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Ndei Beta Cell Slide Kit Biology

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Ndei Beta Cell Slide Kit Biology

  1. 1. Section 1 Normal Biology of Pancreatic  -Cells and Insulin Secretion
  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. Normal Islet Function: Glucose Regulation Adapted from Matschinsky FM, Bedoya FJ. In: Endocrinology . Vol 2. 2nd ed. 1989:1290-1303.  Insulin secretion (  -cell)  Glucagon secretion (  -cell) Low  Glucagon secretion (  -cell)  Insulin secretion (  -cell) High Detect changes in blood glucose
  5. 5. Regulation of Insulin Secretion <ul><li>Drugs </li></ul><ul><li>Sulfonylureas </li></ul><ul><li>Meglitanides </li></ul><ul><li>Diazoxide </li></ul><ul><li>Neurotransmitters </li></ul><ul><li>Norepinephrine </li></ul><ul><li>Nutrients </li></ul><ul><li>Amino acids </li></ul><ul><li>Glucose </li></ul><ul><li>Hormones </li></ul><ul><li>GIP </li></ul><ul><li>GLP-1 </li></ul>Adapted from Fajans SS et al. N Engl J Med . 2001;345:971-980.
  6. 6.  -Cells Maintain Normal Glucose Levels in the Face of Varying Insulin Needs <ul><li>Acute response </li></ul><ul><ul><li>increased insulin secretion per  -cell (eg, response to meals) </li></ul></ul><ul><li>Chronic response (eg, insulin resistance) </li></ul><ul><ul><li>enhanced function of individual cells and increased  -cell mass </li></ul></ul>
  7. 7.  -Cell Adaptation to Chronic Insulin Resistance in Obesity Polonsky KS et al. J Clin Invest . 1988;81:442-448. 160 8 AM 12 PM 4 PM 8 PM 12 AM 4 AM Normal (acute) Obese (chronic) Clock time (hours) Glucose (mg/dL) Meals 150 140 130 120 110 100 90 80 Clock time (hours) Insulin (  U/mL) 160 Meals 8 AM 12 PM 4 PM 8 PM 12 AM 4 AM 140 130 100 80 60 40 20 0 Normal (acute) Obese (chronic)
  8. 8. What Methods Do  -Cells Use to Adapt to Changing Insulin Sensitivity? <ul><li>Change the function of individual  -cells </li></ul><ul><li>Change  -cell mass </li></ul>
  9. 9. Normal Relationship Between Insulin Sensitivity and Response: The Disposition Index Bergman RN et al. Diabetes . 2002;51(suppl 1):S212-S220. Insulin sensitivity Insulin sensitivity x insulin response = constant Insulin response 6,000 4,000 2,000 0 0 1 2 3 4
  10. 10.  -Cell Adaptation to Insulin Resistance: Cross-sectional Data Fasting insulin (pmol/L) Insulin sensitivity index (x10 -5 min -1 /pmol/L) r=-0.73; P <0.0001 Kahn SE et al. Diabetes . 1993;42:1663-1672. Males (n=55 ) Females (n=38) 0 50 100 150 200 250 300 0 5 10 15 20 25 50th
  11. 11.  -Cell Adaptation to Insulin Resistance: Longitudinal Data in Normal Women Insulin sensitivity index (  mol/kg/min per pmol/L) 400 800 600 200 0 0 0.2 0.1 0.3 0.4 3rd trimester Nonpregnant postpartum Insulin secretion rate (pmol/min) Buchanan TA. J Clin Endocrinol Metab . 2001;86:989-993. 1,000
  12. 12. Regulation of  -Cell Mass: A Dynamic Process Increased  -cell mass Decreased  -cell mass  -Cell mass Replication Apoptosis Neogenesis Hypertrophy Necrosis
  13. 13.  -Cell Mass in Lean and Obese People: Autopsy Studies  -Cell volume (mL) 0 0.3 0.4 0.2 0.1 0.5 Obese Lean Kl ö ppel G et al. Surv Synth Pathol Res . 1985;4:110-125. Obese Lean 0 1.0 2.0 3.0 4.0  -Cell volume (%) Butler AE et al. Diabetes. 2003;52:102-110.
  14. 14. Alteration in  -Cell Mass Is a Consequence of Increased Insulin Demand <ul><li>Increased  -cell mass in obese vs lean individuals has been described in several autopsy studies </li></ul><ul><li>Increase in </li></ul><ul><ul><li>numbers of islets and  -cells </li></ul></ul><ul><ul><li>size of  -cells </li></ul></ul><ul><li>In animal models of insulin resistance, there is both replication (of existing  -cells) and neogenesis (new cells) from ductal precursor cells </li></ul>
  15. 15. Plasticity of Islets: Experimental Increase in  -Cell Mass in Response to IR Lingohr MK et al. Trends in Mol Med . 2002;8:375-384. Experimental overfeeding results in increased  -cell numbers (hyperplasia) and increased  -cell size (hypertrophy) SC=standard chow HF=high-fat (diet) SC HF H and E Insulin Glucagon/somatostatin Islet area  -Cell size  -/  -Cell size
  16. 16. Effect of High-Fat Diet on Islet Size and  -Cell Hypertrophy Lingohr MK et al. Trends in Mol Med . 2002;8:375-384. SC=standard chow HF=high-fat (diet) * P <0.001 3 2 1 0 SC HF SC HF SC HF 200 100 0 0 200 100 47.5% 34.4% Islet area (% total pancreatic area)  -Cell diameter (  M)  -/  -Cell diameter (  M) * *
  17. 17. Neogenesis May Contribute to Increased Islet Mass in Obese Humans Section of pancreas stained for insulin Butler AE et al. Diabetes . 2003;52:102-110.

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