Can Islet Cell Function Be Improved Through Incretin Enhancement? Novel Mechanisms for Achieving Glycemic Control

A CME symposium supported by an educational grant from Merck

James R Gavin III, MD, PhD
Steven E Kahn, MB, ChB
David D’Alessio, MD
Daniel J Drucker, MD
Edward S Horton, MD

Reported by Joelle Escoffery, PhD

The prevalence of obesity and type 2 diabetes continues to increase, causing considerable mortality, morbidity, and both financial and societal burden. Intensive therapy can improve risk factors for diabetic complications; however, many patients still fail to meet targets for glycemic control, lipids, blood pressure, and albuminuria. Patient adherence, the progressive nature of type 2 diabetes, and clinical inertia all present formidable challenges to meeting glycemic targets.

Defects in insulin secretion and insulin action are both present in patients with type 2 diabetes. It is highly comorbid with obesity, lipid abnormalities, and vascular disease, and it is thought to have both a genetic and an environmental basis. Early in the natural history of the disease, insulin resistance is present, but compensatory hyperinsulinemia prevents glucose levels from becoming elevated. Increases in insulin resistance are associated with a decline in β-cell function. One marker for β-cell decline is first-phase insulin response, which is greatly diminished in patients with type 2 diabetes. Furthermore, patients who secrete suboptimal levels of insulin fail to suppress hepatic glucose production. In addition to the β-cell dysfunction seen in type 2 diabetes, patients also experience dysfunction in the pancreatic α cells. In type 2 diabetes, postprandial glucagon is not suppressed, and the α cells are insensitive to glucose, which further contributes to abnormal glucose tolerance.

Incretin hormone levels rise rapidly in response to nutrient ingestion and promote glucose-dependent insulin secretion. They were discovered following the observation that orally-administered glucose produces a greater insulin response than insulin administered intraveneously. There are 2 primary incretin hormones: glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). In patients with diabetes, GIP levels are normal or slightly elevated, but the insulin secretory response to GIP is blunted or absent. Recent evidence suggests that this impairment may be acquired. GLP-1 stimulates glucose-dependent insulin secretion, suppresses glucagon secretion. Slows gastric emptying, improves insulin sensitivity, and reduces food intake. Both GLP-1 and GIP are rapidly degraded by the protease dipeptidyl peptidase IV (DPP-IV). Patients with type 2 diabetes retain their sensitivity to GLP-1, although GLP-1 production is decreased. GLP-1 also has numerous effects on islet cells, including the promotion of exocrine cell differentaiation, islet proliferation in vitro and in vivo, islet neogenesis in vivo, and antiapoptotic actions.

Two strategies have been employed to enhance action in type 2 diabetes: the use of GLP-1 analogs or compounds that mimic the actions of GLP-1, and agents that inactivate the degrading enzyme DPP-IV. The use of the incretin mimetic exenatide has been shown to be associated with durable decreases in both A1C and weight, and produces an A1C reduction comparable to insulin glargine. The second strategy, inhibition of the degrading enzyme DPP-IV, increases GLP-1 levels. In clinical research, the DPP-IV inhibitors sitagliptin and vildagliptin (used as a monotherapy and in combination with metformin and thiazolidinedione therapy) have been shown to improve glycemic control with no increase in weight. Further, the effect appears t be durable over a 1-year period.