G12/13-mediated signaling stimulates hepatic glucose production and has a major impact on whole body glucose homeostasis
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 G<sub>12/13</sub>, 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 G<sub>12/13</sub> 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 G<sub>12/13</sub>-dependent fashion. Studies with human liver samples indicate that hepatic GNA12 (encoding Gα<sub>12</sub>) expression levels positively correlate with indices of insulin resistance and impaired glucose homeostasis, consistent with a potential pathophysiological role of enhanced hepatic G<sub>12/13</sub> signaling.
Authors
- Srinivas Pittala (ORCID: https://orcid.org/0000-0002-8873-1320)
- Young‐Bum Kim (ORCID: https://orcid.org/0000-0001-9471-6330)
- Yinghong Cui (ORCID: https://orcid.org/0000-0002-9889-6655)
- Yaron Rotman (ORCID: https://orcid.org/0000-0002-7549-8216)
- Jürgen Wess (ORCID: https://orcid.org/0000-0003-0818-1232)
- Owen P. McGuinness (ORCID: https://orcid.org/0000-0002-1778-3203)
- Roger J. Davis (ORCID: https://orcid.org/0000-0002-0130-1652)
- Won‐Mo Yang (ORCID: https://orcid.org/0000-0001-6742-720X)
- Allison Wing
- Asuka Inoue (ORCID: https://orcid.org/0000-0003-0805-4049)
- Dhanush Haspula (ORCID: https://orcid.org/0000-0003-2096-6163)
Institutions
- National Institutes of Health (US)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- University of Massachusetts Chan Medical School (US)
- Vanderbilt University (US)
- Tohoku University (JP)
- Kyoto University (JP)
- Kyoto Pharmaceutical University (JP)
- National Institute of Diabetes and Digestive and Kidney Diseases (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-19
- DOI
- https://doi.org/10.1038/s41467-024-54299-7
- Citations
- 5
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 2.86
Funders
- Japan Agency for Medical Research and Development
- National Institutes of Health
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- National Institute of Diabetes and Digestive and Kidney Diseases