Title

Role of the Incretin Pathway in the Pathogenesis of Type 2 Diabetes Mellitus

Document Type

Article

Publication Date

12-1-2009

Abstract

Nutrient intake stimulates the secretion of the gastrointestinal incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which exert glucose-dependent insulinotropic effects and assist pancreatic insulin and glucagon in maintaining glucose homeostasis. GLP-1 also suppresses glucose-dependent glucagon secretion, slows gastric emptying, increases satiety, and reduces food intake. An impaired incretin system, characterized by decreased responsiveness to GIP and markedly reduced GLP-1 concentration, occurs in individuals with type 2 diabetes mellitus (T2DM). The administration of GLP-1 improves glycemic control, but GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4). Exenatide, a DPP-4-resistant exendin-4 GLP-1 receptor agonist, exhibits the glucoregulatory actions of GLP-1 and reduces body weight in patients with T2DM. It may possess cardiometabolic actions with the potential to improve the cardiovascular risk profile of patients with T2DM. DPP-4 inhibitors such as sitagliptin and saxagliptin increase endogenous GLP-1 concentration and demonstrate incretin-associated glucoregulatory actions in patients with T2DM. DPP-4 inhibitors are weight neutral. A growing understanding of the roles of incretin hormones in T2DM may further clarify the application of incretin-based treatment strategies.

Publication Title

Cleveland Clinic Journal of Medicine

Volume

76

Issue

Supplement 5

First Page

S12

Last Page

S19

PubMed ID

19952298

Comments

This article was published in Cleveland Clinic Journal of Medicine, Volume 76, Supplement 5, December 2009, Pages S12-S19.

The published version is available at http://dx.doi.org/10.3949/ccjm.76.s5.03

Copyright © 2009 The Cleveland Clinic Foundation

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