Agonist-independent Gαz activity negatively regulates β-cell compensation in a diet-induced obesity model of type 2 diabetes

The inhibitory G protein alpha subunit, Gαz, is an important modulator of beta-cell function. Full-body Gαz-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 wild-type mice are only mildly glucose intolerant, transcriptomics analyses reveal islets from HFD-fed Gαz KO mice have a dramatically altered gene expression pattern as compared to WT HFD-fed mice, with entire gene pathways not only being more strongly up- or down-regulated vs. 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 study end. The protection of Gαz-null mice from HFD-induced diabetes is β-cell autonomous, as β-cell-specific Gαz-null (βKO) mice phenocopy the full-body knockouts. The glucose-stimulated and incretin-potentiated insulin secretion response of islets from HFD-fed βKO mice is significantly improved as compared to islets from HFD-fed wild-type controls, which, along with no impact of Gαz loss or HFD feeding on beta-cell proliferation or surrogates of beta-cell mass supports a secretion-specific mechanism. Gαz is coupled to the Prostaglandin EP3 receptor in pancreatic beta-cells. We confirm the EP3γ splice variant has both constitutive and agonist-sensitive activity to inhibit cyclic AMP production and downstream β-cell function, with both activities being dependent on the presence of beta-cell Gαz.