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


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 G?q and G?11 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.

SUBMITTER: Bone DBJ 

PROVIDER: S-EPMC6610017 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Skeletal Muscle-Specific Activation of G<sub>q</sub> Signaling Maintains Glucose Homeostasis.

Bone Derek B J DBJ   Meister Jaroslawna J   Knudsen Jonas R JR   Dattaroy Diptadip D   Cohen Amanda A   Lee Regina R   Lu Huiyan H   Metzger Daniel D   Jensen Thomas E TE   Wess Jürgen J  

Diabetes 20190401 6


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 selectiv  ...[more]

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