Effects of incretin hormones on beta-cell mass and function, body weight, and hepatic and myocardial function

Abstract

Type 2 diabetes mellitus is a chronic debilitating disease characterized by insulin resistance and progressive pancreatic dysfunction. Concomitant with declining pancreatic function and decreasing insulin production, there is a progressive increase in blood glucose levels. Hyperglycemia plays a major role in the development of the microvascular and macrovascular complications of diabetes. Traditional agents used for the treatment of type 2 diabetes are able to improve glycemia, but their use is often limited by treatment-associated side effects, including hypoglycemia, weight gain, and edema. Moreover, these agents do not have any sustained effect on beta-cell mass or function. The introduction of incretin hormone-based therapies represents a novel therapeutic strategy, because these drugs not only improve glycemia with minimal risk of hypoglycemia but also have other extraglycemic beneficial effects. In clinical studies, both exenatide (the first dipeptidyl peptidase-4-resistant glucagonlike peptide-1 receptor agonist approved by the US Food and Drug Administration [FDA]), and liraglutide (a long-acting incretin mimetic), improve beta-cell function and glycemia with minimal hypoglycemia. Both agents have trophic effects on beta-cell mass in animal studies. The use of these agents is also associated with reduced body weight and improvements in blood pressure, diabetic dyslipidemia, hepatic function, and myocardial function. These effects have the potential to reduce the burden of cardiovascular disease, which is a major cause of mortality in patients with diabetes.