| First Author | Pittala S | Year | 2024 |
| Journal | Nat Commun | Volume | 15 |
| Issue | 1 | Pages | 9996 |
| PubMed ID | 39557854 | Mgi Jnum | J:375654 |
| Mgi Id | MGI:7783097 | Doi | 10.1038/s41467-024-54299-7 |
| Citation | Pittala S, et al. (2024) G(12/13)-mediated signaling stimulates hepatic glucose production and has a major impact on whole body glucose homeostasis. Nat Commun 15(1):9996 |
| abstractText | 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(12/13), 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 G(12/13) 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 G(12/13)-dependent fashion. Studies with human liver samples indicate that hepatic GNA12 (encoding Galpha(12)) expression levels positively correlate with indices of insulin resistance and impaired glucose homeostasis, consistent with a potential pathophysiological role of enhanced hepatic G(12/13) signaling. |
