1. Are all Type 2 Diabetes Created the Same?: How Better Understanding Leads to Efficient Management Osama Hamdy, MD, PhD, FACE Medical Director Joslin Obesity Clinical Program Director of Inpatient Diabetes Program Joslin Diabetes Center Harvard Medical School

3. 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/m 2 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?

4. Diabetes Today: Pathophysiology

5. Years of Diabetes 0 – 50 – 100 – 150 – 200 – 250 – -10-5051015202530 Relative Function (%) Obesity Prediabetes Diabetes Uncontrolled Hyperglycemia Insulin Resistance Years before Diabetes Natural History of Diabetes -cell function Controllable Hyperglycemia or Diabetes Remission

6. Is this true? Adapted from Lebovitz H. Diabetes Rev. 1999;7:139-153. UKPDS 16. Diabetes. 1995;44:1249-1258. Rx: Insulin, Metformin, Sulfonylurea -Cell Function (%) Postprandial Hyperglycemia IGT Type 2 Diabetes Phase I Type 2 Diabetes Phase II Type 2 Diabetes Phase III 25 100 75 0 50 -12-10-6-202 6 1014 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

7. 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

8. Sjöström L et al. N Eng J Med. 2004;351:2683-2693. Effect of Bariatric Surgery on Diabetes in Severely Obese Patients

9. Are all Type 2 diabetes created the same?

10. Measurement of Insulin Sensitivity and -Cell Glucose Sensitivity from the Response to IV Glucose Bergman RN et al. J Clin Invest. 1981;68:1456-1467.

11. Measurement of Insulin Sensitivity and -Cell Glucose Sensitivity from the Response to IV Glucose

12. Bergman RN et al. J Clin Invest. 1981;68:1456-1467. Measurement of Insulin Sensitivity and -Cell Glucose Sensitivity from the Response to IV Glucose

13. Insulin Resistance is the Core Target for Intervention Type 2 diabetes Hypertension Atherosclerosis Dyslipidemia Endothelial dysfunction Coagulation/Fibrinolytic defects Insulin Resistance 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.

14. GenotypeNormal Trp/Trp Heterozygous Trp/Arg Homozygous Arg/Arg BMI (kg/m 2 ) 32.3+4.533.2+5.934.1+1.7 Body Fat% 41.8+2.842.9+6.7*44.8+2.8* Visceral Fat (cm 2 ) 121+46178+47**172+17** SBP (mmHg) 133+26141+27165+32* BG (AUC) 926+4071344+635**1283+32** F. Insulin (pmol/l) 43+2972.29**79+22** TC (mmol/l) 4.9+0.75.4+1.2*5.9+0.9** TG (mmol/l) 1.4+0.81.3+0.52.4+0.8** HDL (mmol/l) 1.4+0.31.3+0.31.1+0.1* Sakane N et al. Diabetologia 1997;40:200-204 3 -adrenergic-receptor polymorphism in obese subjects: Genetic markers for visceral fat and the metabolic syndrome

15. 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

16. How to modify insulin resistance?

17. 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 Medications Metformin TZDs SGLT-2 inhibitors

18. Copyright © 2014 by Joslin Diabetes Center. All Rights Reserved. 1- Can we Modify Visceral Fat?

19. % Change in insulin Sensitivity Index 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)

20. Weight Loss (%) Duration in Months Total Group n=129 Group 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% Remission 21% Stopped insulin 50-60% Reduction in Medications

21. Obese Patients With Insulin Resistance +/– T2D Effects of Short-term Weight Loss on Insulin Sensitivity Change From Baseline (%) 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.

22. Obese Patients With Insulin Resistance +/– T2 DM Effects of Short-term Weight Loss on Inflammatory Markers NS P<0.01P<0.001 NS P<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. Change (%)

23. Impact of Dietary Composition on DM 2- Role of Medical Nutrition Therapy

24. The Impact of Nutrition on Diabetes: Before the Era of Diabetes Medications 1869-1962 Joslin Clinic Boston, MA 1879–1964 Physiatric Institute Morristown, NJ

25. Strict diet: Meats, poultry, game, fish, clear soups, gelatin, eggs, butter, olive oil, coffee, tea Osler W & McCrae T, The Principles and Practice of Medicine, 1923; Westman EC, Perspect Biol Med, 2006 Joslin Diabetes Diet, 1923 Quantity of food required by severe diabetic patient weighing 60 Kg FoodCalories (%) Protein75 g300 (17%) Fat150 g1350 (75%) Carbohydrate10 g40 (2%) Alcohol15 g105 (6%) 1795

26. Response of Fat Mass to Early Calorie Restriction Bujo LY et al Exp Biol Med 2003; 228:1118-1123

27. Weight Loss and Glucostatic Parameters Before and After RYGB and VLCD Jackness C et al. Diabetes. 2013;62(9):3027-32

28. Relationship Between Insulin Sensitivity and Insulin Secretion Before and After Interventions Jackness C et al. Diabetes. 2013;62(9):3027-32

29. High Carbohydrates Low Carbohydrates Visceral Fat (cm 2 ) % Decrease in basal Insulin 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 25 High Carbs 62 10 26 n= 22 * p<0.05 * * Visceral Fat Serum Insulin

30. 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

31. Visceral Fat BP & lipids Metabolic Control Physical Fitness & QOL Maintenance of Weight Loss Metabolic Control Physical Fitness & QOL Maintenance of Weight Loss Vascular Resistance 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

32. 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 Muscle Mass (gm/year) * *

33. Insulin Sensitizers 4- Role of Medications

34. 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

35. Cell Entry and Mechanism of Metformin Shu et al. J Clin Invest 2007; 117: 1422-1431 Metformin Cell Entry Cell Target for Metformin Activation of AMP Kinase Improves Lipotoxicity

36. LKB1 and Anti-Tumour Activity Cheng & Fantus. CMAJ 2005; 172: 213-26 Hawley. J Biol 2003; 2:28 LKB1 Tumour Suppressor

37. 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

38. 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 -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

39. Targeting Insulin Resistance Bariatric Surgery Testosterone High dose Salicylates Low Carbohydrates Very Low Calorie Diet TZDs Visceral Fat Metformin Hamdy O. Joslin Diabetes Center, 2014 Lipotoxicity Glucose Toxicity Inflammation Growth Hormone Insulin SGLT2-I Non-surgical Weight Reduction Insulin Sensitivity Exercise

40. 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

41. Thank You