title: GLP-1 receptor independent pathways: emerging beneficial effects of GLP-1 breakdown products.
abstract: The glucagon-like peptide-1 (GLP-1) axis has emerged as a major therapeutic target for the treatment of type 2 diabetes and, recently, of obesity. The insulinotropic activity of the native incretin hormone GLP-1(7-36)amide, which is mainly exerted through a unique G protein-coupled receptor (GLP-1R), is terminated via enzymatic cleavage by dipeptidyl peptidase-IV that generates a C-terminal GLP-1 metabolite GLP-1(9-36)amide, the major circulating form in plasma. GLP-1(28-36)amide and GLP-1(32-36)amide are further cleavage products derived from GLP-1(7-36)amide and GLP-1(9-36)amide by the action of a neutral endopeptidase known as neprilysin. Until recently, GLP-1-derived metabolites were generally considered metabolically inactive. However, emerging evidence indicates that GLP-1 byproducts have insulinomimetic activities that may contribute to the pleiotropic effects of GLP-1 independently of the canonical GLP-1R. The recent studies reporting the beneficial effects of the administration of these metabolites in vivo and in vitro are the focus of this review. Collectively, these results suggest that GLP-1 metabolites inhibit hepatic glucose production, exert antioxidant cardio- and neuroprotective actions, reduce oxidative stress in vasculature and have both anti-apoptotic and proliferative effects in pancreatic β-cells, putatively by the modulation of mitochondrial functions. These findings have implication in energy homeostasis, obesity and its associated metabolic and cardiovascular complications as well as incretin-based therapies for the treatment of diabetes and obesity.
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.|Internal Medicine Unit and Obesity Center, University Hospital Policlinico Tor Vergata, Rome, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Guglielmi
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy. sbraccia@med.uniroma2.it.|Internal Medicine Unit and Obesity Center, University Hospital Policlinico Tor Vergata, Rome, Italy. sbraccia@med.uniroma2.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Sbraccia
mesh_terms: D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4; D005947:Glucose
keywords: Dipeptidyl peptidase IV; GLP-1 metabolites; GLP-1(28–36)amide; GLP-1(32–36)amide; GLP-1(9–36)amide; Neprilysin