Mode of action of GLP-1 receptor agonists
A substitution of alanine in position 2 does stabilise the GLP-1 molecule against the degrading actions of DPP-4, and does not harm the biological activity of the peptide. However, the stabilised molecule is still eliminated extremely rapidly in the kidneys (with a half life of 4-5 min), so such analogues are also unsuitable for clinical use. Nevertheless, recently GLP-1 receptor agonists for clinical use have become available for the treatment of patients with type 2 diabetes, and these agents exploit the physiology of GLP-1, which in a pleiotropic manner is able to address several of the pathophysiological features of type 2 diabetes.
The GLP-1 receptor (GLP-1R) is widely distributed in pancreatic islets, brain, heart, kidney, and the gastrointestinal tract including the stomach. Its function is not known for all these locations and numerous attempts have been made to identify alternative GLP-1R or subtypes, but at present only a single GLP-1R has been identified. Binding of GLP-1 to the GLP-1R on the beta cell results in stimulation of insulin secretion in a strict glucose-dependant manner, but preclinical data have demonstrated that GLP-1 also has potential effects on beta cell mass by stimulation of beta cell proliferation, differentiation of new beta cells from progenitor cells and by inhibition of beta cell apoptosis1. Furthermore, GLP-1 robustly inhibits glucagon secretion, and the combined effects on insulin and glucagon secretion results in inhibition of hepatic glucose production, which contributes significantly to the overall glucose lowering effect of GLP-1. Additionally GLP-1 decreases gastrointestinal motility and promotes satiety, probably through activation of GLP-1Rs in the brain in combination with GLP-1-induced decrease in gastric emptying. Clinical data have now demonstrated that chronic administration of GLP-1 receptor agonists leads to weight loss.
^ Holst JJ. The physiology of glucagon-like peptide 1. Physiol. Rev. 2007 Oct;87(4):1409–39.
^ Shyangdan DS, Royle P, Clar C, Sharma P, Waugh N, Snaith A. Glucagon-like peptide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2011;(10):CD006423.
^ Vilsbøll T, Christensen M, Junker AE, Knop FK, Gluud LL. Effects of glucagon-like peptide-1 receptor agonists on weight systematic review and meta-analyses of randomised controlled trials. BMJ. 2012;344:d7771.