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Ndei Beta Cell Slide Kit   Future Therapies
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Ndei Beta Cell Slide Kit Future Therapies

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  • What’s on the Horizon: Emerging Therapies This section provides information on a new class of drugs that is on the horizon for the prevention and treatment of type 2 diabetes – the incretins.

Transcript

  • 1. Section 5 What’s on the Horizon: Emerging Therapies
  • 2.  -Cell Adaptation and Failure: Opportunities for Prevention and Treatment of Type 2 Diabetes
  • 3. 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 .
  • 4. Future Therapies: Incretins
    • GLP-1 agonists
    • Exendin-4 agonists
    • DPP-IV inhibitors
    Drucker DJ. Diabetes Care . 2003;26:2929-2940.
  • 5. Glucagon-Like Peptide-1
    • Secreted from intestinal L-cells with meal ingestion
    • In humans and animals
      • enhances glucose-stimulated insulin release
      • decreases glucagon release
      • slows gastric emptying
      • reduces food intake
    • In animals and in vitro
      • increases insulin gene transcription
      • increases  -cell mass and  -cell differentiation
    Drucker DJ. Curr Pharm Des . 2001;7:1399-1412. Drucker DJ. Mol Endocrinol . 2003;17:161-171.
  • 6. Insulin and GLP-1 Responses to Meals Ørskov C et al. Scand J Gastroenterol . 1996;31:665-670. Insulin (pmol/L) GLP-1 (pmol/L) 0 20 40 0 200 400 9 AM 1 PM 7 PM 10 PM 9 AM Hours Meal Meal Meal
  • 7. GLP-1 Release Is Reduced in Type 2 Diabetes Toft-Nielsen MB et al. J Clin Endocrinol Metab . 2001;86:3717-3723. GLP-1 (pmol/L) 0 5 10 15 20 0 60 120 180 240 NGT (n=33) IGT (n=15) Time (min) * * * * * * * * Type 2 diabetes (n=54) * P <0.05 between type 2 diabetes and NGT groups. Meal
  • 8. Effect of GLP-1 on the  -Cell
    • Stimulation of insulin secretion
    • Stimulation of insulin gene transcription
    • Stimulation of insulin synthesis
    • Increased  -cell mass (stimulation of new  -cell formation, inhibition of apoptosis)
  • 9. GLP-1 Infusion Improves  -Cell Insulin Secretion C-peptide (pmol/L) Zander M et al. Lancet . 2002;359:824-830. 0 1,000 2,000 3,000 4,000 5,000 6,000 7,000 0 20 40 60 80 Time (min) Saline GLP-1 0 weeks 1 week 6 weeks 10 30 50 70 90
  • 10. GLP-1 and First-Phase Insulin Secretion Insulin pmol/L 1,800 750 Time (min) Time (min) 1,500 1,200 900 600 300 0 600 450 300 150 0 -15 0 15 30 45 60 -15 0 15 30 45 60 IV Glucose IV Glucose Data are mean  SEM Subjects Without Diabetes Subjects With Diabetes Quddusi S et al. Diabetes Care. 2003;26:791-798. Saline Control GLP-1-Acute GLP-1-Prolonged (2 minutes) (3 hours)
  • 11. Exenatide: Effect on the  -Cell
    • Synthetic peptide, which mimics actions of glucagon-like protein 1 (GLP-1)
      • enhances glucose-dependent insulin secretion
      • suppresses inappropriately elevated glucagon secretion
      • delays gastric emptying
    • Effect on  -cells
      • Animals, cell-line studies
        • increase expression of key  -cell function genes
        • increase insulin biosynthesis and processing
        • augment  -cell mass (increase neogenesis and proliferation, reduce apoptosis)
      • Human trials
        • treated patients demonstrate improved proinsulin:insulin ratio
        • robust insulin secretion to meal stimulus despite lower fasting and postprandial glucose concentrations
    Buse JB et al. Diabetes Care . 2004;27:2628-2635. DeFronzo RA et al. Diabetes Care . 2005;28:1092-1100. Kendall DM et al. Diabetes Care . 2005;28:1083-1091. Nielsen LL et al. Regul Pept . 2004;117:77-88.
  • 12. Exenatide: Effects on Glycemic Control in Combination With Current Oral Therapies Exenatide + Met Exenatide + SU Exenatide + Met + SU Placebo 5  g BID 10  g BID 0.40 -1.20 -1.00 -0.80 -0.60 -0.40 -0.20 0.00 0.20 Change in A1C from baseline (%) * † * † † † Buse JB et al. Diabetes Care. 2004;27:2628-2635. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. Kendall DM et al. Diabetes Care. 2005;28:1083-1091. * P <0.001 vs placebo; † P <0.0001 vs placebo . Met=metformin; SU=sulfonylurea.
  • 13. Exenatide: Proportion of Patients Achieving A1C  7% 0 5 10 15 20 25 30 35 40 45 50 Ex + Met Ex + SU Ex + Met + SU Proportion achieving A1C  7% † † † † * Buse JB et al. Diabetes Care. 2004;27:2628-2635. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. Kendall DM et al. Diabetes Care. 2005;28:1083-1091. * P <0.01 vs placebo; † P <0.0001 vs placebo. Ex=exenatide; Met=metformin; SU=sulfonylurea. † Placebo 5  g BID 10  g BID
  • 14. Summary
    • Increases in  -cell demand result in an adaptive response with increased  -cell function and mass
    • In individuals susceptible to type 2 diabetes, there is a gradual decrease in  -cell function and mass
    • To prevent loss of  -cell function and mass, the  -cell work must decrease