Agonist-independent Gα(z) activity negatively regulates beta-cell compensation in a diet-induced obesity model of type 2 diabetes

The inhibitory G protein alpha-subunit (Gα(z)) is an important modulator of beta-cell function. Full-body Gα(z)-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 Gα(z) 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 Gα(z)-null mice from HFD-induced diabetes is beta-cell autonomous, as beta cell–specific Gα(z)-null mice phenocopy the full-body KOs. The glucose-stimulated and incretin-potentiated insulin secretion response of islets from HFD-fed beta cell–specific Gα(z)-null mice is significantly improved as compared with islets from HFD-fed WT controls, which, along with no impact of Gα(z) loss or HFD feeding on beta-cell proliferation or surrogates of beta-cell mass, supports a secretion-specific mechanism. Gα(z) 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 cAMP production and downstream beta-cell function, with both activities being dependent on the presence of beta-cell Gα(z).