Journal Article

Revisiting the Complexity of GLP-1 Action from Sites of Synthesis to Receptor Activation

McLean, Brent A, Campbell, Jonathan E, Trapp, Stefan, Drucker, Daniel J, Wong, Chi Kin, Hodson, David J

2021

Overview

Abstract Glucagon-like peptide-1 (GLP-1) is produced in gut endocrine cells and in the brain, and acts through hormonal and neural pathways to regulate islet function, satiety, and gut motility, supporting development of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes and obesity. Classic notions of GLP-1 acting as a meal-stimulated hormone from the distal gut are challenged by data supporting production of GLP-1 in the endocrine pancreas, and by the importance of brain-derived GLP-1 in the control of neural activity. Moreover, attribution of direct vs indirect actions of GLP-1 is difficult, as many tissue and cellular targets of GLP-1 action do not exhibit robust or detectable GLP-1R expression. Furthermore, reliable detection of the GLP-1R is technically challenging, highly method dependent, and subject to misinterpretation. Here we revisit the actions of GLP-1, scrutinizing key concepts supporting gut vs extra-intestinal GLP-1 synthesis and secretion. We discuss new insights refining cellular localization of GLP-1R expression and integrate recent data to refine our understanding of how and where GLP-1 acts to control inflammation, cardiovascular function, islet hormone secretion, gastric emptying, appetite, and body weight. These findings update our knowledge of cell types and mechanisms linking endogenous vs pharmacological GLP-1 action to activation of the canonical GLP-1R, and the control of metabolic activity in multiple organs. Graphical Abstract Graphical Abstract

• Publisher: Oxford University Press
• Subject: Appetite / Body fat / Body weight / Brain / Brain research / Cardiovascular system / Cloning / Diabetes / Diabetes mellitus / Diabetes therapy / Digestive system / Endocrinology / Gastric emptying / Gastric motility / Gastrointestinal system / Gastrointestinal tract / Glucagon / Glucagon-like peptide 1 / Glucagon-Like Peptide 1 - metabolism / Glucagon-Like Peptide-1 Receptor Agonists / Humans / Inflammation / Intestine / Kinases / Localization / Metabolism / Nervous system / Neurosciences / Obesity / Organs / Pancreas / Peptides / Physiology / Polymerase chain reaction / Proteins / Receptor mechanisms / Receptors / Reviews / Ribonucleic acid / RNA / Satiety / Secretion / Synthesis / T cell receptors / Type 2 diabetes / Weight control