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Evidence of the presence of gut-secreted ‘incretin’ hormones that help to promote secretion of insulin by the pancreatic beta cells was discovered almost a century ago. It then took many decades before the two best-studied incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were isolated in 1971 and 1983, respectively. Although GIP was the first incretin to be isolated, its function remained unclear, and the multiple physiological effects of GLP-1 made it an obvious drug target for treatment of type 2 diabetes mellitus. Exenatide was the first GLP-1 receptor agonist to be approved by the United States Food and Drug Administration (FDA) in 2005, followed in later years by several analogues of human GLP-1 with enhanced benefits.
Only in recent years has research investigated the synergistic action of GLP-1 and GIP and the translation of this synergy into a pharmacotherapy. GIP and GLP-1 receptors are both found in pancreatic cells, where the co-activation results in a larger glucagonostatic effect, greater reductions in food intake, body weight and fat mass and enhancement of insulin secretion and sensitivity than the administration of GLP-1 alone.
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