Gastrointestinal hormones and the regulation of β-cell mass

Type 2 diabetes occurs due to a relative deficit in β-cell mass or function. Glucagon-like peptide 1 (GLP-1), 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 β-cell mass. In this review, we focus upon β-cell mass regulation. β-cell mass expands through β-cell proliferation and islet neogenesis; β-cell mass is lost via apoptosis. GLP-1 and GIP are well-studied gastrointestinal hormones and influence β-cell proliferation, apoptosis, and islet neogenesis. CCK regulates β-cell apoptosis and mitogenesis, and gastrin stimulates islet neogenesis. GLP-1 and GIP bind to G protein-coupled receptors and regulate β-cell mass via multiple signaling pathways. The protein kinase A pathway is central to this process because it directly regulates proliferative and anti-apoptotic 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 β-cell mass remain unidentified. Gastrointestinal hormones integrate nutrient signals from the gut to the β-cell, regulating insulin secretion and β-cell mass adaptation.