1. Diabetes and Obesity and Aging ~20% of men and women over 65 years have type 2 diabetes (ADA criteria). ~24% in this age group have diabetes according to WHO criteria (IPH). Prevalence of obesity is much lower in older (>65y) men and women compared to men and women in their 50’s (14% vs. 24%).

2. Metabolically Obese Normal Weight Individuals “Individuals who are not obese based on height and weight, but who, like those with overt obesity, are hyperinsulinemic, insulin resistant, predisposed to type 2 diabetes, hypertriglyceridemia, and premature coronary heart disease.” Ruderman

3. IMFSCTFMAVAFSCAF -0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5 -0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5 Standardized beta coefficient -0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5 -0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5 Standardized beta coefficient * * * * * * * * * * * A B BMI 15.0 - 24.9 BMI 25.0 - 29.9 BMI >29.9 BMI 15.0 - 24.9 BMI 25.0 - 29.9 BMI >29.9 IMFSCTFMAVAFSCAF Association between fasting insulin and regional fat depots in men (A) and women (B) from Health ABC

4. Distribution of adipose tissue in subjects with normal glucose tolerance (GT), impaired glucose tolerance (IGT) and in elderly patients with type 2 diabetes mellitus (DM). GTIGT*DM** Overall p-value Men ( n=866) (n=300) (n=325) Visceral145 ± 66163 ± 72174 ± 80 0.0001 Subcutaneous221 ± 86244 ± 95245 ± 42 0.0001 Women (n=904) (n=428) (n=252) Visceral 116 ± 54144 ± 61 163 ± 67 0.0001 Subcutaneous 322 ± 122 342 ± 132 381 ± 127 0.0001 Abdominal Adipose Tissue (cm2)

5. Mid-thigh muscle attenuation in elderly subjects with normal glucose tolerance (GT), impaired glucose tolerance (IGT) and in patients with type 2 diabetes mellitus (DM). GT IGT* DM** Overall p-value Men(n=866) (n=300) (n=325) Muscle Attenuation (HU) 37.9 ± 6.3 36.7 ± 6.636.2 ± 6.9 † 0.0002 Muscle Area (cm 2 ) 131.2 ± 21.4 132.8 ± 23.3136.7 ± 23.6 † 0.0024 Mid-Thigh Adipose Tissue (cm 2 ) Subcutaneous 46.7 ± 19.7 50.3 ± 21.7 † 46.5 ± 20.3 † 0.031 Intermuscular 9.1 ± 5.8 10.4 ± 5.8 † 11.9 ± 10.6 † 0.0001 Women (n=904) (n=428) (n=252) Muscle Attenuation (HU)34.5 ± 6.6 33.3 ± 7.2 † 32.5 ± 7.2 † 0.0002 Muscle Area (cm 2 )90.9 ± 17.0 93.7 ± 17.2 † 101.9 ± 17.1† 0.0001 Mid-Thigh Adipose Tissue (cm 2 ) Subcutaneous105.6 ± 46.5 108.9 ± 46.9 109.8 ± 48.5 0.372 Intermuscular 9.6 ± 5.4 11.0 ± 6.3 † 12.7 ± 6.6 †0.0001

6. Liver and Spleen CT with Regions of Interest (ROI) L/S Ratio = mean Hounsfield Unit (HU) of Liver ROI  mean HU of Spleen ROI Spleen ROI 1 = 53.1 HU 2 = 52.6 HU 3 = 52.7 HU Liver ROI 4 = 9.8 HU 5 = 0.5 HU 6 = -2.4 HU L/S Ratio = 0.05 indicating severe fatty liver infiltration

7. Ectopic Fat: Liver in Type 2 DM NS p=0.001 p<0.001

8. Relation of Fatty Liver to VAT µEq/L

9. Relation of Fatty Liver to Fatty Acids

10. Stepped Care: Type 2 Diabetes Step 1: Nutrition therapy, exercise, lifestyle changes Training in self-management and self-monitoring of blood glucose Step 2: Add oral agents -monotherapy -combination therapy Step 3: Add or change to insulin C

12. Effect of Glyburide in Type 2 Diabetes: Enhanced  -Cell Responsiveness Shapiro ET et al. J Clin Endocrinol Metab. 1989;69:571-576. 0600 10001400180022000200 0600 0 100 200 300 400 500 600 700 800 06001200180024000600 20 15 10 5 0 Glucose (mmol/L) Insulin secretion (pmol/min) Clock time Before After C © 1999 PPS

13. Insulin resistance Blood glucose Insulin resistance 1Intestine: glucose absorption 3Pancreas: insulin secretion Meglitinides Insulin secretion 4Liver: hepatic glucose output 2Muscle and adipose tissue: glucose uptake Wolffenbuttel BHR et al. Eur J Clin Pharmacol. 1993;45:113-116. C Meglitinides: Mechanism of Action © 1998 PPS

14. 1 Intestine: glucose absorption  -glucosidase inhibitors glucose absorption secondary to digestion of carbohydrate Insulin resistance 4Liver: hepatic glucose output Amatruda JM. In: Diabetes Mellitus. 1996:643-646. Blood glucose Insulin resistance 3 Pancreas: insulin secretion 2Muscle and adipose tissue: glucose uptake C  -Glucosidase Inhibitors: Mechanism of Action © 1997 PPS

15. Wu MS et al. Diabetes Care. 1990;13:1-8. BeforeAfter 812111910234812111910234 Plasma glucose (mg/dL) 300 250 200 150 100 50 0 20 40 60 Plasma Insulin (  U/mL) Time of day Treatment With Metformin in Type 2 Diabetes C © 1999 PPS

16. PPAR-  Binding and Gene Activation by the Thiazolidinediones Troglitazone Rosiglitazone Troglitazone Gene Activation Pioglitazone PPAR-   Courtesy of CharlesBurant, MD.

17. Treatment Effect on Fatty Liver l Both groups had “fatty liver” at baseline l No change during Metformin RX l Decrease in fatty liver with Rosiglitazone

20. Treatment Effect on VAT l No change in VAT during Metformin treatment l Reduction in VAT during Rosiglitazone Rx; (p=0.06).

21. Treatment Effect on SAT l Reduction in SAT during Metformin Rx l Moderate increase in SAT during Rosiglitazone Rx l Similar patterns seem with FM, thigh SubQ AT

22. Treatment Effect on Muscle TG Content l Oil Red O staining and fiber type determination used to measure muscle lipid. l Significant decrease with Metformin, no change with Rosiglitazone

23. Combination Therapy for Type 2 Diabetes l Established combinations * –SU + metformin –SU + troglitazone or pioglitazone –Metformin + troglitazone, rosiglitazone, or pioglitazone –SU + insulin –Troglitazone or pioglitazone + insulin –Metformin + insulin –Acarbose or miglitol + any other glucose-lowering drug –Metformin + repaglinide –SU + metformin + troglitazone –Repaglinide + metformin l Potentially useful combinations † l Repaglinide + troglitazone, rosiglitazone, or pioglitazone –Repaglinide + SU –Repaglinide + metformin + troglitazone, rosiglitazone, or pioglitazone * Supported by literature or PI † Investigational C © 1998 PPS

24. © 1997 PPS Insulin Therapy in Type 2 Diabetes l Bedtime intermediate-acting insulin or suppertime premixed insulin with oral agent l NPH plus regular or rapid-acting insulin bid or premixed insulin bid l NPH plus regular or rapid-acting insulin at suppertime, NPH at hs l Glargine insulin once daily

25. Therapeutic Options: Use of Insulin in Elderly Type 2 Diabetes Patients Advantages: l Effective in virtually all patients l Safe in renal/hepatic insufficiency l Useful in patients with major illness, eating difficulty l Encourages active self-care l No major drug interactions l No contraindications

26. Management Goals to Minimize Diabetes Complications Control Glucose Levels l Regular home blood glucose monitoring l HbA 1c <7%* l Preprandial blood glucose: 80-120 mg/dL* l Bedtime blood glucose: 100-140 mg/dL* l Peak postprandial blood glucose <160 mg/dL * ADA recommendations

27. Relationship of the Incidence of Myocardial Infarction and Microvascular Complications to Mean HbA 1c Concentration Adapted from Stratton IM, et al. BMJ 2000;321-405-12. Mean HbA 1c (%)

28. Setting Hyperglycemia Treatment Goals for Elderly Patients with Diabetes Mellitus l Patient’s estimated remaining life expectancy l Patient’s preference and commitment l Availability of support services l Economic issues

29. Basic Care Management Goals l Reduce cardiovascular risk factors: hypertension, dyslipidemia, cigarettes l Prevent metabolic decompensation –Average circulating glucose level ~200 mg/dL –FPG ~160 mg/dL –HbA 1c within 3-4% of upper limit of normal

30. Conclusions Among elderly people: l There is a high rate of IGT and type 2 diabetes l IPH/early insulin response may be important l Special considerations may affect treatment goals and therapy: comorbidities, functional status, and polypharmacy l Various therapeutic regimens are available