Skeletal muscle-specific activation of Gq signaling maintains glucose homeostasis
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Skeletal muscle-specific activation of Gq signaling maintains glucose homeostasis. / Bone, Derek B J; Meister, Jaroslawna; Knudsen, Jonas Roland; Dattaroy, Diptadip; Cohen, Amanda; Lee, Regina; Lu, Huiyan; Metzger, Daniel; Jensen, Thomas Elbenhardt; Wess, Jürgen.
I: Diabetes, Bind 68, Nr. 6, 2019, s. 1341-1352.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Skeletal muscle-specific activation of Gq signaling maintains glucose homeostasis
AU - Bone, Derek B J
AU - Meister, Jaroslawna
AU - Knudsen, Jonas Roland
AU - Dattaroy, Diptadip
AU - Cohen, Amanda
AU - Lee, Regina
AU - Lu, Huiyan
AU - Metzger, Daniel
AU - Jensen, Thomas Elbenhardt
AU - Wess, Jürgen
N1 - CURIS 2019 NEXS 178 © 2019 by the American Diabetes Association.
PY - 2019
Y1 - 2019
N2 - 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 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.
AB - 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 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.
U2 - 10.2337/db18-0796
DO - 10.2337/db18-0796
M3 - Journal article
C2 - 30936140
VL - 68
SP - 1341
EP - 1352
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 6
ER -
ID: 216024570