Focus on Incretin-Based Therapies: Targeting the Core Defects of Type 2 Diabetes

Abstract

Glucose homeostasis is regulated by a complex interaction of hormones, principally including insulin, glucagon, amylin, and the incretins. Glucagon, cortisol, catecholamines, and growth hormone serve as the classic glucose counterregulatory hormones. The incretins are hormones released by enteroendocrine cells in the intestine in response to a meal. Classically, type 2 diabetes mellitus (T2DM) has been considered to be a triad of insulin resistance, increased hepatic gluconeogenesis, and progressive β-cell exhaustion/failure. However, disordered enteroendocrine physiology, specifically the reduced activity of glucagon-like peptide-1 (GLP-1), is also a principal pathophysiologic abnormality of the disease. Glucagon-like peptide-1 receptor agonists that have been studied include exenatide and liraglutide, which have been approved by the US Food and Drug Administration for use in patients with T2DM. Sitagliptin and saxagliptin, both approved for use in the United States, modulate incretin physiology by inhibiting degradation of GLP-1 by the enzyme dipeptidyl peptidase-4 (DPP-4). Modulators of incretin physiology have been shown to improve glycemic control with a low risk for hypoglycemia and beneficially affect β-cell function. Unlike the DPP-4 inhibitors, GLP-1 receptor agonist therapy also produces weight loss, an important consideration given the close association among T2DM, overweight/obesity, and cardiovascular disease. The GLP-1 receptor agonists have also demonstrated beneficial effects on cardiovascular risk factors other than hyperglycemia and excess body weight, such as lipid concentrations and blood pressure. This article describes incretin physiology and studies of pharmacologic therapy designed to address the blunted incretin response in patients with T2DM. Information was obtained by a search of the PubMed and MEDLINE databases for articles published from January 1, 1995 to June 1, 2009.

Keywords:

• diabetes mellitus
• DPP-4 inhibitors
• GLP-1 receptor agonists
• incretins
• pathophysiology