Skeletal muscle-specific activation of Gq signaling maintains glucose homeostasis

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Derek B J Bone
  • Jaroslawna Meister
  • Jonas Roland Knudsen
  • Diptadip Dattaroy
  • Amanda Cohen
  • Regina Lee
  • Huiyan Lu
  • Daniel Metzger
  • Jensen, Thomas Elbenhardt
  • Jürgen Wess

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.

OriginalsprogEngelsk
TidsskriftDiabetes
Vol/bind68
Udgave nummer6
Sider (fra-til)1341-1352
Antal sider12
ISSN0012-1797
DOI
StatusUdgivet - 2019

Bibliografisk note

CURIS 2019 NEXS 178
© 2019 by the American Diabetes Association.

ID: 216024570