Section 4 Clinical Implications

 -Cell Adaptation and Failure: Opportunities for Prevention and Treatment of Type 2 Diabetes

Disclosure This slide kit is intended to provide current information on issues concerning  -cells in patients with type 2 diabetes. Some of the information and agents mentioned may include discussions of off-label, non–FDA-approved, or investigational uses. Please refer to each manufacturer’s full prescribing information before prescribing any of the agents mentioned in this program. Slides that include discussion of off-label uses are identified with the symbol .

This slide kit is intended to provide current information on issues concerning  -cells in patients with type 2 diabetes.

Some of the information and agents mentioned may include discussions of off-label, non–FDA-approved, or investigational uses. Please refer to each manufacturer’s full prescribing information before prescribing any of the agents mentioned in this program.

Slides that include discussion of off-label uses are identified with the symbol .

Treatment of Type 2 Diabetes: Getting Back on the Curve Reestablishing Insulin Sensitivity-Secretion Relationships Resistant Insulin sensitivity Sensitive Insulin level Normal curve Diabetes Insulin or Secretagogue Diet+Exercise, Metformin, TZDs Combination Therapy

Short-term Methods to Improve  -Cell Insulin Secretion Reverse glucotoxicity in severely decompensated individuals Add insulin secretagogues Administer exogenous insulin

Reverse glucotoxicity in severely decompensated individuals

Add insulin secretagogues

Administer exogenous insulin

Lowering Glucose Levels Improves  -Cell Function 14 subjects age: 50 ± 3 years diabetes duration: 7.8 ± 2.1 years (new onset to 20 years) fasting glucose: 286 ± 17 mg/dL plasma insulin: 15 ± 2 U/mL 22 days of CSII euglycemic clamp and hepatic glucose output insulin secretion over 24 hrs and IV glucose and glucagon Garvey WT et al. Diabetes. 1985;34:222-234.

14 subjects

age: 50 ± 3 years

diabetes duration: 7.8 ± 2.1 years (new onset to 20 years)

fasting glucose: 286 ± 17 mg/dL

plasma insulin: 15 ± 2 U/mL

22 days of CSII

euglycemic clamp and hepatic glucose output

insulin secretion over 24 hrs and IV glucose and glucagon

Increased Insulin Secretion Following Elimination of Glucotoxicity Garvey WT et al. Diabetes. 1985;34:222-234. Glucose (mg/dL) Insulin (  U/mL) 450 400 350 300 250 200 150 100 50 40 30 20 10 Before After After Before Time 8 am 12 pm 4 pm 8 pm 12 am 4 am 8 am Meals

Insulin Secretagogues: Sulfonylureas and Glitinides Bind to K ATP channels on the  -cell and directly increase insulin secretion sulfonylureas (longer half-life) glimepiride glipizide glyburide glitinides (shorter half-life) nateglinide repaglinide Krentz AJ et al. Drugs . 2005;65:385-411.

Bind to K ATP channels on the  -cell and directly increase insulin secretion

sulfonylureas (longer half-life)

glimepiride

glipizide

glyburide

glitinides (shorter half-life)

nateglinide

repaglinide

Effect of Glyburide in Hyperglycemia: Enhanced  -Cell Responsiveness Shapiro ET et al. J Clin Endocrinol Metab . 1989;69:571-576. Solid red line (left graph) and shaded red area (right graph) represent mean ± SEM for a group of subjects without diabetes. Clock time Clock time Before glyburide After glyburide 6 am 10 am 2 pm 6 pm 10 pm 2 am 6 am 0 100 200 300 400 500 600 700 800 6 am 12 pm 6 pm 12 am 6 am 20 15 10 5 0 Glucose (mmol/L) Insulin secretion (pmol/min) Meals Meals Before glyburide After glyburide

Long-term Improvement or Stabilization of Islet Function All therapies for diabetes appear to lose effectiveness with time, primarily due to a progressive decline in  -cell function Therapies that decrease  -cell secretory demand can prevent or possibly reverse islet dysfunction

All therapies for diabetes appear to lose effectiveness with time, primarily due to a progressive decline in  -cell function

Therapies that decrease  -cell secretory demand can prevent or possibly reverse islet dysfunction

Progressive Hyperglycemia in Type 2 Diabetes Despite Therapy 0 6 7 8 9 2 4 6 8 10 A1C (%) Years after randomization 0 Conventional (diet) Intensive: Upper Normal The UKPDS Study UKPDS Group. Lancet. 1998;352:854-865. Chlorpropamide Glibenclamide Insulin Metformin

Prevention and Early Treatment of Type 2 Diabetes: Changing the Focus  -Cell function (%) UKPDS Data Prevention and Early Treatment -12 -10 -8 -6 -4 -2 0 2 4 6 0 20 40 60 80 100 Years from diagnosis Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25.

Prevention and Early Treatment of Type 2 Diabetes: Three Levels of Opportunity 3  -Cell Failure Hyperglycemia Robust  -Cells Hyperinsulinemia Weak  -Cells Adipose Tissue Adipokines Fatty Acids Insulin Resistance 2 Insulin Resistance Liver & Muscle 1 Obesity Energy Balance Negative Positive Lifestyle Interventions Fat Accumulation

Weight Loss Can Improve Diabetic Control and Prevent the Deterioration in  -Cell Function Lifestyle interventions (diet and exercise) are the mainstays of treatment for type 2 diabetes Exercise and weight loss improve insulin sensitivity, resulting in reduced insulin secretion

Lifestyle interventions (diet and exercise) are the mainstays of treatment for type 2 diabetes

Exercise and weight loss improve insulin sensitivity, resulting in reduced insulin secretion

Effect of Weight Loss on  -Cell Function in Obese Patients With Type 2 Diabetes Gumbiner B et al. J Clin Endocrinol Metab . 1990;70:1594-1602. 0 60 120 180 300 250 200 150 100 50 0 Insulin secretion (pmol/min/m²) Minutes 0 60 120 180 0 6 8 10 12 14 16 18 22 20 Glucose (mmol/L) Before (mean BMI 35.5 kg/m 2 ) After (mean BMI 29.5 kg/m 2 ) Minutes

Weight Loss Improves Insulin Secretion in Obese Patients With Type 2 Diabetes Gumbiner B et al. J Clin Endocrinol Metab . 1990;70:1594-1602. Minutes Minutes 25 20 15 10 5 0 Glucose (mmol/L) 0 60 120 180 240 300 360 300 250 200 150 100 50 0 Insulin secretion (pmol/min/m 2 ) 0 60 120 180 240 300 360 Before (mean BMI 35.5 kg/m 2 ) After (mean BMI 29.5 kg/m 2 )

Prevention of Type 2 Diabetes Results of Recent Randomized Trials Buchanan TA et al. Diabetes. 2002;51:2796-2803. Chiasson JL et al. Lancet. 2002;359:2072-2077. Knowler WC et al. N Engl J Med. 2002;346:393-403. Torgerson JS et al. Diabetes Care . 2004;27:155-161. Toumilehto J et al. N Engl J Med . 2001;344:1343-1350. Relative Risk Study Subjects Intervention Reduction Finnish DPS IGT Lifestyle 58% US DPP IGT Lifestyle 58% US DPP IGT Metformin 31% Stop-NIDDM IGT Acarbose 25% TRIPOD Prior GDM Troglitazone 55% XENDOS IGT Orlistat 45% Behavior Medication

Finnish Diabetes Prevention Study: Effect of Lifestyle Intervention Cumulative probability of remaining free of diabetes Toumilehto J et al. N Engl J Med . 2001;344:1343-1350. 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 5 6 Years on trial Intensive Lifestyle (11%) Control (23%) 58% Relative Risk Reduction

US Diabetes Prevention Program: Effect of Lifestyle Intervention Years from randomization Cumulative incidence of diabetes (%) 0 1 2 3 4 0 10 20 30 40 Placebo Lifestyle 58% Relative Risk Reduction Adapted from Knowler WC et al. N Engl J Med. 2002;346:393-403.

US Diabetes Prevention Program: Effect of Metformin 0 1 2 3 4 0 10 20 30 40 Placebo Metformin 31% Relative Risk Reduction Years from randomization Adapted from Knowler WC et al. N Engl J Med. 2002;346:393-403. Cumulative incidence of diabetes (%)

Metformin and Islet Function Metformin directly reduces glucose production by the liver, resulting in lower insulin levels Metformin has a minimal peripheral insulin-sensitizing effect Metformin does not directly affect insulin secretion Metformin usually results in modest weight loss Krentz AJ et al. Drugs . 2005;65:385-411.

Metformin directly reduces glucose production by the liver, resulting in lower insulin levels

Metformin has a minimal peripheral insulin-sensitizing effect

Metformin does not directly affect insulin secretion

Metformin usually results in modest weight loss

Metformin in Type 2 Diabetes: Improved Glucose Without Changes in Insulin Secretion Wu MS et al. Diabetes Care . 1990;13:1-8. Before After 8 12 1 11 9 10 2 3 4 Plasma glucose (mg/dL) 300 250 200 150 100 50 0 20 40 60 Plasma insulin (  U/mL) Time of day Time of day 8 12 1 11 9 10 2 3 4

 -Glucosidase Inhibitors Decrease the rate of digestion of complex carbohydrates in the small intestine Delay glucose absorption and attenuate postprandial rises in blood glucose and insulin Efficacious as first-line therapy and in combination with sulfonylureas, metformin, and insulin Beneficial effects on hyperglycemia and hyperinsulinemia Do not cause weight gain May lower triglyceride levels Krentz AJ, Bailey CJ. Drugs . 2005;65:385-411.

Decrease the rate of digestion of complex carbohydrates in the small intestine

Delay glucose absorption and attenuate postprandial rises in blood glucose and insulin

Efficacious as first-line therapy and in combination with sulfonylureas, metformin, and insulin

Beneficial effects on hyperglycemia and hyperinsulinemia

Do not cause weight gain

May lower triglyceride levels

The STOP-NIDDM Study: Effect of Acarbose Cumulative probability of remaining free of diabetes Days after randomization Acarbose Placebo 25% Relative Risk Reduction Chiasson JL et al. Lancet. 2002;359:2072-2077. 1.00 0.95 0.90 0.85 0.80 0.75 0.70 0.65 0.60 0.55 0.50 0.45 0.40 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300

Lipase Inhibitor: Orlistat Inhibits intestinal lipase, decreasing the absorption of fat in the small intestine In clinical trials, orlistat-treated patients lost 5% to 10% of body weight vs 2% to 7% in placebo-treated patients following 6 to 48 months of treatment Reduces LDL cholesterol and insulin levels Curran MP, Scott LJ. Drugs . 2004;64:2845-2864.

Inhibits intestinal lipase, decreasing the absorption of fat in the small intestine

In clinical trials, orlistat-treated patients lost 5% to 10% of body weight vs 2% to 7% in placebo-treated patients following 6 to 48 months of treatment

Reduces LDL cholesterol and insulin levels

The XENDOS Study: Effect of Orlistat Week Cumulative incidence of diabetes (%) Placebo + lifestyle - IGT patients Orlistat + lifestyle - IGT patients Placebo + lifestyle - all patients Orlistat + lifestyle - all patients 45% Relative Risk Reduction P =0.0024 P =0.0032 0 26 52 78 104 130 156 182 208 0 5 10 15 20 25 30 Torgerson JS et al. Diabetes Care . 2004;27:155-161. 37% Relative Risk Reduction

PPAR  Activators and Islet Function The thiazolidinediones and other PPAR  activators improve insulin sensitivity in muscle and liver primarily by redirecting FFAs to adipose tissue, reducing TG levels improve insulin sensitivity by reducing insulin concentrations improve  -cell secretion patterns prevent diabetes in high-risk populations Krentz AJ et al. Drugs . 2005;65:385-411.

The thiazolidinediones and other PPAR  activators

improve insulin sensitivity in muscle and liver primarily by redirecting FFAs to adipose tissue, reducing TG levels

improve insulin sensitivity by reducing insulin concentrations

improve  -cell secretion patterns

prevent diabetes in high-risk populations

TRIPOD Study: Effect of Troglitazone Buchanan TA et al. Diabetes. 2002;51:2796-2803. Months on study 55% Relative Risk Reduction 50 40 20 0 0 12 24 36 48 60 Placebo Troglitazone 30 10 Patients with diabetes (%) 12.1% Annual Incidence Rate 5.4% Annual Incidence Rate

Stabilization of  -Cell Function at IGT Stage: Evidence From the TRIPOD Study P =0.01 between groups Baseline 8 Months post-trial Placebo (n=40) 0 2 4 6 MINMOD S i Acute insulin response (  U/mL x min) 200 400 600 800 0 0 2 4 6 MINMOD S i 39% decrease in  -cell compensation Stable Buchanan TA et al. Diabetes. 2002;51:2796-2803. 1,000 200 400 600 800 0 1,000 Troglitazone (n=44)

Stabilization of  -Cell Function at Early Diabetes: Evidence From the TRIPOD Study Years Disposition index ( S i x AIRg) 0 1 2 3 4 5 0 200 400 600 800 On Trial Off Trial Troglitazone Placebo P =0.82 -3% P =0.02 -35% Xiang AH et al. J Clin Endocrinol Metab . 2004;89:2846-2851.

Effect of Troglitazone on  -Cell Function in PCOS Ehrmann DA et al. J Clin Endocrinol Metab . 1997;82:2108-2116. P <0.005 P <0.005 NS S i (10 -5 min -1 /pmol/L) AIR glucose (pmol/L) 0 100 200 300 400 500 600 700 800 900 0 250 500 750 1,000 1,250 1,500 1.25 1.00 0.75 0.50 0.25 0 Data are the mean±SEM. Disposition index Before treatment After treatment

Prevention of Type 2 Diabetes Tools for identification of high-risk people Step 1: Find Insulin Resistance Overweight by BMI (ethnicity-specific) Increased waist circumference Components of the metabolic syndrome Family history of type 2 diabetes and/or metabolic syndrome Step 2: Find  -Cell Dysfunction Impaired fasting glucose (100-125 mg/dL) Impaired 2-hour postprandial glucose (140-199 mg/dL) Rising glucose levels over time

Tools for identification of high-risk people

Step 1: Find Insulin Resistance

Overweight by BMI (ethnicity-specific)

Increased waist circumference

Components of the metabolic syndrome

Family history of type 2 diabetes and/or metabolic syndrome

Step 2: Find  -Cell Dysfunction

Impaired fasting glucose (100-125 mg/dL)

Impaired 2-hour postprandial glucose (140-199 mg/dL)

Rising glucose levels over time

Prevention of Type 2 Diabetes: One Clinical Strategy At-Risk Clinical Characteristics Higher Risk Impaired Continue Lifestyle Intervention Stable Glycemia Consider Pharmacologic Treatment Rising Glycemia Measure Glucose Lower Risk Normal Lifestyle Advice Follow-up Glucose Testing Diabetes Treat to Achieve an A1C <6.5%-7% Diabetic Lifestyle Intervention