The class B G-protein-coupled GLP-1 receptor: an important target for the treatment of type-2 diabetes mellitus.

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone secreted from L cells in the distal small intestine and proximal colon after a meal that acts as an incretin to augment the insulin response, while also inhibiting glucagon and slowing gastric emptying. These characteristics of GLP-1, as well as its ability to reduce islet beta cell apoptosis and expand beta cell mass and its cardioprotective and neuroprotective effects, provide a broad spectrum of actions potentially useful for the management of type-2 diabetes mellitus. GLP-1 also has the added advantage of having its incretin effects dependent on the level of serum glucose, only acting in the presence of hyperglycaemia, and thereby preventing hypoglycemic responses. Although natural GLP-1 has a very short half-life, limiting its therapeutic usefulness, a variety of analogues and formulations have been developed to provide extended actions and to limit side effects. However, all of these peptides require parenteral administration. Potentially orally active small-molecule agonists acting at the GLP-1 receptor are also being developed, but have not yet been approved for clinical use. Recent insights into the molecular nature of the class B G-protein-coupled GLP-1 receptor has provided insights into the modes of binding these types of ligands, as well as providing opportunities for rational enhancement. The advantages and disadvantages of each of these agents and their possible clinical utility will be explored.