Ndei Beta Cell Slide Kit Insulin Secretion

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  • Pancreatic  -Cells and Insulin Secretion in Type 2 Diabetes This section focuses on the pathophysiology of  -cells in type 2 diabetes.
  • Ndei Beta Cell Slide Kit Insulin Secretion

    1. 1. Section 2 Pancreatic  -Cells and Insulin Secretion in Type 2 Diabetes
    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. Hypothetical Relationships Determine Categories of Glucose Tolerance Adapted from Kahn SE et al. Diabetes . 1993;42:1663-1672. Type 2 Diabetes Insulin sensitivity index (x10 -5 min -1 /pmol/L) AIRglucose (pmol/L) IGT Normal 0 500 1,000 1,500 95th 75th 50th 25th 5th 0 2 4 6 8 10
    5. 5. Hypothetical Outcomes of Interventions to Treat Type 2 Diabetes Adapted from Kahn SE et al. Diabetes . 1993;42:1663-1672. Type 2 Diabetes IGT Insulin sensitivity index (x10 -5 min -1 /pmol/L) Increased Insulin Secretion Normal Increased Insulin Sensitivity 0 500 1,000 1,500 95th 75th 50th 25th 5th 0 2 4 6 8 10 AIRglucose (pmol/L)
    6. 6. Hypothetical Outcomes of Interventions to Prevent Type 2 Diabetes Adapted from Kahn SE et al. Diabetes . 1993;42:1663-1672. 0 0 2 4 6 8 10 Type 2 Diabetes 95th 75th 50th 25th 5th 500 1,000 1,500 IGT Insulin sensitivity index (x10 -5 min -1 /pmol/L) Increased Insulin Sensitivity Increased Insulin Secretion Normal AIRglucose (pmol/L)
    7. 7. Type 2 Diabetes: Pathogenesis in a Nutshell <ul><li>A failure of the  -cell to compensate adequately for insulin resistance </li></ul><ul><li>Obesity is the most common cause of insulin resistance </li></ul><ul><li>Most obese people have adequate  -cell compensation and therefore do not get diabetes </li></ul><ul><li>There is a genetic predisposition to  -cell failure </li></ul>Buchanan TA. Clin Ther . 2003;25(suppl B):B32-B46. DeFronzo RA. Med Clin North Am . 2004;88:787-835. Kahn SE. J Clin Endocrinol Metab . 2001;86:4047-4058.
    8. 8. Type 2 Diabetes: Pathogenesis in a Nutshell (cont.) <ul><li>Type 2 diabetes is a PROGRESSIVE disease </li></ul><ul><ul><li> -cell dysfunction first leads to impaired glucose tolerance, which progresses in some individuals to type 2 diabetes </li></ul></ul><ul><ul><li> -cell dysfunction starts long before blood glucose rises and worsens after diabetes develops </li></ul></ul><ul><li>Hyperglycemia may cause additional defects in insulin secretion and insulin action (glucotoxicity) </li></ul>Buchanan TA. Clin Ther . 2003;25(suppl B):B32-B46. DeFronzo RA. Med Clin North Am . 2004;88:787-835. Kahn SE. J Clin Endocrinol Metab . 2001;86:4047-4058.
    9. 9. Decreased  -Cell Function in Groups With Diabetes and at High Risk Insulin sensitivity index ( S i ; x10 -5 min -1 /pmol/L) Vidal J, Kahn SE. In: Lowe WL Jr, ed. Genetics of Diabetes Mellitus . 2001:109-131. 0 1 2 3 4 5 6 7 0 100 200 300 400 500 600 700 50th 25th 75th 5th Relatives of Patients With Type 2 Diabetes PCOS Women Former GDMs IGT Type 2 Diabetes Older Subjects AIRglucose (pmol/L)
    10. 10. Short-term  -Cell Adaptation: Response to Pregnancy Insulin sensitivity index (  mol/kg/min per pmol/L) Insulin secretion rate (pmol/min) Buchanan TA. J Clin Endocrinol Metab . 2001;86:989-993. 0.3 400 800 600 200 0 0 0.2 0.1 0.4 3rd trimester Nonpregnant postpartum Gestational Diabetes 1,000 Normal
    11. 11. Pathogenesis of Type 2 Diabetes:  -Cell Dysfunction vs Insulin Resistance <ul><li>48 Pima Indians were studied </li></ul><ul><ul><li>17 progressed from NGT to type 2 diabetes (over 5.1 ± 1.4 years) </li></ul></ul><ul><ul><li>31 subjects maintained NGT (4.8 ± 2.3 years) </li></ul></ul>Weyer C et al. J Clin Invest . 1999;104:787-794.
    12. 12. Declining  -Cell Function: Best Correlation of Progression Acute insulin response (  U/mL) Weyer C et al. J Clin Invest . 1999;104:787-794. EMBS=estimated metabolic body size 500 400 300 200 100 0 0 1 2 3 4 5 Measure of insulin resistance (mg/kg EMBS/min) Nonprogressors Progressors DIA IGT NGT NGT NGT NGT
    13. 13. Loss of  -Cell Function in People Who Develop Type 2 Diabetes: Longitudinal Data Insulin Action Insulin Secretion M-low (mg/kg EMBS/min) 0 1 2 3 4 NGT IGT Diabetes * AIR (  U/mL) * 0 50 100 150 200 250 300 NGT Diabetes † IGT * P <0.05; † P <0.01 Adapted from Weyer C et al. J Clin Invest . 1999;104:787-794. EMBS=estimated metabolic body size
    14. 14. Changing Glucose: Different Rates at Different Clinical Stages Ferrannini E et al. Diabetes. 2004;53:160-165. Fasting plasma glucose (mmol/L) Baseline 3.25 years 7 years 10 NGT  NGT  NGT NGT  D  D NGT  NGT  D IGT  D  D IGT  IGT  D 9 8 7 6 5 4 3
    15. 15. Functional Defects in  -Cells in the Development of Diabetes <ul><li>Progressive decrease in  -cell insulin secretion in response to nutrients </li></ul><ul><ul><li>first manifested as a decrease in early or acute insulin secretion (decreased first phase insulin secretion) </li></ul></ul><ul><li>Loss of normal minute-by-minute pulsatile insulin secretion and daily ultradian rhythm of secretion </li></ul><ul><li>Decreases in insulin processing with increased proinsulin:insulin ratio </li></ul>
    16. 16. UKPDS: Progressive Deterioration in Glycemic Control Over Time <ul><ul><li>0 </li></ul></ul>Intensive Conventional Time from randomization (y) <ul><ul><li>6 </li></ul></ul><ul><ul><li>3 </li></ul></ul><ul><ul><li>9 </li></ul></ul><ul><ul><li>12 </li></ul></ul><ul><ul><li>15 </li></ul></ul>Median A1C (%) <ul><ul><li>A1C </li></ul></ul>Years from diagnosis  -Cell function (%) 100 80 60 40 20 0 UKPDS Group. Lancet . 1998;352:837-853. -12 -10 -8 -6 -4 -2 0 2 4 6 Holman RR. Diabetes Res Clin Pract . 1998;40(suppl):S21-S25. 9 8 7 6 0
    17. 17. UKPDS: Progressive Deterioration in  -Cell Function Over Time Holman RR. Diabetes Res Clin Pract . 1998;40(suppl):S21-S25.  -Cell function (%) Years from diagnosis 100 80 60 40 20 0 -12 -10 -8 -6 -4 -2 0 2 4 6
    18. 18. Insulin and Glucose Patterns: Normal and Type 2 Diabetes Polonsky KS et al. N Engl J Med. 1988;318:1231-1239. 100 200 300 400 0600 1000 1800 1400 0200 2200 0600 Time of day 0600 1000 1800 1400 0200 2200 0600 Time of day 20 40 60 80 100 120 B L S B L S Normal Type 2 diabetes Glucose (mg/dL) Insulin (  U/mL) (meals) (meals)
    19. 19. Early Nutrient-Induced Insulin Secretion <ul><li>A crucial factor of postmeal glucose tolerance </li></ul><ul><li>Loss of first-phase insulin release can result in glucose intolerance </li></ul><ul><li>In type 2 diabetes, restoring first-phase response improves postmeal glycemia and FFA levels </li></ul><ul><li>Intensive blood glucose control can partially restore first-phase insulin secretion </li></ul>
    20. 20. Fasting Plasma Glucose and the Acute Insulin Response Relative acute insulin response (% increase) Brunzell JD et al. J Clin Endocrinol Metab . 1976;42:222-229. Time (min) 79–89 90–99 100–114 115–149 150–349 n 24 20 7 3 12 FPG (mg/dL) 800 600 400 200 0 -100 0 15 30 60 90 120
    21. 21. Acute Insulin Response to Glucose Time (min) Pfeifer MA et al. Am J Med . 1981;70:579-588. Plasma IRI (  U/mL) Control (n=9) Type 2 Diabetes (n=9) =20g IV glucose 120 100 80 60 40 20 0 -30 0 30 -30 0 30 120 100 80 60 40 20 0 Plasma IRI (  U/mL) IRI=immunoreactive insulin
    22. 22. Acute Insulin Response to Arginine Ward WK et al. J Clin Invest . 1984;74:1318-1328. Acute insulin response to arginine (  U/mL) Plasma glucose (mg/dL) 400 300 200 100 0 0 200 400 600 Controls (n=8) Type 2 diabetes (n=8)
    23. 23. Decreases in Insulin Response r=-0.58; P =0.07 Røder ME et al. J Clin Endocrinol Metab . 1998;83:604-608. AIR max (pmol/L) Fasting glucose (mmol/L) 0 4 8 12 16 20 0 200 400 600 800 1,000 Type 2 diabetes=9 Healthy subjects=10
    24. 24. Disproportionate Increase in Proinsulin in Patients With Type 2 Diabetes Ward WK et al. Diabetologia . 1987;30:698-702. Basal (%) PI IRI Controls (n=28) Type 2 diabetes (n=22) P <0.001 0 10 20 30 40 50 60 70
    25. 25. Mechanisms Responsible for Changes in  -Cell Function <ul><li>Normal  -cell adaptation to insulin resistance </li></ul><ul><ul><li>increased secretion from each cell </li></ul></ul><ul><ul><li>increased  -cell mass </li></ul></ul><ul><li>Impaired  -cell adaptation in type 2 diabetes result of </li></ul><ul><ul><li>decreased secretion from each cell </li></ul></ul><ul><ul><li>reduced  -cell mass </li></ul></ul>
    26. 26.  -Cell Mass in Normal Patients and Patients With Diabetes: Autopsy Study  -Cell volume (%) Normal Impaired Diabetes Normal Diabetes Obese Lean 0 1 2 3 4 - 41% - 40% -63% * * † * P <0.05; † P <0.01 Butler AE et al. Diabetes. 2003;52:102-110.
    27. 27. Altered  -Cell Mass and Function in Islets From Subjects With Type 2 Diabetes 0 1,000 2,000 3,000 4,000 5,000 6,000 7,000 8,000 9,000 Control (n=14) Type 2 diabetes (n=14) Islet mass (IEq/g pancreas) GSIR=glucose-stimulated insulin release Deng S et al. Diabetes. 2004;53:624-632. 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Control (n=14) Type 2 diabetes (n=14) GSIR (ng/min/100 islets)  -Cell Mass  -Cell Function * P <0.001; † P <0.05 * †
    28. 28. Potential Causes for Falling Insulin Secretion: Glucolipotoxicity <ul><li>Increased flux of FFAs into a genetically susceptible  -cell is thought to result in multiple deleterious effects </li></ul><ul><ul><li>inhibition of proper glucose utilization </li></ul></ul><ul><ul><li>disruption of normal cell signaling cascades </li></ul></ul><ul><ul><li>mitochondrial damage from reactive oxygen species </li></ul></ul><ul><ul><li>activation of cellular stress responses, which cause impairment in multiple metabolic pathways </li></ul></ul><ul><ul><li>nitric oxide generation, which can also alter multiple metabolic pathways </li></ul></ul>
    29. 29. Potential Causes for Falling Insulin Secretion: Glucolipotoxicity (cont.) <ul><li>Additional deleterious effects are </li></ul><ul><ul><li>altered secretion of cytokines that can affect islet response to nutrients </li></ul></ul><ul><ul><li>decreased  -cell neogenesis or ability of  -cells to proliferate in response to increased metabolic demand </li></ul></ul><ul><li>As a consequence of decreasing  -cell function and loss of  -cell mass, remaining  -cells work harder, increasing their potential for damage </li></ul>
    30. 30. Role of Islet Amyloid in  -Cell Dysfunction <ul><li>IAPP/amylin cosecreted with insulin </li></ul><ul><li>Islet amyloid present in up to 90% of patients with type 2 diabetes at autopsy </li></ul><ul><li>Extent of deposits related to disease severity </li></ul><ul><li>Early deposition of fibrils seen in many individuals </li></ul><ul><li>Similar to amyloid deposits in Alzheimer’s disease, rheumatoid arthritis, and multiple myeloma </li></ul>Kahn SE et al. Diabetes . 1999;48:241-253.
    31. 31. Amyloid Deposits in Pancreatic Islets in Type 2 Diabetes Verchere CB et al. Proc Natl Acad Sci USA . 1996;93:3492-3496. Amyloid deposits in pancreatic islets of human with type 2 diabetes 50  m

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