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1. Section 1 Normal Biology of Pancreatic  -Cells and Insulin Secretion

2.  -Cell Adaptation and Failure: Opportunities for Prevention and Treatment of Type 2 Diabetes

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

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)

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.  -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.  -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. Regulation of  -Cell Mass: A Dynamic Process Increased  -cell mass Decreased  -cell mass  -Cell mass Replication Apoptosis Neogenesis Hypertrophy Necrosis

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.

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. 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. 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.