The incretins are gastrointestinal hormones that promote the release of insulin. They thus represent promising therapeutic tools to tackle the current type 2 diabetes epidemic. Exploitation of the incretin glucagon-like peptide 1 (GLP-1) has resulted in effective pharmacological agents for the treatment of diabetes. Current GLP-1-based therapies are limited by the nausea they engender at relatively high doses and by the need to administer them parenterally. In this issue of PNAS, Chen et al. (1) and Knudsen et al. (2) describe nonpeptidic molecules that act as specific GLP-1 receptor agonists. These molecules therefore may provide valuable clues to the development of orally active GLP-1 receptor agonists for therapeutic use.
GLP-1 has a number of propitious effects on glucose control. It directly stimulates insulin release from the pancreatic beta cell and suppresses the release of glucagon from the alpha cell. Gastric emptying is slowed by GLP-1 administration, thus slowing digestion and absorption and moderating blood glucose excursions. Acute central or peripheral GLP-1 administration suppresses appetite in animals and humans and chronically reduces body weight. Perhaps most excitingly, GLP-1 has been reported to increase beta cell mass in rodents, reduce cell apoptosis and increase the glucose responsiveness of rodent and human islets in vitro, and stimulate the differentiation of rodent and human islet precursor cells into beta cells (3–5).
Unfortunately, its short half-life in conjunction with the required i.v. or s.c. administration route makes it impractical to use GLP-1 itself as a therapy. In addition, high doses of GLP-1 are associated with nausea, making it impossible to administer larger doses to compensate for the short half-life. Molecules that can activate the same pathways as GLP-1 but have improved pharmacological characteristics are therefore of great interest.