Skeletal Muscle-Specific Activation of G Signaling Maintains Glucose Homeostasis.
Fiche publication
Date publication
avril 2019
Journal
Diabetes
Auteurs
Membres identifiés du Cancéropôle Est :
Dr METZGER Daniel
Tous les auteurs :
Bone DBJ, Meister J, Knudsen JR, Dattaroy D, Cohen A, Lee R, Lu H, Metzger D, Jensen TE, Wess J
Lien Pubmed
Résumé
Skeletal muscle (SKM) insulin resistance plays a central role in the pathogenesis of type 2 diabetes. Since G protein-coupled receptors (GPCRs) represent excellent drug targets, we hypothesized that activation of specific functional classes of SKM GPCRs might lead to improved glucose homeostasis in type 2 diabetes. At present, little is known about the metabolic roles of the various distinct GPCR signaling pathways operative in SKM. In this study, we tested the hypothesis that selective activation of SKM G signaling can improve SKM glucose uptake and whole body glucose homeostasis under physiological and pathophysiological conditions. Studies with transgenic mice expressing a G-linked designer GPCR selectively in SKM cells demonstrated that receptor-mediated activation of SKM G signaling greatly promoted glucose uptake into SKM and significantly improved glucose homeostasis in obese, glucose-intolerant mice. These beneficial metabolic effects required the activity of SKM AMPK. In contrast, obese mutant mice that lacked both Gα and Gα selectively in SKM showed severe deficits in glucose homeostasis. Moreover, GPCR-mediated activation of G signaling also stimulated glucose uptake in primary human SKM cells. Taken together, these findings strongly suggest that agents capable of enhancing SKM G signaling may prove useful as novel antidiabetic drugs.
Référence
Diabetes. 2019 Apr 1;: