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

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