| First Author | Schaid MD | Year | 2021 |
| Journal | J Biol Chem | Volume | 296 |
| Pages | 100056 | PubMed ID | 33172888 |
| Mgi Jnum | J:338706 | Mgi Id | MGI:6807244 |
| Doi | 10.1074/jbc.RA120.015585 | Citation | Schaid MD, et al. (2021) Agonist-independent Galphaz activity negatively regulates beta-cell compensation in a diet-induced obesity model of type 2 diabetes. J Biol Chem 296:100056 |
| abstractText | The inhibitory G protein alpha-subunit (Galphaz) is an important modulator of beta-cell function. Full-body Galphaz-null mice are protected from hyperglycemia and glucose intolerance after long-term high-fat diet (HFD) feeding. In this study, at a time point in the feeding regimen where WT mice are only mildly glucose intolerant, transcriptomics analyses reveal islets from HFD-fed Galphaz KO mice have a dramatically altered gene expression pattern as compared with WT HFD-fed mice, with entire gene pathways not only being more strongly upregulated or downregulated versus control-diet fed groups but actually reversed in direction. Genes involved in the "pancreatic secretion" pathway are the most strongly differentially regulated: a finding that correlates with enhanced islet insulin secretion and decreased glucagon secretion at the study end. The protection of Galphaz-null mice from HFD-induced diabetes is beta-cell autonomous, as beta cell-specific Galphaz-null mice phenocopy the full-body KOs. The glucose-stimulated and incretin-potentiated insulin secretion response of islets from HFD-fed beta cell-specific Galphaz-null mice is significantly improved as compared with islets from HFD-fed WT controls, which, along with no impact of Galphaz loss or HFD feeding on beta-cell proliferation or surrogates of beta-cell mass, supports a secretion-specific mechanism. Galphaz is coupled to the prostaglandin EP3 receptor in pancreatic beta cells. We confirm the EP3gamma splice variant has both constitutive and agonist-sensitive activity to inhibit cAMP production and downstream beta-cell function, with both activities being dependent on the presence of beta-cell Galphaz. |
