G<sub>12/13</sub>-mediated signaling stimulates hepatic glucose production and has a major impact on whole body glucose homeostasis.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 39557854.
- Also identified by DOI 10.1038/s41467-024-54299-7 and PMC identifier 11574106.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 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.
Medical subject headings
- Glucose
- Liver
- GTP-Binding Protein alpha Subunits, G12-G13
- Hepatocytes
- Homeostasis
- Signal Transduction