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

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

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 .

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 .

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

Regulation of Insulin Secretion Drugs Sulfonylureas Meglitanides Diazoxide Neurotransmitters Norepinephrine Nutrients Amino acids Glucose Hormones GIP GLP-1 Adapted from Fajans SS et al. N Engl J Med . 2001;345:971-980.

Drugs

Sulfonylureas

Meglitanides

Diazoxide

Neurotransmitters

Norepinephrine

Nutrients

Amino acids

Glucose

Hormones

GIP

GLP-1

 -Cells Maintain Normal Glucose Levels in the Face of Varying Insulin Needs Acute response increased insulin secretion per  -cell (eg, response to meals) Chronic response (eg, insulin resistance) enhanced function of individual cells and increased  -cell mass

Acute response

increased insulin secretion per  -cell (eg, response to meals)

Chronic response (eg, insulin resistance)

enhanced function of individual cells and increased  -cell mass

 -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)

What Methods Do  -Cells Use to Adapt to Changing Insulin Sensitivity? Change the function of individual  -cells Change  -cell mass

Change the function of individual  -cells

Change  -cell mass

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

 -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

 -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

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

 -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.

Alteration in  -Cell Mass Is a Consequence of Increased Insulin Demand Increased  -cell mass in obese vs lean individuals has been described in several autopsy studies Increase in numbers of islets and  -cells size of  -cells In animal models of insulin resistance, there is both replication (of existing  -cells) and neogenesis (new cells) from ductal precursor cells

Increased  -cell mass in obese vs lean individuals has been described in several autopsy studies

Increase in

numbers of islets and  -cells

size of  -cells

In animal models of insulin resistance, there is both replication (of existing  -cells) and neogenesis (new cells) from ductal precursor cells

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

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) * *

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.