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Diabetes. 2019 Jun;68(6):1341-1352. doi: 10.2337/db18-0796. Epub 2019 Apr 1.

Skeletal Muscle-Specific Activation of Gq Signaling Maintains Glucose Homeostasis.

Author information

1
Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD.
2
Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.
3
Mouse Transgenic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD.
4
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U1258, Université de Strasbourg, Illkirch, France.
5
Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD jurgenw@niddk.nih.gov.

Abstract

Skeletal muscle (SKM) insulin resistance plays a central role in the pathogenesis of type 2 diabetes. Because 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 in vivo metabolic roles of the various distinct GPCR signaling pathways operative in SKM. In this study, we tested the hypothesis that selective activation of SKM Gq signaling can improve SKM glucose uptake and whole-body glucose homeostasis under physiological and pathophysiological conditions. Studies with transgenic mice expressing a Gq-linked designer GPCR selectively in SKM cells demonstrated that receptor-mediated activation of SKM Gq 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 Gαq and Gα11 selectively in SKM showed severe deficits in glucose homeostasis. Moreover, GPCR-mediated activation of Gq signaling also stimulated glucose uptake in primary human SKM cells. Taken together, these findings strongly suggest that agents capable of enhancing SKM Gq signaling may prove useful as novel antidiabetic drugs.

PMID:
30936140
PMCID:
PMC6610017
[Available on 2020-06-01]
DOI:
10.2337/db18-0796

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