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.

Guglielmi, V., Sbraccia, P. (2017). GLP-1 receptor independent pathways: emerging beneficial effects of GLP-1 breakdown products. EATING AND WEIGHT DISORDERS, 22(2), 231-240 [10.1007/s40519-016-0352-y].

GLP-1 receptor independent pathways: emerging beneficial effects of GLP-1 breakdown products

Guglielmi, V;SBRACCIA, PAOLO
2017-01-01

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.
2017
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/09 - MEDICINA INTERNA
English
Dipeptidyl peptidase IV; GLP-1 metabolites; GLP-1(28–36)amide; GLP-1(32–36)amide; GLP-1(9–36)amide; Neprilysin
Guglielmi, V., Sbraccia, P. (2017). GLP-1 receptor independent pathways: emerging beneficial effects of GLP-1 breakdown products. EATING AND WEIGHT DISORDERS, 22(2), 231-240 [10.1007/s40519-016-0352-y].
Guglielmi, V; Sbraccia, P
Articolo su rivista
File in questo prodotto:
File Dimensione Formato  
GLP-1R independ pathways EWD 2017.pdf

solo utenti autorizzati

Licenza: Copyright dell'editore
Dimensione 892.14 kB
Formato Adobe PDF
892.14 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/170669
Citazioni
  • ???jsp.display-item.citation.pmc??? 13
  • Scopus 26
  • ???jsp.display-item.citation.isi??? 24
social impact