Control of insulin secretion by GLP-1

• Published in: Peptides (New York, N.Y. : 1980) Vol. 100; pp. 75 - 84
• Main Authors: Jones, Ben, Bloom, Stephen R., Buenaventura, Teresa, Tomas, Alejandra, Rutter, Guy A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2018
• Subjects: Bariatric Surgery; Beta cells; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - surgery; Endocytic trafficking; GLP-1; GLP-1 receptor; Glucagon-Like Peptide 1 - metabolism; Glucagon-Like Peptide-1 Receptor - metabolism; Glucagon-Like Peptide-1 Receptor - therapeutic use; Humans; Incretins - metabolism; Insulin - chemistry; Insulin - metabolism; Insulin secretion; Insulin Secretion - drug effects; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Ligands; MAP Kinase Signaling System - drug effects; Obesity - drug therapy; Obesity - metabolism; Obesity - surgery; Peptides - chemistry; Peptides - therapeutic use; Receptor signalling; Beta cells; GLP-1; Endocytic trafficking; Receptor signalling; GLP-1 receptor; Insulin secretion
• ISSN: 0196-9781; 1873-5169; 1873-5169
• DOI: 10.1016/j.peptides.2017.12.013

•Beta cell GLP-1 receptors are an important target in type 2 diabetes.•Recent work highlights several intracellular signalling pathways that are modulated by GLP-1.•The agonist-stimulated GLP-1 receptor is subject to trafficking between different subcellular compartments.•“Biased” agonism may allow pathway- and temporo-spatially-specific signalling to selectively enhance beneficial actions of GLP-1. Stimulation of insulin secretion by glucagon-like peptide-1 (GLP-1) and other gut-derived peptides is central to the incretin response to ingesting nutriments. Analogues of GLP-1, and inhibitors of its breakdown, have found widespread clinical use for the treatment of type 2 diabetes (T2D) and obesity. The release of these peptides underlies the improvements in glycaemic control and disease remission after bariatric surgery. Given therapeutically, GLP-1 analogues can lead to side effects including nausea, which limit dosage. Greater understanding of the interactions between the GLP-1 receptor (GLP-1R) and both the endogenous and artificial ligands therefore holds promise to provide more efficacious compounds. Here, we discuss recent findings concerning the signalling and trafficking of the GLP-1R in pancreatic beta cells. Leveraging “bias” at the receptor towards cAMP generation versus the recruitment of β-arrestins and extracellular signal-regulated kinases (ERK1/2) activation may allow the development of new analogues with significantly improved clinical efficacy. We describe how, unexpectedly, relatively low-affinity agonists, which prompt less receptor internalisation than the parent compound, provoke greater insulin secretion and consequent improvements in glycaemia.