Perspectives in GLP-1 Research: New Targets, New Receptors

The incretin hormone glucagon-like peptide-1 (GLP-1) binds to and activates its G-protein-coupled-receptor GLP-1R to reduce glycaemia through the stimulation of insulin and suppression of pancreatic glucagon secretion. Recently, GLP-1 effects unrelated to glucose homeostasis have been discovered in myocardium, bone, adipose tissue, and other target organs, which appear to be mainly mediated by GLP-1R-independent pathways. Here, we summarize knowledge on GLP-1R agonists (GLP-1RAs) as they relate to the improvement of glucose control, and focus on the most recently described effects, discussing the preclinical evidence of the involvement of alternative receptors and signalling mechanisms. It is now evident that the universe of GLP-1RAs is expanding further from the initial incretin effect, opening new unforeseen avenues for research and clinical applications.

TrendsGLP-1 and its synthetic analogues, used in the treatment of type 2 diabetes (T2D), reduce blood glucose through the modulation of pancreatic hormone secretion. Recently, novel actions on non-pancreatic targets have been described.Many extrapancreatic beneficial effects of GLP-1 seem to be mediated by a still unknown signalling pathway different from the classical GLP-1 receptor.The effects mediated by alternative pathways mainly influence cell survival and differentiation, as well as specific cell functions intrinsic to target organs and tissues.GLP-1 activities mediated by pathways different from the classical receptor could be the target of a new class of drugs, different from GLP-1 receptor agonists, and with different biological effects.