Gastrointestinal hormones and the regulation of beta-cell mass

Type 2 diabetes occurs due to a relative deficit in beta-cell mass or function. Glucagon-like peptide I (GLP-I), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), and gastrin are gastrointestinal hormones that are secreted in response to nutrient intake, regulating digestion, insulin secretion, satiety, and beta-cell mass. In this review, we focus upon beta-cell mass regulation. beta-cell mass expands through beta-cell proliferation and islet neogenesis; beta-cell mass is lost via apoptosis. GLP-I and GIP are well-studied gastrointestinal hormones and influence beta-cell proliferation, apoptosis, and islet neogenesis. CCK regulates beta-cell apoptosis and mitogenesis, and gastrin stimulates islet neogenesis. GLP-I and GIP bind to G protein-coupled receptors and regulate beta-cell mass via multiple signaling pathways. The protein kinase A pathway is central to this process because it directly regulates proliferative and antiapoptotic genes and transactivates several signaling cascades, including Akt and mitogen-activated protein kinases. However, the signaling pathways downstream of G protein-coupled CCK receptors that influence beta-cell mass remain unidentified. Gastrointestinal hormones integrate nutrient signals from the gut to the beta-cell, regulating insulin secretion and beta-cell mass adaptation.