Section 5 What’s on the Horizon: Emerging Therapies

 -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 .

Future Therapies: Incretins GLP-1 agonists Exendin-4 agonists DPP-IV inhibitors Drucker DJ. Diabetes Care . 2003;26:2929-2940.

GLP-1 agonists

Exendin-4 agonists

DPP-IV inhibitors

Glucagon-Like Peptide-1 Secreted from intestinal L-cells with meal ingestion In humans and animals enhances glucose-stimulated insulin release decreases glucagon release slows gastric emptying reduces food intake In animals and in vitro increases insulin gene transcription increases  -cell mass and  -cell differentiation Drucker DJ. Curr Pharm Des . 2001;7:1399-1412. Drucker DJ. Mol Endocrinol . 2003;17:161-171.

Secreted from intestinal L-cells with meal ingestion

In humans and animals

enhances glucose-stimulated insulin release

decreases glucagon release

slows gastric emptying

reduces food intake

In animals and in vitro

increases insulin gene transcription

increases  -cell mass and  -cell differentiation

Insulin and GLP-1 Responses to Meals Ørskov C et al. Scand J Gastroenterol . 1996;31:665-670. Insulin (pmol/L) GLP-1 (pmol/L) 0 20 40 0 200 400 9 AM 1 PM 7 PM 10 PM 9 AM Hours Meal Meal Meal

GLP-1 Release Is Reduced in Type 2 Diabetes Toft-Nielsen MB et al. J Clin Endocrinol Metab . 2001;86:3717-3723. GLP-1 (pmol/L) 0 5 10 15 20 0 60 120 180 240 NGT (n=33) IGT (n=15) Time (min) * * * * * * * * Type 2 diabetes (n=54) * P <0.05 between type 2 diabetes and NGT groups. Meal

Effect of GLP-1 on the  -Cell Stimulation of insulin secretion Stimulation of insulin gene transcription Stimulation of insulin synthesis Increased  -cell mass (stimulation of new  -cell formation, inhibition of apoptosis)

Stimulation of insulin secretion

Stimulation of insulin gene transcription

Stimulation of insulin synthesis

Increased  -cell mass (stimulation of new  -cell formation, inhibition of apoptosis)

GLP-1 Infusion Improves  -Cell Insulin Secretion C-peptide (pmol/L) Zander M et al. Lancet . 2002;359:824-830. 0 1,000 2,000 3,000 4,000 5,000 6,000 7,000 0 20 40 60 80 Time (min) Saline GLP-1 0 weeks 1 week 6 weeks 10 30 50 70 90

GLP-1 and First-Phase Insulin Secretion Insulin pmol/L 1,800 750 Time (min) Time (min) 1,500 1,200 900 600 300 0 600 450 300 150 0 -15 0 15 30 45 60 -15 0 15 30 45 60 IV Glucose IV Glucose Data are mean  SEM Subjects Without Diabetes Subjects With Diabetes Quddusi S et al. Diabetes Care. 2003;26:791-798. Saline Control GLP-1-Acute GLP-1-Prolonged (2 minutes) (3 hours)

Exenatide: Effect on the  -Cell Synthetic peptide, which mimics actions of glucagon-like protein 1 (GLP-1) enhances glucose-dependent insulin secretion suppresses inappropriately elevated glucagon secretion delays gastric emptying Effect on  -cells Animals, cell-line studies increase expression of key  -cell function genes increase insulin biosynthesis and processing augment  -cell mass (increase neogenesis and proliferation, reduce apoptosis) Human trials treated patients demonstrate improved proinsulin:insulin ratio robust insulin secretion to meal stimulus despite lower fasting and postprandial glucose concentrations Buse JB et al. Diabetes Care . 2004;27:2628-2635. DeFronzo RA et al. Diabetes Care . 2005;28:1092-1100. Kendall DM et al. Diabetes Care . 2005;28:1083-1091. Nielsen LL et al. Regul Pept . 2004;117:77-88.

Synthetic peptide, which mimics actions of glucagon-like protein 1 (GLP-1)

enhances glucose-dependent insulin secretion

suppresses inappropriately elevated glucagon secretion

delays gastric emptying

Effect on  -cells

Animals, cell-line studies

increase expression of key  -cell function genes

increase insulin biosynthesis and processing

augment  -cell mass (increase neogenesis and proliferation, reduce apoptosis)

Human trials

treated patients demonstrate improved proinsulin:insulin ratio

robust insulin secretion to meal stimulus despite lower fasting and postprandial glucose concentrations

Exenatide: Effects on Glycemic Control in Combination With Current Oral Therapies Exenatide + Met Exenatide + SU Exenatide + Met + SU Placebo 5  g BID 10  g BID 0.40 -1.20 -1.00 -0.80 -0.60 -0.40 -0.20 0.00 0.20 Change in A1C from baseline (%) * † * † † † Buse JB et al. Diabetes Care. 2004;27:2628-2635. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. Kendall DM et al. Diabetes Care. 2005;28:1083-1091. * P <0.001 vs placebo; † P <0.0001 vs placebo . Met=metformin; SU=sulfonylurea.

Exenatide: Proportion of Patients Achieving A1C  7% 0 5 10 15 20 25 30 35 40 45 50 Ex + Met Ex + SU Ex + Met + SU Proportion achieving A1C  7% † † † † * Buse JB et al. Diabetes Care. 2004;27:2628-2635. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. Kendall DM et al. Diabetes Care. 2005;28:1083-1091. * P <0.01 vs placebo; † P <0.0001 vs placebo. Ex=exenatide; Met=metformin; SU=sulfonylurea. † Placebo 5  g BID 10  g BID

Summary Increases in  -cell demand result in an adaptive response with increased  -cell function and mass In individuals susceptible to type 2 diabetes, there is a gradual decrease in  -cell function and mass To prevent loss of  -cell function and mass, the  -cell work must decrease

Increases in  -cell demand result in an adaptive response with increased  -cell function and mass

In individuals susceptible to type 2 diabetes, there is a gradual decrease in  -cell function and mass

To prevent loss of  -cell function and mass, the  -cell work must decrease