard Medical School
Type 2 Diabetes Risk Factors• Donna is 65 year old African American lady diagnosed with type 2 diabetes 22 years
ago. • Managed on 3 oral medications plus 90 units of glaragine insulin. Here BMI is 36
Kg/m2 and her A1C 8.3%.
• She enrolled in the Joslin Why WAIT program in 2009 and lost 21 lbs (9.5 Kg) in 12 weeks. She continued to lose weight after the program. Current weight loss is 37 lbs (16.5 Kg).
• Donna stopped all her antihyperglycemic medications and her A1C on 3/2014 was 6%.
What is going on?
Diabetes Today:Pathophysiology
Years of Diabetes
0 –
50 –
100 –
150 –
200 –
250 –
-10 -5 0 5 10 15 20 25 30
Rel
ativ
e Fu
nctio
n (%
)
Obesity Prediabetes
Diabetes
UncontrolledHyperglycemia
Insulin Resistance
Years before Diabetes
Natural History of Diabetes
b-cell function
ControllableHyperglycemia
Controllable Hyperglycemia
or Diabetes
Remission
Diabetes Remission
Is this true?
Adapted from Lebovitz H. Diabetes Rev. 1999;7:139-153.UKPDS 16. Diabetes. 1995;44:1249-1258.
Rx: Insulin, Metformin, Sulfonylurea
-CellFunction
(%)PostprandialHyperglycemia
IGT Type 2DiabetesPhase I
Type 2DiabetesPhase II
Type 2 DiabetesPhase III25
100
75
0
50
-12 -10 -6 -2 0 2 6 10 14
Years From Diagnosis
Dashed line shows extrapolation forward and backward from years 0 to 6 based on HOMA data from UKPDS.
Decline in -Cell Function With Diabetes Progression: UKPDS
Lee CW et al. Curr Opin Gastroenterol. 2007;23(6):636-643.
Gastric Bypass (RYGB)
• Advantages• Rapid initial weight loss• Minimally invasive approach is
possible• Longer experience in U.S.• Higher total average weight loss
reported than with LAGB or VBG
Disadvantages• Complications due to
malabsorption are common• Nonadjustable • Higher cost
0%10%20%30%40%50%60%70%80%90%
100%
2 years 10 years
Reco
very
From
Dia
bete
s Control Bariatric Surgery
Sjöström L et al. N Eng J Med. 2004;351:2683-2693.
Effect of Bariatric Surgery on Diabetes in Severely Obese Patients
Are all Type 2 diabetes created the same?
Measurement of Insulin Sensitivity and b-Cell Glucose Sensitivity from the Response to IV Glucose
Bergman RN et al. J Clin Invest. 1981;68:1456-1467.
Bergman RN et al. J Clin Invest. 1981;68:1456-1467.
Measurement of Insulin Sensitivity and b-Cell Glucose Sensitivity from the Response to IV Glucose
Bergman RN et al. J Clin Invest. 1981;68:1456-1467.
Measurement of Insulin Sensitivity and b-Cell Glucose Sensitivity from the Response to IV Glucose
Insulin Resistance is the Core Target for Intervention
Type 2 diabetes Hypertension
Atherosclerosis
Dyslipidemia
Endothelial dysfunction
Coagulation/Fibrinolytic defects
InsulinResistance
Visceral Fat Accumulation (genetic, ethnic)
Inflammation (subclinical)
Lipotoxicity (increased FFA)
Glucose Toxicity (sig. increased plasma glucose)
Oxidative Stress
Hamdy O. Curr Diab Rep. 2005;5(5):317-9.
Genotype Normal
Trp/Trp
Heterozygous
Trp/Arg
Homozygous
Arg/Arg
BMI (kg/m2) 32.3+4.5 33.2+5.9 34.1+1.7
Body Fat% 41.8+2.8 42.9+6.7* 44.8+2.8*
Visceral Fat (cm2) 121+46 178+47** 172+17**
SBP (mmHg) 133+26 141+27 165+32*
BG (AUC) 926+407 1344+635** 1283+32**
F. Insulin (pmol/l) 43+29 72.29** 79+22**
TC (mmol/l) 4.9+0.7 5.4+1.2* 5.9+0.9**
TG (mmol/l)
1.4+0.8 1.3+0.5 2.4+0.8**
HDL (mmol/l)
1.4+0.3 1.3+0.3 1.1+0.1*
Sakane N et al. Diabetologia 1997;40:200-204
b3-adrenergic-receptor polymorphism in obese subjects:
Genetic markers for visceral fat and the metabolic syndrome
Markers of insulin resistance
• High basal insulin and C-peptide• Progressive central adiposity• High CRP (high TNF-a, IL-6, PAI-1)• Skin tags• Acanthosis negricans• Polycystic ovary• High TG and VLDL and low HDL• Increasing blood pressure• Increasing plasma glucose
How to modifyinsulin resistance?
Optimal Improvement of Insulin Sensitivity
Weight reduction is the prime target
Proper Medical Nutrition Therapy (MNT)
• Dietary Composition
Proper Exercise
• Type
• Duration
• Frequency
Reduction of Visceral fat
• Hormonal role
Patient adherence and compliance for long-term success
Medications
• Metformin
• TZDs
• SGLT-2 inhibitors
Copyright © 2014 by Joslin Diabetes Center. All Rights Reserved.
1- Can we Modify Visceral Fat?
-30
-10
10
30
50
70
90 84
73.2
33.5
22.6
0.7
-6.8
% C
han
ge
in in
sulin
Sen
siti
vity
Ind
ex
Changes in insulin sensitivity after 6-month of laparoscopic omentectomy in 6 patients with newly-
diagnosed Type 2 DM
Insulin sensitivity measured by hyperinsulinemic euglycemic clamp method at 0 and 6 months
Hamdy O. et al, 2008 (Unpublished pilot data)
0 3M 6M 9M 12M 15M 18M 21M 24M 27M 30M 33M 36M 39M 42M 45M 48M 51M 54M 57M 60M
-16.0
-14.0
-12.0
-10.0
-8.0
-6.0
-4.0
-2.0
0.0
****** ***
***
******
*** *** *** *** *** *** *** *** *** *** *** ***
Wei
ght L
oss
(%)
Duration in Months
Total Group n=129Group 1 n=61 (Participants maintained <7% weight loss at 1 year)Group 2 n=68 (Participants maintained > 7% weight loss at 1 year)
*** p<0.001 (group 1 vs. group 2)
*** ***
-9.0%
-3.5%
-6.4%
Percentage Weight Reduction in Patients with Diabetes in the Real-World Clinical Practice over 5 years (Joslin Why WAIT Program)
14% Remission21% Stopped insulin
50-60% Reduction in Medications
Obese Patients With Insulin Resistance +/– T2D
Effects of Short-term Weight Loss on Insulin Sensitivity
WGT* BMI W-H IS-10
0
10
20
30
40
50
60
70
-7.1 -7.4-3.1
56.8
Cha
nge
From
Bas
elin
e (%
)
WGT, weight; BMI, body mass index; W-H, waist-to-hip ratio; IS, insulin sensitivity.*P<0.001.Hamdy O. Diabetes Care. 2003;26:2119-2125.
Obese Patients With Insulin Resistance +/– T2 DM
Effects of Short-term Weight Loss on Inflammatory Markers
NS
P<0.01P<0.001NSP<0.05 NS
IL, interleukin; TNF, tumor necrosis factor; hCRP, human C-reactive protein; PAI, plasminogen activator inhibitor.Hamdy O. Diabetes Care. 2003;26:2119-2125; Monzillo LU. Obes Res. 2003;11(9):1048-1054.
Chan
ge (%
)
Impact of Dietary Composition on DM
2- Role of Medical Nutrition Therapy
The Impact of Nutrition on Diabetes: Before the Era of Diabetes Medications
1869-1962Joslin ClinicBoston, MA
1879–1964Physiatric InstituteMorristown, NJ
Elliott P. Joslin Frederick M. Allen
“Strict diet”: Meats, poultry, game, fish, clear soups, gelatin, eggs, butter, olive oil, coffee, teaOsler W & McCrae T, The Principles and Practice of Medicine, 1923; Westman EC, Perspect Biol Med, 2006
Joslin Diabetes Diet, 1923Quantity of food required by severe diabetic patient weighing 60 Kg
Food Calories (%)
Protein 75 g 300 (17%)
Fat 150 g 1350 (75%)
Carbohydrate 10 g 40 (2%)
Alcohol 15 g 105 (6%)
1795
Response of Fat Mass to Early Calorie Restriction
Bujo LY et al Exp Biol Med 2003; 228:1118-1123
Weight Loss and Glucostatic Parameters Before and After RYGB and VLCD
Jackness C et al. Diabetes. 2013;62(9):3027-32
Relationship Between Insulin Sensitivity and Insulin Secretion Before and After
Interventions
Jackness C et al. Diabetes. 2013;62(9):3027-32
Before Diet
After Diet
50
100
150
Series1
-50
-40
-30
-20
-10
0
High Carbohydrates
Low Carbohydrates
Visc
eral
Fat
(cm
2 )
% D
ecre
ase
in b
asal
Insu
lin
Miyashita Y et al Diabetes Res Clin Pract. 2004 Sep;65(3):235-41
Effects of Low Carbohydrates in Low Calorie Diet on Visceral
Fat and Basal Insulin in Obese Type 2 Diabetic Patients C F P
Low Carbs 39 35 25High Carbs 62 10 26
n= 22* p<0.05
*
*
Visceral Fat Serum Insulin
Twenty-four–hour plasma glucose response of subjects to the control (15% protein) and high-protein (30% protein) diets
*Significantly different from control diet, P < 0.05
Twenty-four–hour triacylglycerol response of subjects to the control (15% protein) and high-protein (30% protein) diets.
*Significantly different from the fasting control value, P < 0.03
Adapted from Gannon MC et al. Amer J Clin Nutr 2003;78:734-741
The Metabolic Effect of Different Protein/Carbohydrates Ratios in Type 2 DM
Protein to carbohydrate to fat: 30:40:30 Versus 15:55:30
-40% Reduction
Visceral Fat
BP & lipids
Metabolic ControlPhysical Fitness & QOLMaintenance of Weight Loss
Vascular Resistance
The benefits of Exercise and or
Increased Physical Activity include
3- Gradual, balanced and individualized physical activity - Duration of exercise
- Type of exercise- Short versus long-bouts of exercise- Exercise records/exercise monitor
Diabetes, a Common Comorbidity, Significantly Accelerates Loss of Muscle
Mass, Strength and Quality
p<0.05*Park SW, et al. Diabetes Care 2009;32:1993-1997.
Loss of Total Muscle Mass[g/ year]
Loss
of M
uscl
e M
ass
(gm
/yea
r)
*
*
Insulin Sensitizers
4- Role of Medications
Metformin - Recommended first line therapy
• Why?
• Improves insulin sensitivity• Effective reduction in A1c (1-1.5%)• No hypoglycemia or weight gain• Inexpensive• Long-term safety• Reduction in CV risk & Mortality• May also reduce mortality and cancer risk
Cell Entry and Mechanism of Metformin
Shu et al. J Clin Invest 2007; 117: 1422-1431
Metformin
Cell Entry
Cell Targetfor Metformin
Activation of AMP Kinase
Improves Lipotoxicity
LKB1 and Anti-Tumour Activity
Cheng & Fantus. CMAJ 2005; 172: 213-26Hawley. J Biol 2003; 2:28
LKB1
Tumour Suppressor
Thiazolidinediones (TZDs)
• Highly efficacious in reducing insulin resistance and plasma glucose without hypoglycemia
• Improves lipotoxicity and hence improves insulin sensitivity• Proliferates fat cells that scavenger FFA
• Side effects limiting use: weight gain, edema• Increased bone fracture rates in women• Cardiovascular issues incompletely resolved:
– Clear data for CHF contraindication– Ischemic CVD: Remained a question mark for long time (FDA cleared it)
• Bladder cancer risk incompletely resolved– Any effect is likely dose- and duration-dependent– Restrictions on pioglitazone use
Sodium-Glucose-Cotransporter-2 (SGLT2) Inhibitors: The Latest Class of Oral Agents
• Canagliflozin and Dapagliflozin are the first FAD approved SGLT-2 In• Lowers blood glucose by blocking the reabsorption of glucose by the
kidney and increasing excretion of glucose into the urine• Improves glucose toxicity and hence improves insulin sensitivity and b-
cell function• Low risk of hypoglycemia and induce weight loss
• Potential side effects:– Urinary tract infections– Genital infections– Orthostatic hypotension/dizziness– Increase LDL– Dehydration and electrolytes disturbance
Targeting Insulin Resistance
Bariatric Surgery
Testosterone
High dose Salicylates
Low CarbohydratesVery Low Calorie Diet
TZDs
VisceralFat
Metformin
Hamdy O. Joslin Diabetes Center, 2014
LipotoxicityGlucose Toxicity
Inflammation
Growth Hormone
InsulinSGLT2-I
Non-surgical Weight Reduction
Insulin Sensitivity
Exercise
Summary and Take Home Messages
• Insulin resistance is the core problem in overweight and obese patients with type 2 diabetes
• Reduction of body weight improves insulin sensitivity, prevents diabetes and may reverse the progressive course of type 2 diabetes
• Remission of type 2 diabetes is possible through significant weight reduction by surgical and non-surgical interventions
• Changing dietary composition with the addition of strength exercise reduce visceral fat and improve metabolic control
• Clearing lipotoxicity or glucose toxicity improves insulin sensitivity
• Insulin sensitizers, particularly metformin, are essential in managing type 2 diabetes
Thank You