Section 4 Clinical Implications
 -Cell Adaptation and Failure: Opportunities for Prevention and Treatment of Type 2 Diabetes
Disclosure <ul><li>This slide kit is intended to provide current information on issues concerning   -cells in patients wi...
Treatment of Type 2 Diabetes: Getting Back on the Curve Reestablishing Insulin Sensitivity-Secretion Relationships Resista...
Short-term Methods to Improve   -Cell Insulin Secretion <ul><li>Reverse glucotoxicity in severely decompensated individua...
Lowering Glucose Levels Improves   -Cell Function <ul><li>14 subjects </li></ul><ul><ul><li>age: 50 ± 3 years </li></ul><...
Increased Insulin Secretion Following Elimination of Glucotoxicity Garvey WT et al.  Diabetes.  1985;34:222-234. Glucose (...
Insulin Secretagogues: Sulfonylureas and Glitinides <ul><li>Bind to K ATP  channels on the   -cell and directly increase ...
Effect of Glyburide in Hyperglycemia: Enhanced   -Cell Responsiveness Shapiro ET et al.  J Clin Endocrinol Metab . 1989;6...
Long-term Improvement or Stabilization of Islet Function <ul><li>All therapies for diabetes appear to lose effectiveness w...
Progressive Hyperglycemia in Type 2 Diabetes Despite Therapy 0 6 7 8 9 2 4 6 8 10 A1C (%) Years after randomization 0 Conv...
Prevention and Early Treatment of Type 2 Diabetes: Changing the Focus  -Cell  function (%) UKPDS Data Prevention and Earl...
Prevention and Early Treatment of Type 2 Diabetes: Three Levels of Opportunity 3  -Cell Failure Hyperglycemia Robust   -...
Weight Loss Can Improve Diabetic Control and Prevent the Deterioration in   -Cell Function <ul><li>Lifestyle intervention...
Effect of Weight Loss on   -Cell Function in Obese Patients With Type 2 Diabetes  Gumbiner B et al.  J Clin Endocrinol Me...
Weight Loss Improves Insulin Secretion in Obese Patients With Type 2 Diabetes Gumbiner B et al.  J Clin Endocrinol Metab ....
Prevention of Type 2 Diabetes Results of Recent Randomized Trials Buchanan TA et al.  Diabetes.  2002;51:2796-2803. Chiass...
Finnish Diabetes Prevention Study: Effect of Lifestyle Intervention Cumulative probability of remaining free  of diabetes ...
US Diabetes Prevention Program: Effect of Lifestyle Intervention Years from randomization Cumulative  incidence  of diabet...
US Diabetes Prevention Program: Effect of Metformin 0 1 2 3 4 0 10 20 30 40 Placebo Metformin 31% Relative Risk Reduction ...
Metformin and Islet Function <ul><li>Metformin directly reduces glucose production by the liver, resulting in lower insuli...
Metformin in Type 2 Diabetes: Improved Glucose Without Changes in Insulin Secretion Wu MS et al.  Diabetes Care . 1990;13:...
 -Glucosidase Inhibitors <ul><li>Decrease the rate of digestion of complex carbohydrates in the small intestine </li></ul...
The STOP-NIDDM Study: Effect of Acarbose Cumulative probability of remaining free of diabetes Days after randomization Aca...
Lipase Inhibitor: Orlistat <ul><li>Inhibits intestinal lipase, decreasing the absorption of fat in the small intestine </l...
The XENDOS Study:  Effect of Orlistat Week Cumulative incidence of diabetes (%) Placebo + lifestyle - IGT patients Orlista...
PPAR   Activators and Islet Function <ul><li>The thiazolidinediones and other PPAR   activators  </li></ul><ul><ul><li>i...
TRIPOD Study: Effect of Troglitazone  Buchanan TA et al.  Diabetes.  2002;51:2796-2803. Months on study 55% Relative Risk ...
Stabilization of   -Cell Function at IGT Stage: Evidence From the TRIPOD Study P =0.01 between groups Baseline 8 Months p...
Stabilization of   -Cell Function at  Early Diabetes: Evidence From the TRIPOD Study Years Disposition  index ( S i  x AI...
Effect of Troglitazone on   -Cell Function in PCOS Ehrmann DA et al.  J Clin Endocrinol Metab . 1997;82:2108-2116. P <0.0...
Prevention of Type 2 Diabetes <ul><li>Tools for identification of high-risk people </li></ul><ul><li>Step 1: Find Insulin ...
Prevention of Type 2 Diabetes: One Clinical Strategy At-Risk Clinical Characteristics Higher Risk Impaired Continue Lifest...
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Ndei Beta Cell Slide Kit Clinical Implications

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  • Clinical Implications This module addresses clinical and management issues related to type 2 diabetes.
  • Transcript of "Ndei Beta Cell Slide Kit Clinical Implications"

    1. 1. Section 4 Clinical Implications
    2. 2.  -Cell Adaptation and Failure: Opportunities for Prevention and Treatment of Type 2 Diabetes
    3. 3. Disclosure <ul><li>This slide kit is intended to provide current information on issues concerning  -cells in patients with type 2 diabetes. </li></ul><ul><li>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. </li></ul><ul><li>Slides that include discussion of off-label uses are identified with the symbol . </li></ul>
    4. 4. 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
    5. 5. Short-term Methods to Improve  -Cell Insulin Secretion <ul><li>Reverse glucotoxicity in severely decompensated individuals </li></ul><ul><li>Add insulin secretagogues </li></ul><ul><li>Administer exogenous insulin </li></ul>
    6. 6. Lowering Glucose Levels Improves  -Cell Function <ul><li>14 subjects </li></ul><ul><ul><li>age: 50 ± 3 years </li></ul></ul><ul><ul><li>diabetes duration: 7.8 ± 2.1 years (new onset to 20 years) </li></ul></ul><ul><ul><li>fasting glucose: 286 ± 17 mg/dL </li></ul></ul><ul><ul><li>plasma insulin: 15 ± 2 U/mL </li></ul></ul><ul><li>22 days of CSII </li></ul><ul><ul><li>euglycemic clamp and hepatic glucose output </li></ul></ul><ul><ul><li>insulin secretion over 24 hrs and IV glucose and glucagon </li></ul></ul>Garvey WT et al. Diabetes. 1985;34:222-234.
    7. 7. 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
    8. 8. Insulin Secretagogues: Sulfonylureas and Glitinides <ul><li>Bind to K ATP channels on the  -cell and directly increase insulin secretion </li></ul><ul><ul><li>sulfonylureas (longer half-life) </li></ul></ul><ul><ul><ul><li>glimepiride </li></ul></ul></ul><ul><ul><ul><li>glipizide </li></ul></ul></ul><ul><ul><ul><li>glyburide </li></ul></ul></ul><ul><ul><li>glitinides (shorter half-life) </li></ul></ul><ul><ul><ul><li>nateglinide </li></ul></ul></ul><ul><ul><ul><li>repaglinide </li></ul></ul></ul>Krentz AJ et al. Drugs . 2005;65:385-411.
    9. 9. 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
    10. 10. Long-term Improvement or Stabilization of Islet Function <ul><li>All therapies for diabetes appear to lose effectiveness with time, primarily due to a progressive decline in  -cell function </li></ul><ul><li>Therapies that decrease  -cell secretory demand can prevent or possibly reverse islet dysfunction </li></ul>
    11. 11. 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
    12. 12. 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.
    13. 13. 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
    14. 14. Weight Loss Can Improve Diabetic Control and Prevent the Deterioration in  -Cell Function <ul><li>Lifestyle interventions (diet and exercise) are the mainstays of treatment for type 2 diabetes </li></ul><ul><li>Exercise and weight loss improve insulin sensitivity, resulting in reduced insulin secretion </li></ul>
    15. 15. 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
    16. 16. 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 )
    17. 17. 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
    18. 18. 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
    19. 19. 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.
    20. 20. 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 (%)
    21. 21. Metformin and Islet Function <ul><li>Metformin directly reduces glucose production by the liver, resulting in lower insulin levels </li></ul><ul><li>Metformin has a minimal peripheral insulin-sensitizing effect </li></ul><ul><li>Metformin does not directly affect insulin secretion </li></ul><ul><li>Metformin usually results in modest weight loss </li></ul>Krentz AJ et al. Drugs . 2005;65:385-411.
    22. 22. 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
    23. 23.  -Glucosidase Inhibitors <ul><li>Decrease the rate of digestion of complex carbohydrates in the small intestine </li></ul><ul><li>Delay glucose absorption and attenuate postprandial rises in blood glucose and insulin </li></ul><ul><li>Efficacious as first-line therapy and in combination with sulfonylureas, metformin, and insulin </li></ul><ul><li>Beneficial effects on hyperglycemia and hyperinsulinemia </li></ul><ul><li>Do not cause weight gain </li></ul><ul><li>May lower triglyceride levels </li></ul>Krentz AJ, Bailey CJ. Drugs . 2005;65:385-411.
    24. 24. 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
    25. 25. Lipase Inhibitor: Orlistat <ul><li>Inhibits intestinal lipase, decreasing the absorption of fat in the small intestine </li></ul><ul><li>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 </li></ul><ul><li>Reduces LDL cholesterol and insulin levels </li></ul>Curran MP, Scott LJ. Drugs . 2004;64:2845-2864.
    26. 26. 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
    27. 27. PPAR  Activators and Islet Function <ul><li>The thiazolidinediones and other PPAR  activators </li></ul><ul><ul><li>improve insulin sensitivity in muscle and liver primarily by redirecting FFAs to adipose tissue, reducing TG levels </li></ul></ul><ul><ul><li>improve insulin sensitivity by reducing insulin concentrations </li></ul></ul><ul><ul><li>improve  -cell secretion patterns </li></ul></ul><ul><ul><li>prevent diabetes in high-risk populations </li></ul></ul>Krentz AJ et al. Drugs . 2005;65:385-411.
    28. 28. 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
    29. 29. 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)
    30. 30. 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.
    31. 31. 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
    32. 32. Prevention of Type 2 Diabetes <ul><li>Tools for identification of high-risk people </li></ul><ul><li>Step 1: Find Insulin Resistance </li></ul><ul><ul><li>Overweight by BMI (ethnicity-specific) </li></ul></ul><ul><ul><li>Increased waist circumference </li></ul></ul><ul><ul><li>Components of the metabolic syndrome </li></ul></ul><ul><ul><li>Family history of type 2 diabetes and/or metabolic syndrome </li></ul></ul><ul><li>Step 2: Find  -Cell Dysfunction </li></ul><ul><ul><li>Impaired fasting glucose (100-125 mg/dL) </li></ul></ul><ul><ul><li>Impaired 2-hour postprandial glucose (140-199 mg/dL) </li></ul></ul><ul><ul><li>Rising glucose levels over time </li></ul></ul>
    33. 33. 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

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