Gastrointestinal hormones and the regulation of β‐cell mass

Abstract

Type 2 diabetes occurs due to a relative deficit in β-cell mass or function. Glucagon-like peptide 1 (GLP-1), glucosedependent 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 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 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.

Gastrin Protects Against Myocardial Ischemia/Reperfusion Injury via Activation of RISK (Reperfusion Injury Salvage Kinase) and SAFE (Survivor Activating Factor Enhancement) Pathways

“…In recent years, however, several lines of evidence have emerged to suggest that there is much more to the biology of gastrin than is indicated by earlier work 25, 35. Gastrin has been shown to display proliferative,36, 37 antiapoptotic,38 and cell migration39 properties. In previous reports, the concentration of gastrin in serum was found to be significantly increased during myocardial infarction 13.…”

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

“…The mechanism(s) adopted by GLP-1 and GIP to modulate cell proliferation and function implicates multiple signalling pathways. The pathways characterised include those acting via the G-protein-coupled receptors that lead to activation of cAMP, protein kinase A (PKA) and the cAMP response element-binding protein (CREB) cascade to directly regulate genes involved in proliferation and apoptosis, and other pathways determining phosphorylation of Akt and mitogen-activated protein kinases [108]. The ghrelin genederived peptides and exendin-4 exert cyto-protective effects in human pancreatic islet endothelial cells.…”

Is the Gut the “Sweet Spot” for the Treatment of Diabetes?

“…b-cells (18). Increased expression of islet GLP-1 receptor after RYGB as reported by Lindqvist et al could contribute to increased b-cell mass.…”

“…Since then, several animal and human investigations have shown that RYGB and other procedures can improve T2D through a variety of GI mechanisms, including changes in gut hormones (18,19,21), bile acids metabolism (28), intestinal microbiota, nutrient sensing (29), and reprogramming of intestinal glucose metabolism (30). This demonstrates a critical and previously underappreciated role of the gut in glucose metabolism and underscores the importance of further research on the mechanisms of action of GI surgery.…”