GIP is a glucagon-like peptide that has been shown to stimulate insulin secretion from pancreatic beta cells and suppress gastric acid secretion. It belongs to the incretin family of peptide hormones, which also includes GLP-1 and GLP-2. Both GIP and GLP-1 have been proposed as potential therapeutic agents for treatment of type 2 diabetes because they enhance insulin secretion following oral glucose load, promote weight loss, improve triglyceride clearance, and offer cardiovascular benefits.
Physiologically, GIP is released from duodenal endocrine K cells immediately upon the absorption of fat or glucose (Falko et al., 1975Miyawaki et al., 2002Woods et al., 1981). It was initially assumed that the principal action of GIP is to enhance insulin secretion following glucose load but recent studies suggest that it may also have a role in inhibiting glucagon secretion from pancreatic b cells.
In addition to its incretin effects, GIP has been shown to have non-insulinotropic functions that include inhibition of gastrointestinal motility and reduction of cardiac contractility (GLP-1R agonists have similar actions). In vivo experiments with GIPR-deficient mice have suggested that these non-insulinotropic actions contribute to the protective effect of GIP on type 2 diabetes.
Binding of GIP to GIPR results in phosphorylation of the nuclear transcription factor Foxo1. Phosphorylated Foxo1 is then able to downregulate the proapoptotic gene bax and upregulate the anti-apoptotic gene bcl-2, thereby protecting pancreatic beta cells from glucolipotoxicity. This mechanism is different from that used by GLP-1, and may help explain why GIPR signaling is selectively impaired in hyperglycemic conditions.