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%).

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

IMFSCTFMAVAFSCAF Standardized beta coefficient Standardized beta coefficient * * * * * * * * * * * A B BMI BMI BMI >29.9 BMI BMI BMI >29.9 IMFSCTFMAVAFSCAF Association between fasting insulin and regional fat depots in men (A) and women (B) from Health ABC

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 ± ± ± Subcutaneous221 ± ± ± Women (n=904) (n=428) (n=252) Visceral 116 ± ± ± Subcutaneous 322 ± ± ± Abdominal Adipose Tissue (cm2)

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 ± ± ± 6.9 † Muscle Area (cm 2 ) ± ± ± 23.6 † Mid-Thigh Adipose Tissue (cm 2 ) Subcutaneous 46.7 ± ± 21.7 † 46.5 ± 20.3 † Intermuscular 9.1 ± ± 5.8 † 11.9 ± 10.6 † Women (n=904) (n=428) (n=252) Muscle Attenuation (HU)34.5 ± ± 7.2 † 32.5 ± 7.2 † Muscle Area (cm 2 )90.9 ± ± 17.2 † ± 17.1† Mid-Thigh Adipose Tissue (cm 2 ) Subcutaneous105.6 ± ± ± Intermuscular 9.6 ± ± 6.3 † 12.7 ± 6.6 †0.0001

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

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

Relation of Fatty Liver to VAT µEq/L

Relation of Fatty Liver to Fatty Acids

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

Effect of Glyburide in Type 2 Diabetes: Enhanced  -Cell Responsiveness Shapiro ET et al. J Clin Endocrinol Metab. 1989;69: Glucose (mmol/L) Insulin secretion (pmol/min) Clock time Before After C © 1999 PPS

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: C Meglitinides: Mechanism of Action © 1998 PPS

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: Blood glucose Insulin resistance 3 Pancreas: insulin secretion 2Muscle and adipose tissue: glucose uptake C  -Glucosidase Inhibitors: Mechanism of Action © 1997 PPS

Wu MS et al. Diabetes Care. 1990;13:1-8. BeforeAfter Plasma glucose (mg/dL) Plasma Insulin (  U/mL) Time of day Treatment With Metformin in Type 2 Diabetes C © 1999 PPS

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

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

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

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

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

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

© 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

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

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

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

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

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

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