The incretin pathway as a new therapeutic target for obesity

Abstract

The global obesity epidemic fuelled by our obesogenic environment, and the prevention and treatment of obesity are some of the most important health-care challenges of our time. Although influenced largely by genetic factors, body mass index (BMI) is also heavily dependent upon environmental (principally dietary) factors. Whilst bariatric surgery often results in weight loss, its associated cost is prohibitive for widespread application. Current options for medical treatment of obesity are limited by recent withdrawals of Rimonabant and Sibutramine, enhancing the need for further development of novel weight-loss drugs. The incretin effect results from release of the incretin hormones Glucagon like peptide-1 (GLP-1) and Glucose-dependent insulinotropic polypeptide (GIP) from intestinal cells in response to glucose ingestion. This in turn has direct effects on the endocrine pancreas to enhance insulin release in a glucose-dependent manner and suppress glucagon release, the net effects of which are to reduce post-prandial excursions of plasma glucose. Administration of novel GLP-1-mimetic therapies to patients with type 2 diabetes mellitus (T2D) has been shown to improve and stabilise glycaemic control. In addition, such treatment often leads to substantial and sustained weight loss through pleiotropic effects. These include primary central suppressive effects on hypothalamic appetite control and secondary central effects including inhibition of gastric emptying inducing a feeling of fullness during meals. Although not currently licensed for use as weight-loss therapies, application of GLP-1-mimetic drugs for such a purpose would seem to offer great potential, and should be a focus for further research including a full assessment of safety issues.