Section 2 Pancreatic  -Cells and Insulin Secretion in Type 2 Diabetes

 -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 .

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

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)

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)

Type 2 Diabetes: Pathogenesis in a Nutshell A failure of the  -cell to compensate adequately for insulin resistance Obesity is the most common cause of insulin resistance Most obese people have adequate  -cell compensation and therefore do not get diabetes There is a genetic predisposition to  -cell failure 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.

A failure of the  -cell to compensate adequately for insulin resistance

Obesity is the most common cause of insulin resistance

Most obese people have adequate  -cell compensation and therefore do not get diabetes

There is a genetic predisposition to  -cell failure

Type 2 Diabetes: Pathogenesis in a Nutshell (cont.) Type 2 diabetes is a PROGRESSIVE disease  -cell dysfunction first leads to impaired glucose tolerance, which progresses in some individuals to type 2 diabetes  -cell dysfunction starts long before blood glucose rises and worsens after diabetes develops Hyperglycemia may cause additional defects in insulin secretion and insulin action (glucotoxicity) 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.

Type 2 diabetes is a PROGRESSIVE disease

 -cell dysfunction first leads to impaired glucose tolerance, which progresses in some individuals to type 2 diabetes

 -cell dysfunction starts long before blood glucose rises and worsens after diabetes develops

Hyperglycemia may cause additional defects in insulin secretion and insulin action (glucotoxicity)

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)

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

Pathogenesis of Type 2 Diabetes:  -Cell Dysfunction vs Insulin Resistance 48 Pima Indians were studied 17 progressed from NGT to type 2 diabetes (over 5.1 ± 1.4 years) 31 subjects maintained NGT (4.8 ± 2.3 years) Weyer C et al. J Clin Invest . 1999;104:787-794.

48 Pima Indians were studied

17 progressed from NGT to type 2 diabetes (over 5.1 ± 1.4 years)

31 subjects maintained NGT (4.8 ± 2.3 years)

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

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

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

Functional Defects in  -Cells in the Development of Diabetes Progressive decrease in  -cell insulin secretion in response to nutrients first manifested as a decrease in early or acute insulin secretion (decreased first phase insulin secretion) Loss of normal minute-by-minute pulsatile insulin secretion and daily ultradian rhythm of secretion Decreases in insulin processing with increased proinsulin:insulin ratio

Progressive decrease in  -cell insulin secretion in response to nutrients

first manifested as a decrease in early or acute insulin secretion (decreased first phase insulin secretion)

Loss of normal minute-by-minute pulsatile insulin secretion and daily ultradian rhythm of secretion

Decreases in insulin processing with increased proinsulin:insulin ratio

UKPDS: Progressive Deterioration in Glycemic Control Over Time 0 Intensive Conventional Time from randomization (y) 6 3 9 12 15 Median A1C (%) A1C 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

0

6

3

9

12

15

A1C

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

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)

Early Nutrient-Induced Insulin Secretion A crucial factor of postmeal glucose tolerance Loss of first-phase insulin release can result in glucose intolerance In type 2 diabetes, restoring first-phase response improves postmeal glycemia and FFA levels Intensive blood glucose control can partially restore first-phase insulin secretion

A crucial factor of postmeal glucose tolerance

Loss of first-phase insulin release can result in glucose intolerance

In type 2 diabetes, restoring first-phase response improves postmeal glycemia and FFA levels

Intensive blood glucose control can partially restore first-phase insulin secretion

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

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

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)

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

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

Mechanisms Responsible for Changes in  -Cell Function Normal  -cell adaptation to insulin resistance increased secretion from each cell increased  -cell mass Impaired  -cell adaptation in type 2 diabetes result of decreased secretion from each cell reduced  -cell mass

Normal  -cell adaptation to insulin resistance

increased secretion from each cell

increased  -cell mass

Impaired  -cell adaptation in type 2 diabetes result of

decreased secretion from each cell

reduced  -cell mass

 -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.

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 * †

Potential Causes for Falling Insulin Secretion: Glucolipotoxicity Increased flux of FFAs into a genetically susceptible  -cell is thought to result in multiple deleterious effects inhibition of proper glucose utilization disruption of normal cell signaling cascades mitochondrial damage from reactive oxygen species activation of cellular stress responses, which cause impairment in multiple metabolic pathways nitric oxide generation, which can also alter multiple metabolic pathways

Increased flux of FFAs into a genetically susceptible  -cell is thought to result in multiple deleterious effects

inhibition of proper glucose utilization

disruption of normal cell signaling cascades

mitochondrial damage from reactive oxygen species

activation of cellular stress responses, which cause impairment in multiple metabolic pathways

nitric oxide generation, which can also alter multiple metabolic pathways

Potential Causes for Falling Insulin Secretion: Glucolipotoxicity (cont.) Additional deleterious effects are altered secretion of cytokines that can affect islet response to nutrients decreased  -cell neogenesis or ability of  -cells to proliferate in response to increased metabolic demand As a consequence of decreasing  -cell function and loss of  -cell mass, remaining  -cells work harder, increasing their potential for damage

Additional deleterious effects are

altered secretion of cytokines that can affect islet response to nutrients

decreased  -cell neogenesis or ability of  -cells to proliferate in response to increased metabolic demand

As a consequence of decreasing  -cell function and loss of  -cell mass, remaining  -cells work harder, increasing their potential for damage

Role of Islet Amyloid in  -Cell Dysfunction IAPP/amylin cosecreted with insulin Islet amyloid present in up to 90% of patients with type 2 diabetes at autopsy Extent of deposits related to disease severity Early deposition of fibrils seen in many individuals Similar to amyloid deposits in Alzheimer’s disease, rheumatoid arthritis, and multiple myeloma Kahn SE et al. Diabetes . 1999;48:241-253.

IAPP/amylin cosecreted with insulin

Islet amyloid present in up to 90% of patients with type 2 diabetes at autopsy

Extent of deposits related to disease severity

Early deposition of fibrils seen in many individuals

Similar to amyloid deposits in Alzheimer’s disease, rheumatoid arthritis, and multiple myeloma

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