Faculty:
Daniel Drucker, MD, FRCPC
Jens Juul Hols, MD, PhD
Robert E Ratner, MD
Dr Drucker began the symposium with a discussion of the role of the beta cell in type 2 diabetes. Progressive beta-cell failure has been shown to be associated with increased apoptosis. Beta-cell dysfunction is not only present in type 2 diabetes, but also in people at risk for developing type 2 diabetes. However, the beta cell represents only part of the story for patients with type 2 diabetes, who also have elevated postprandial glucagon secretion, inappropriately increasing hepatic glucose output. The postprandial glucagon secretion seen in people with type 2 diabetes is not corrected with exogenous insulin administration. Agents using the incretin pathway are now available for treating type 2 diabetes. These treatments capitalize on the actions of GLP-1, which has been shown to stimulate insulin secretion in a glucose-dependent fashion, suppress postprandial glucagon secretion, slow gastric emptying, enhance satiety and reduce food intake, improve insulin sensitivity, and promote beta-cell neogenesis and proliferation. In short, GLP-1 has numerous beneficial direct and indirect effects.
Next, Dr Holst discussed incretin physiology. The incretin effect refers to the fact that oral glucose administration produces a larger insulin response than the same amount of glucose delivered intravenously, suggesting the influence of gut factors in glucoregulation. The incretin effect is blunted in type 2 diabetes. Of the 2 main incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), GLP-1 has been more extensively pursued as a therapeutic target, due to the fact that GLP-1 secretion is impaired, but some sensitivity to GLP-1 remains in people with type 2 diabetes. GLP-1 in patients with type 2 diabetes has been shown to improve glucose tolerance. GLP-1 has also been shown to delay gastric emptying and blunt postprandial glucose excursions. In vivo studies have shown effects of the beta cell, and numerous cardiovascular benefits of GLP-1 have been demonstrated in both animal models and humans. Two strategies are being employed to achieve the benefits of prolonging GLP-1: incretin mimetics that mimic native GLP-1 and incretin enhancers that block the degrading enzyme dipeptidyl peptidase-4 (DPP-4). Incretin enhancers are orally available but they do not promote weight loss.
The last presentation was delivered by Dr Ratner, who discussed clinical research with incretin mimetics and incretin enhancers. The incretin enhancers have been shown to provide durable glycemic control. Incretin mimetics have been shown to stimulate insulin in a glucose-dependent fashion, acting only when needed. Similarly, they suppress glucagon only when needed and do not suppress it when blood glucose values are low. The incretin mimetic liraglutide is currently being tested as a monotherapy and has been shown to result in a 1.5% decrease in A1C as well as a weight loss. Liraglutide is also being tested in combination with metformin and sulfonylurea therapy. When used as monotherapy, no hypoglycemic episodes were seen, and few were seen overall. Exenatide therapy has been shown to have durable effects on A1C and weight loss. When comparing incretin mimetics and incretin enhancers, both promote glucose-dependent insulin secretion, decrease glucagon secretion, and affect beta-cell neogenesis and apoptosis. Incretin mimetics have the added advantages of restoring first-phase insulin secretion, regulating gastric emptying, decreasing food intake, and promoting weight loss. However, incretin enhancers have the advantage of being orally available. |
