2. What Causes Microvascular and Macrovascular Complications in Patients with Type 2 Diabetes? Charles A. Reasner, MD Professor of Medicine University of Texas Health Science Center San Antonio, Texas

3. Type 2 Diabetes Mellitus Every 24 Hours CDC. National Diabetes Fact Sheet, 2007. Available at: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf. Why does this occur? How do we prevent this morbidity and mortality? New cases4384 Amputations195>60% of nontraumatic amputations annually Blindness66Number 1 cause Kidney failure128 Deaths64068% due to cardiovascular disease, 2- to 4-fold higher than in adults without diabetes

4. Physiologic Defects Associated with Type 2 Diabetes Mellitus

5. Regulation of Normal Glucose Homeostasis Liver Muscle Adipose tissue Blood glucose Glucose output Glucose uptake Glucagon (alpha cell) Insulin (beta cell) Pancreas Fasting state Fed state Porte D Jr, et al. Clin Invest Med. 1995;18:247-254. Kahn CR, et al. In: Joslin’s Diabetes Mellitus. Lippincott Williams & Wilkins; 2005:145-168.

6. With permission from DeFronzo RA. Diabetes. 1988;37:667-687. Insulin Resistance and Insulin Deficiency Abbreviations: DIAB, diabetes; Hi INS, hyperinsulinemic; IGT, impaired glucose tolerance; Lo INS, hypoinsulinemic; NGT, normal glucose tolerance; OB, obese; OGTT, oral glucose tolerance test.

7. Insulin Receptor Plasma Membrane Insulin Signal Transduction System in Humans Abdul-Ghani MA, et al. J Biomed Biotechnol. 2010;2010:476279. p85 Akt PI-3-kinase p110 IRS-1 Glucose GLUT 4 Abbreviations: GLUT, glucose transporter; IRS, insulin receptor substrate; NOS, nitric oxide synthase; PI-3-kinase, phosphatidylinositol 3-kinase.

8. Beta Cell Dysfunction Ultimately, it is a defect in insulin secretion, not insulin resistance, that causes hyperglycemia and progression of type 2 diabetes mellitus 1 Initially, beta cells increase secretion of insulin to compensate for demands of insulin-resistant tissues 2 –Functional and morphologic changes to beta cells allow them to keep pace 1 –In some people, this compensation remains adequate lifelong It is only when beta cell dysfunction develops that T2DM progresses 1 1. Del Prato S, et al. Horm Metab Res. 2004;36:775-781. 2. Polonsky KS. Int J Obesity. 2000;24(suppl 2):S29-S31.

9. Current Theories on Development of Beta Cell Dysfunction Chronic insulin overproduction may deplete the supply of releaseable insulin (beta cell exhaustion) 1 Glucotoxicity: chronic hyperglycemia may be toxic to beta cells 2 Lipotoxicity: chronic exposure to excess free fatty acids may be toxic to beta cells 2 Glucotoxicity and lipotoxicity may activate apoptotic signaling pathways, leading to islet cell loss 2 Amyloid deposits noted in islet cells of T2DM patients may be a contributing factor 3 1. Rustenbeck I. Biochem Pharmacol. 2002;63:1921-1935. 2. Del Prato S, et al. Horm Metab Res. 2004;36:775-781. 3. Lorenzo A, et al. Nature. 1994;368:756-760.

10. Beta Cell Dysfunction Studies 1. Gastaldelli A, et al. Diabetologia. 2004;47:31-39. 2. Ferrannini E, et al. J Clin Endocrinol Metab. 2005;90:493-500. 3. Abdul-Ghani MA, et al. Diabetes. 2006;55:1430-1435. Number of Patients StudyNGTIGTT2DM SAM 1 13849201 Ferrannini et al 2 6122105 VAGES 3 117930 TOTAL316164306 Abbreviations: IGT, impaired glucose tolerance; NGT, normal glucose tolerance; OGTT, oral glucose tolerance tests; SAM, San Antonio Metabolism Study; T2DM, type 2 diabetes mellitus; VAGES, Veterans Administration Genetic Epidemiology Study. All 3 studies used OGTT and insulin clamp

11. IGT <160 <180 <200 <160 <180 <200 IGT Plasma Glucose and Insulin AUC 0 4 8 12 Glucose AUC (mmol/L  120 min) 0 4 8 12 Insulin AUC (pmol/L  120 min) NGT NGT T2DM Q1 Q2 Q3Q4Q1Q2Q3Q4 T2DM Graphic courtesy of Dr. Ralph A. DeFronzo.

12. IGT <200 <160 <180 Insulin Secretion/Insulin Resistance (DISPOSITION) Index During OGTT 30 20 10 0 40 Insulin Secretion/Insulin Resistance (IR) Index (∆ Insulin/∆ Glucose ÷ IR) Lean NGT <100 <120 <140 Obese 2-h plasma glucose (mg/dL) Obese = BMI ≥30 kg/m 2 Graphic courtesy of Dr. Ralph A. DeFronzo.

13. Fasting Plasma Glucose and Beta Cell Volume in Obese Patients With permission from Butler AE, et al. Diabetes. 2003;52:102-110. FPG (mg/dL) ß-Cell Volume (%) 4 3 2 1 0 250 200 150 100 50 NGT IFG * T2DM * * * *Statistically significant

14. Increased glucagon output Hyperglycemia Decreased glucose uptake Increased hepatic glucose production Del Prato S, et al. Horm Metab Res. 2004;36:775-781. Porte D Jr, et al. Clin Invest Med. 1995;18:247-254. Major Pathophysiologic Defects in Type 2 Diabetes Mellitus Impaired insulin secretion Islet cell dysfunction Insulin resistance

15. Incretins

16. Time (min) IR Insulin (mU/L) nmol/L 0.6 0.5 0.4 0.3 0.2 0.1 0 80 60 40 20 0 180601200 The Incretin Effect in Subjects with and Without Type 2 Diabetes Mellitus Control Subjects (n = 8) Patients with Type 2 Diabetes (n = 14) Time (min) IR Insulin (mU/L) nmol/L 0.6 0.5 0.4 0.3 0.2 0.1 0 80 60 40 20 0 18060120 0 Oral glucose load Intravenous glucose infusion Incretin Effect The incretin effect is diminished in type 2 diabetes. With permission from Nauck M, et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.

17. Incretins GLP-1 GIP Mixed Meal L-cells K-cells  Satiety  Gastric emptying  Glucagon  Insulin DPP-4

18. Preventing Microvascular Complications

19. Diabetes Control and Complications (DCCT) Study Design Primary prevention (n = 726) Secondary intervention * (n = 715) Patients with type 1 diabetes (N = 1441) Conventional (n = 378) Intensive (n = 363) Randomize DCCT Research Group. N Engl J Med. 1993;329:977-986. Graphic courtesy of Dr. Charles A. Reasner. *Patients with retinopathy.

20. DCCT Treatment Conditions Abbreviation: DCCT, Diabetes Control and Complications. 1. DCCT Research Group. N Engl J Med. 1993;329:977-986. 2. Lachin JM, et al. Diabetes. 2008;57:995-1001. Conventional (n = 730)Intensive (n = 711) Aim 1 Avoid hyper-/hypoglycemiaSymptom-free + plasma glucose 3.9–6.7 mmol/L before meals, 3.6 mmol/L at 3:00 AM (measured weekly), and HbA1c <6.05% (measured monthly) Administration 1 1 or 2 insulin injections/d + initial diet and exercise education ≥3 insulin injections/d or insulin pump Monitoring 1 Daily self-monitoring  4 daily blood glucose tests Follow-up clinic visits 1 QuarterlyMonthly Mean HbA1c 2 9.5%7.2%

21. DCCT Intensive Therapy Reduced Microvascular Complications 34% reduction 76% reduction *Urinary albumin excretion ≥40 mg/24 hours. Abbreviation: DCCT, Diabetes Control and Complications. DCCT Research Group. N Engl J Med. 1993;329:977-986. Rate/100 Patient-Years

22. Main randomization of UKPDS 4209 patients in 23 centers Metformin Study 1704 overweight patients in 15 centers UKPDS Randomization of Overweight Patients Conventional tx (diet) 411 Intensive tx 1293 Metformin 342 Sulphonylurea or insulin 542 409 Abbreviations: tx, treatment; UKPDS, United Kingdom Prospective Diabetes Study. UKPDS Group. Lancet. 1998;352:854-865.

23. Microvascular Endpoints Stratton IM, et al. BMJ. 2000;321:404-412. HbA1c Adjusted Rate of Microvascular Events* *Rates/1000 person-years’ follow-up adjusted in Poisson regression model to white men age 50 to 54 years at diagnosis of diabetes and followed up for 7.5 to <12.5 years. N = 4585

24. What About Macrovascular Disease?

25. Why Doesn’t Glucose Reduction Lower the Risk of Macrovascular Disease? Risk factors include not only hyperglycemia but also –Elevated LDL cholesterol –Low HDL cholesterol –Hypertension –Smoking –Obesity These risk factors are common in diabetic populations

26. Adolescent Obesity and Metabolic Impairment Weiss R, et al. N Engl J Med. 2004;350:2362-2374. Graphic courtesy of Dr. Charles A. Reasner. ControlOverweightModerately ObeseSeverely Obese No. of patients2031244195 Mean age (years)12 1311 BMI (kg/m 2 )18253341 Weight (kg)425786100

27. Childhood and Adolescent Metabolic Characteristics Glucose and Insulin Glucose P =.06 Glucose Level (mg/dL) 87 91 90 86 87 88 89 90 91 ControlOverweightModerately Obese Severely Obese Insulin Insulin Level ( μU/mL) P <.001 10 15 31 39 0 5 10 15 20 25 30 35 40 45 ControlOverweightModerately Obese Severely Obese Weiss R, et al. N Engl J Med. 2004;350:2362-2374.

28. Childhood and Adolescent Metabolic Characteristics Triglycerides 0 20 40 60 80 100 120 ControlOverweightModerately Obese Severely Obese Weiss R, et al. N Engl J Med. 2004;350:2362-2374. 48 83 105 97 Mean Triglyceride Level (mg/dL )

29. Childhood and Adolescent Metabolic Characteristics HDL Cholesterol 0 10 20 30 40 50 60 70 59 47 41 40 Control OverweightModerately Obese Severely Obese Weiss R, et al. N Engl J Med. 2004;350:2362-2374. HDL Cholesterol Level (mg/dL) Abbreviation: HDL, high-density lipoprotein.

30. Childhood and Adolescent Metabolic Characteristics Systolic Blood Pressure 95 100 105 110 115 120 125 130 106 116 121 124 ControlOverweightModerately Obese Severely Obese Weiss R, et al. N Engl J Med. 2004;350:2362-2374. Systolic Blood Pressure (mm Hg)

31. Insulin Receptor Plasma Membrane Insulin Signal Transduction System in Humans Abdul-Ghani MA, et al. J Biomed Biotechnol. 2010;2010:476279. NOS + Artery p85 Akt PI-3-kinase p110 IRS-1 Glucose GLUT 4 Abbreviations: GLUT, glucose transporter; IRS, insulin receptor substrate; NOS, nitric oxide synthase; PI-3-kinase, phosphatidylinositol 3-kinase.

32. NOS + Artery Insulin Receptor Plasma Membrane p85 p110 Akt Insulin Signal Transduction System in Type 2 Diabetes Mellitus PI-3-kinase IRS-1 GLUT 4  Glucose  Insulin Abdul-Ghani MA, et al. J Biomed Biotechnol. 2010;2010:476279.

33. Insulin Signal Transduction System in Type 2 Diabetes Mellitus Abdul-Ghani MA, et al. J Biomed Biotechnol. 2010;2010:476279. Cusi K, et al. J Clin Invest. 2000;105:311-320. Osman N, et al. Cardiovasc Hematol Disord Drug Targets. 2008;8:287-292. NO S + Arter y IRS- 1 Insulin Receptor Plasma Membrane p85 p110 Akt Inflammation Cell growth/proliferation MAP kinas e Shc PI-3- kinase IRS-1 GLUT 4  Glucose  Insulin Atherosclerosis

34. Summary There are 3 primary physiologic defects in patients with type 2 diabetes mellitus –Insulin resistance –Beta cell failure –Increase in glucagon Glucose control is critical in reducing microvascular complications Treatment of the components of the metabolic syndrome is necessary to reduce macrovascular disease

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