1. 1 Diabetes: The Burden of Disease Fall, 2007 NUR464

2. 2 Prevalence of Diabetes Is Escalating 2001 19901995 (Includes Gestational Diabetes) Source: Mokdad A, et al. Diabetes Care. 2000;23:1278-1283; Mokdad A, et al. J Am Med Assoc. 2001;286:10; Mokdad A, et al. JAMA. 2003;289:76-79. No Data< 4%4%-6%6%-8%8%-10%> 10%

3. 3 Diabetes Mortality Continues Unabated Year Freid VM, et al. National Center for Health Statistics, 2003. Age­Adjusted Death Rate Relative to 1980

4. 4 Type 2 Accounts for the Vast Majority of Diabetes Mellitus Cases Type 2 diabetes About 90% of the diabetes population Dual impairment: Insulin deficiency & Insulin resistance No longer a disease of adults only Obesity Genetic link Type 1 diabetes Approximately 10% of diabetes population Absolute insulin requirement Autoimmune mediated CDC. National Diabetes Fact Sheet. 2003; Atlanta, GA. US Dept. HHS, Center for Disease Control and Prevention 2003.

5. 5 Link Between Obesity and Type 2 Diabetes: Harvard Nurses’ Health Study Colditz GA, et al. Ann Intern Med. 1995;122:481-486. 0 20 40 60 80 100 120 < 2222­ 22.9 23­ 23.8 24­ 24.9 25­ 26.9 27­ 28.9 29­ 30.9 31­ 32.9 33­ 34.9 > 35 BMI (kg/m 2 ) Age­Adjusted Relative Risk for Diabetes Mellitus

6. 6 2002 — Total Per Capita Health Care Expenditures ADA. Diabetes Care. Mar. 2003;26(3):917-932.

7. 7 Physiologic Blood Insulin Secretion Profile Plasma Insulin (U/mL) Plasma Insulin (µU/mL) 4:00 25 50 75 8:0012:0016:0020:0024:004:00 BreakfastLunchDinner Time 8:00 Adapted from White JR, Campbell RK, Hirsch I. Postgraduate Medicine. June 2003;113(6):30-36.

8. 8 Normal Physiologic Insulin Sensitivity and  ­Cell Function Produce Euglycemia Pancreas Normal Insulin Sensitivity Liver Euglycemia Islet  ­Cell Degranulation; Insulin Released in Response to Elevated Plasma Glucose Muscle Adipose Tissue Increased Glucose Transport Decreased Lipolysis ↓ Glucose Production ↑ Glucose Uptake Normal Physiologic Plasma Insulin Decreased Glucose Output Normal  ­Cell Function Decreased Plasma FFA

9. 9  ­Cell Dysfunction and Insulin Resistance Produce Hyperglycemia in Type 2 Diabetes Pancreas Insulin Resistance Liver Hyperglycemia Islet  ­Cell Degranulation; Reduced Insulin Content Muscle Adipose Tissue Decreased Glucose Transport & Activity (expression) of GLUT4 Increased Lipolysis ↑ Glucose Production ↓ Glucose Uptake Reduced Plasma Insulin Increased Glucose Output  ­Cell Dysfunction Elevated Plasma FFA

10. 10 Frequent Symptoms of Type 2 Diabetes Usually slow onset May be asymptomatic 3 P’s: polyuria, polydipsia, polyphagia Weakness/fatigue Glycosuria Dry, itchy skin Visual changes Skin and mucous membrane infections

11. 11 Stages of Type 2 Diabetes Related to Beta-Cell Function Adapted from Lebovitz HE. Diabetes Reviews. 1999;7(3). 2­12­2­2­10­6­6061014 Beta­Cell Function (%) 0 50 100 75 25 Type 2 Phase 1 IGT Years from Diagnosis Type 2 Phase 2 Type 2 Phase 3 Postprandial Hyperglycemia

12. 12 Significant Loss of Beta­Cell Function at Diagnosis UKPDS At the time diabetes was diagnosed, 50% of beta­cell function was lost Beta­cell function continued to decline over the 10-year course of the study Correlated with loss of response to oral therapy Secondary failure (progressive loss of beta cell) UKPDS 16. Diabetes. 1995;44:1249-1258 Turner RC, et al. JAMA. 1999 Jun 2;281(21):2005-2012.

13. 13 Glucose Excursions in Type 2 Diabetes Time of Day 400 300 200 100 0 0600 10001400180022000200 Glucose (mg/dL) Diabetic Normal Polonsky KS, et al. NEJM. 1988;21;318(19):1237-1239. Meal

14. 14 Insulin Secretion in Type 2 Diabetes Polonsky KS, et al. N Engl J Med. 1996 Mar 21;334(12):777-783. Normal Type 2 diabetes Time (24­hour clock) 060010001400180022000200 800 600 400 200 0 Insulin Secretion (pmol/min) Meal

15. 15 A1C PPGFPG + = Normal A1C < 6.0% CDC. National Diabetes Fact Sheet. 2003; Atlanta, GA. US Dept. HHS, Center for Disease Control and Prevention 2003.

16. 16 2.4 2.0 1.6 1.2 1.0 Relative Risk of Death* < 140 > 199 < 110 110-125 126- 139 >140 140-198 2-h Postprandial Glucose (mg/dL) Fasting Plasma Glucose (mg/dL) Relative Risk for Death Increases with 2­hour Blood Glucose Regardless of the FPG Level *Adjusted for age, sex, study center Adapted from DECODE Study Group. Lancet. 1999;354:617-621.

17. 17 As Patients Get Closer to A1C Goal, the Need to Manage PPG Significantly Increases Adapted from Monnier L, Lapinski H, Collette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of Type 2 diabetic patients: variations with increasing levels of HBA(1c). Diabetes Care. 2003;26:881-885. Increasing Contribution of PPG as A1C Improves % Contribution 0 20 40 60 80 100 A1C Range (%)

18. 18 Blood Glucose Control Guidelines American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S33-S50. American College of Endocrinology. Endocr Pract. 2002;8(suppl 1):40-82. Preprandial blood glucose 90–130 mg/dL< 110 mg/dL Postprandial blood glucose < 180 mg/dL (peak) < 140 mg/dL (2 hour) A1C< 7%≤ 6.5% American Diabetes Association (ADA) American College of Endocrinology (ACE)

19. 19 UKPDS 57: Over Time Increasing Numbers of Patients Require Insulin Patients Requiring Additional Insulin (%) Adapted from: Wright A, et al. Diabetes Care. 2002;25:330 – 336. 20 40 60 0 1245 Years from Randomization 36 Chlorpropamide Glipizide

20. 20 Insulin is Associated with the Most Profound Effects on A1C Diet & Exercise SU & Glitinides Metformin Alpha­ glycosidase Inhibitors TZDsInsulin Typical Change in A1C 0.5­2.01.0­2.0 0.5­1.0 1.5­2.5 Max Dose SU= 20­40 mg/day; Glitinides: 4­120 mg Before meals 2550 mg/day 100 mg w/ meals 16­45 mg/day None Nathan DM. NEJM. Oct 24, 2002;347(17):1342-1349.

21. 21 Human Insulins Regular Neutral Protamine Hagedorn (NPH) Premix 70/30 (70% NPH / 30% Regular)

22. 22 Human Insulin Time-Action Patterns Time (hours) SC injection Normal insulin secretion at mealtime Change in serum insulin Baseline Level Theoretical representation of expected insulin release in nondiabetic subjects

23. 23 Human Insulin Time-Action Patterns Time (hours) SC injection Normal insulin secretion at mealtime Regular insulin (human) Baseline Level Theoretical representation of profile associated with Regular Insulin (human) Change in serum insulin

24. 24 Human Insulin Time-Action Patterns Time (hours) SC injection Normal insulin secretion at mealtime NPH insulin (human) Baseline Level Theoretical representation of profile associated with NPH Insulin Change in serum insulin

25. 25 Human Insulin Time-Action Patterns Time (hours) SC injection Normal insulin secretion at mealtime Human Premix 70/30 (70% NPH & 30% Regular) Baseline Level Theoretical representation of profile associated with Human Premix 70/30 Change in serum insulin

26. 26 Analog Insulins Rapid-acting Basal Premix

27. 27 Analog Insulin Time-Action Patterns Time (hours) SC injection Normal insulin secretion at mealtime Baseline Level Theoretical representation of expected insulin release in nondiabetic subjects Change in serum insulin

28. 28 Analog Insulin Time-Action Patterns Time (hours) SC injection Normal insulin secretion at mealtime Baseline Level Theoretical representation of profile associated with rapid-acting Insulin Analog Change in serum insulin Rapid-Acting Insulin Analog

29. 29 Analog Insulin Time-Action Patterns Time (hours) SC injection Normal insulin secretion at mealtime QD (basal) Analog Insulin Baseline Level Theoretical representation of profile associated with Basal Analog Insulin Change in serum insulin

30. 30 Analog Insulin Time-Action Patterns Time (hours) SC injection Normal insulin secretion at mealtime Baseline Level Theoretical representation of profile associated with Insulin Analog Premix Change in serum insulin Insulin Analog Premix

31. 31 “Although insulin therapy has not traditionally been implemented early in the course of Type 2 diabetes, there is no reason why it should not be…” Nathan DM. NEJM. Oct 24, 2002;347(17):1342-1349.