Molecular Pharmacology of the Incretin Receptors

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are important regulators of insulin and glucagon secretion as well as lipid metabolism and appetite. These biological functions make their respective receptors (GIPR and GLP-1R) attractive targets in the treatment of both type 2 diabetes mellitus (T2DM) and obesity. The use of these native peptides in the treatment of these conditions is limited by their short half-lives. However, long-acting GLP-1R agonists and inhibitors of the enzyme that rapidly inactivates GIP and GLP-1 (dipeptidyl peptidase IV) are in clinical use. Although there is a loss of response to both hormones in T2DM, this effect appears to be more pronounced for GIP. This has made targeting GIPR less successful than GLP-1R. Furthermore, results demonstrating that GIPR knockout mice were resistant to diet-induced obesity suggested that GIPR antagonists may prove to be useful therapeutics. More recently, molecules that activate both receptors have shown promise in terms of glycemic and body weight control. This review focused on recent advances in the understanding of the signaling mechanisms and regulation of these two clinically important receptors.