Mimicking the Effects of GLP-1: Metabolic Control for Type 2 Diabetes at Multiple Sites of Action

Supported by an unrestricted educational grant from Eli Lilly and Company and Amylin Pharmaceuticals
Monday, June 7, 2004
5:45 – 7:45 am

Chair:
Daniel J Drucker, MD

Faculty:
Charles F Burant, MD, PhD
Daniel J Drucker, MD
Robert E Ratner, MD, CDE

Both pancreatic β-cell function and insulin sensitivity are needed for glycemic control. Lipotoxicity, perhaps due to obesity, is thought to damage β-cells, ultimately leading to type 2 diabetes. As insulin resistance increases, compensatory insulin secretion develops with progressive β-cell failure. In an energy-replete society, prevention and treatment of impaired glucose tolerance and type 2 diabetes depends upon unloading or augmenting the action of the β-cell. Oral glucose ingestion results in higher plasma glucose levels than intravenous ingestion; this effect is diminished in type 2 diabetes.1 The heightened response to oral glucose ingestion is called the incretin effect.[1] The first identified incretin was glucose-dependent insulinotropic peptide (GIP), which is synthesized predominantly in the duodenum. Preproglucagon is synthesized predominantly in the ileum and colon; it breaks down into glucagon, the glucagon-like peptides (GLP-1 and GLP-2), and several other substances. Patients with type 2 diabetes lose their responsiveness to GIP, but preserve their responsiveness to GLP-1. GLP-1 has a number of properties that make it an attractive treatment target, including glucose-dependent fasting and postprandial insulin release, modulation of glucagon secretion, appetite inhibition, and restoration of β-cell sensitivity.[2] Experimental studies also suggest that it may preserve and restore islet β-cell mass. Native GLP-1 is rapidly degraded and inactivated by dipeptidyl peptidase-IV (DPP-IV). Treatments based upon chronic GLP-1 infusion, GLP-1-receptor agonism, DPP-IV inhibition, and long-acting synthetic analogs of GLP-1 are in various stages of development. Among these compounds are the DPP-IV–resistant, GLP-1–like agent CJC-1131,[3] exendin-4,[4] liraglutide (NN2211),[5] and the DPP-IV inhibitor LAF237.[6] In clinical trials, treatment with synthetic exendin-4, a long-acting mimetic of human GLP-1, administered with oral antihyperglycemic medications to patients with type 2 diabetes, improved glycemic control and resulted in weight loss, a novel combination of therapeutic benefits.[7-9] Incretins, their analogs, and their mimetics offer new approaches for attaining glycemic control goals in patients with type 2 diabetes.

References

1. Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;29:46-52.
2. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359:824-830.
3. Kim J-G, Baggio LL, Bridon DP, et al. Development and characterization of a glucagon-like peptide 1-albumin conjugate: the ability to activate the glucagon-like peptide 1 receptor in vivo. Diabetes. 2003;52:751-759.
4. Li Y, Hansotia T, Yusta B, et al. Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis. J Biol Chem. 2003;278:471-478.
5. Chang A, Jakobsen G, Sturis J, et al. The GLP-1 derivative NN2211 restores beta-cell sensitivity to glucose in type 2 diabetic patients after a single dose. Diabetes. 2003;52:1786-1791.
6. Ahren B, Landin-Olsson M, Jansson PA, et al. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab. 2004;89:2078-2084.
7. DeFronzo R, Ratner R, Han J, Kim D, Fineman M, Baron A. Effects of exenatide (synthetic exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. American Diabetes Association 64th Annual Scientific Sessions. 2004. #6-LB.
8. Kendall DM, Riddle MC, Dongliang Z, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight in patients with type 2 diabetes treated with metformin and a sulfonylurea. American Diabetes Association 64th Annual Scientific Sessions. 2004. #10-LB.
9. Buse J, Henry R, Han J, Kim DD, Fineman M, Baron AD. Effect of exenatide (exendin-4) on glycemic control and safety over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes. 2004;53(suppl 2):A82.