G12/13-mediated signaling stimulates hepatic glucose production and has a major impact on whole body glucose homeostasis

Srinivas Pittala (), Dhanush Haspula, Yinghong Cui, Won-Mo Yang, Young-Bum Kim, Roger J. Davis, Allison Wing, Yaron Rotman, Owen P. McGuinness, Asuka Inoue and Jürgen Wess ()
Additional contact information
Srinivas Pittala: NIH
Dhanush Haspula: NIH
Yinghong Cui: NIH
Won-Mo Yang: Beth Israel Deaconess Medical Center and Harvard Medical School
Young-Bum Kim: Beth Israel Deaconess Medical Center and Harvard Medical School
Roger J. Davis: University of Massachusetts Chan Medical School
Allison Wing: NIH
Yaron Rotman: NIH
Owen P. McGuinness: Vanderbilt University School of Medicine Basic Sciences
Asuka Inoue: Tohoku University
Jürgen Wess: NIH

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Altered hepatic glucose fluxes are critical during the pathogenesis of type 2 diabetes. G protein-coupled receptors represent important regulators of hepatic glucose production. Recent studies have shown that hepatocytes express GPCRs that can couple to G12/13, a subfamily of heterotrimeric G proteins that has attracted relatively little attention in the past. Here we show, by analyzing several mutant mouse strains, that selective activation of hepatocyte G12/13 signaling leads to pronounced hyperglycemia and that this effect involves the stimulation of the ROCK1-JNK signaling cascade. Using both mouse and human hepatocytes, we also show that activation of endogenous sphingosine-1-phosphate type 1 receptors strongly promotes glucose release in a G12/13-dependent fashion. Studies with human liver samples indicate that hepatic GNA12 (encoding Gα12) expression levels positively correlate with indices of insulin resistance and impaired glucose homeostasis, consistent with a potential pathophysiological role of enhanced hepatic G12/13 signaling.

Date: 2024
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DOI: 10.1038/s41467-024-54299-7

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