1. Type 2 Diabetes in the Elderly: Options for Treatment David Kelley

2. 190019301960199020202050 Decade Population (millions) US Population Aged 85+ Years (1900-2050) Elderly  85 Years of Age Comprise Fastest-Growing Segment of Population 0 5 10 15 20

3. Diagnosing Type 2 Diabetes Type 2 Diabetes*  126 mg/dL  200 mg/dL (7.0 mmol/L)(11.1 mmol/L) Impaired Glucose  126 mg/dL  140 mg/dL (7.8 mmol/L), Tolerance (IGT)(7.0 mmol/L)but  200 mg/dL (11.1 mmol/L) Impaired Fasting  110 mg/dL--- Glucose (IFG)(6.1 mmol/L) but  126 mg/dL *Either of these criteria can establish a diagnosis. Confirmation on a separate day is recommended. Fasting Plasma Glucose (FPG) 2-hr Post-75 g Oral Glucose

4. Harris MI, et al. Diabetes Care. 1998;21:518-524. Resnick HE, et al. Diabetes Care. 2000;23:176-180. Percentage of Population NHANES III High Prevalence of Type 2 Diabetes Among Elderly People 0 5 10 15 20 40-49 50-59 60-74 Age (years) Previously diagnosed diabetes Newly diagnosed diabetes by FPG Newly diagnosed diabetes by OGTT (IPH)

5. Adapted from Resnick HE, et al. Diabetes Care. 2000;23:176-180. NHANES III Percentage of Newly Diagnosed Diabetes Missed 0 20 40 60 80 100 40-4445-4950-5455-5960-6465-6970-74 Age (years) Diagnoses Missed (%)

6. Wahl PW, et al. Lancet. 1998;352:1012-1015. Rodriguez BL, et al. Diabetes Care. 1996;19:587-590. Prevalence (%) Age (years) Diabetes Persists in Populations  70 Years of Age 0 5 10 15 20 25 30 35 40 70-74 75-79 80-84 85+ Cardiovascular Health Study Honolulu Heart Study

7. Cardiovascular Health Study Wahl PW, et al. Lancet. 1998;352:1012-1015. Prevalence (%) NormoglycemicIFGIGTNew Diabetes Identifying Diabetes Mellitus in Elderly People: OGTT vs. FPG 0 20 40 60 80 Classification Based on FPG Based on OGTT

8. Isolated Postchallenge Hyperglycemia in Elderly Patients l IPH = FPG <126 mg/dL (7.0 mmol/L) + 2-hr postchallenge PG  200 mg/dL (11.1 mmol/L) l Prevalence of IPH increases with age l Clinicians who rely solely on FPG may miss the diagnosis in many elderly patients

9. Rancho Bernardo Study Barrett-Connor E, et al. Diabetes Care. 1998;21:1236-1239. Relative Risk *P=0.005 **P=0.01 Clinical Importance of IPH in Elderly Patients 0 1 2 3 4 CVD MortalityIHD Mortality Classification Men Women * **

10. Weyer C, et al. J Clin Invest. 1999;104:787-794. Inadequate  -cell Compensation for Insulin Resistance 0 100 200 300 400 500 012345 NGT IGT DIA Nonprogressors (N = 31) Progressors (N = 17)  -cell Function Insulin Sensitivity NGT

11. 20g Glucose Ward WK, et al. Diabetes Care. 1984;7:491-502. Time (min) 20g Glucose Plasma IRI (pmol/L) Loss of First Phase Insulin Secretion in Type 2 Diabetes Normal Type 2 Diabetes

12. Changes in Postprandial Glucose and Insulin Levels with Aging Chen M, et al. J Am Geriatr Soc. 1987;35:417-424. Insulin (mcg/mL) Time (min) Glucose (mg/dL) Time (min) OldYoung

13. IGT, obeseNormal, obese IGT, nonobeseNormal, nonobese Link between Impaired Early Insulin Release and Excessive Prandial Glucose Excursions Mitrakou A, et al. N Engl J Med. 1992;326:22-29. 2-hour Plasma Glucose (mmol/L) Insulin Concentration at 2 Hours (pmol/L) r = 0.52 P < 0.01 2-hour Plasma Glucose (mmol/L) Insulin Concentration at 30 Minutes (pmol/L) r = -0.75 P < 0.0001

14. Kelley D, et al. Metabolism. 1994;43:1549-1557. Mechanism of Postprandial Hyperglycemia: Glucose Production Time (min) Type 2 DiabetesControl Endogenous Glucose (µmol/min/kg) Ingested Glucose (µmol/min/kg)

15. Adapted from Halter JB. In: Masoro EJ (ed). Handbook of Physiology, Volume on Aging. 1995. Insulin Resistance Mild Hyperglycemia  -cell Function Normal Hyperinsulinemia Euglycemia Abnormal Impaired Insulin Secretion Hyperglycemia AdaptationMaladaptation Interaction Between Impaired Insulin Secretion and Insulin Resistance in Type 2 Diabetes

16. Pathophysiology of Type 2 Diabetes in Elderly People: Impaired Insulin Secretion Factors Predisposing the Elderly to Diabetes Age-related Decreased Insulin Secretion Age-related Insulin Resistance Decreased Physical Activity Drugs Genetics Coexisting Illness Adiposity

17. Pathophysiology of Type 2 Diabetes in Elderly People: Impaired Insulin Sensitivity Factors Predisposing the Elderly to Diabetes Age-related Decreased Insulin Secretion Age-related Insulin Resistance Decreased Physical Activity Drugs Genetics Coexisting Illness Adiposity

18. *BMI  30 19911995 2000 Mokdad A H, et al. JAMA. 1999;282:1519-1522, 2001;286:1195-2000. Obesity* Trends Among U.S. Adults BRFSS, 1991, 1995 and 2000 No Data <10%10-14%15-19%  20%

19. * Diagnosed diabetes including women with a history of GDM 19901995 2000 Diabetes* Trends Among U.S. Adults BRFSS, 1990, 1995 and 2000 No Data <4%4-6%>6%

20. BMI and Risk of Type 2 Diabetes Mellitus in Women Colditz GA. Ann Intern Med. 1995;122:481-486. BMI (kg/m 2 ) Relative Risk (Age adjusted)

21. Correlation Between BMI and Body Fat Percentage Jackson A.S. et al Int. J. Obesity 2002;26:789-796. Body Mass Index (wt/kg 2 ) Percent Body Fat (%) Men Women

22. Abdominal CT Visceral Adipose Tissue Subcutaneous Adipose Tissue

23. Probability of Developing Diabetes: BMI and WHR WHR = waist to hip ratio. Ohlson LO et al, Diabetes. 34:1055-8, 1985 Relative Risk BMI Tertile WHR Tertile

24. Relationship Between Visceral Adipose Tissue and Insulin Action Banerji, M et al Am J Physiol 1997; 273:E425-E432 Glucose Disposal (mg/kg LBM/min) Visceral adipose tissue volume per unit surface area (L/m 2 ) Women Men

25. Skeletal Muscle fat LessMore Most

27. Loci of IR in Skeletal Muscle:

28. Healthy Aging and and Body Composition (HEALTH ABC) Epidemiology, Demography and Biometry Program, NIA Objective: To relate changes in body composition in old age, particularly increases in body fat and decline in lean mass and bone mineral, to disease and disability. 3,075 men and women age 70-79 y high proportion of African-Americans free from disability and free of functional limitations Major outcome variables to be examined yearly over 7 years: Self-reported disability Measures of physical function, eg. Rising from a chair, balance Measures of muscle strength Walking endurance

29. We Lose Muscle as We Age “Sarcopenia” Men Women

30. BMI (kgm -2 ) Muscle attenuation is associated with obesity in Health ABC