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

The inhibitory G protein alpha-subunit (G alpha(z)) is an important modulator of beta-cell function. Full-body G alpha(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 G alpha(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 G alpha(z)-null mice from HFD-induced diabetes is beta-cell autonomous, as beta cell-specific G alpha(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 G alpha(z)-null mice is significantly improved as compared with islets from HFD-fed WT controls, which, along with no impact of G alpha(z) loss or HFD feeding on beta-cell proliferation or surrogates of beta-cell mass, supports a secretion-specific mechanism. G alpha(z) is coupled to the prostaglandin EP3 receptor in pancreatic beta cells. We confirm the EP3. 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 G alpha(z).

Automated summary

The inhibitory G protein alpha-subunit (G alpha(z)) plays a crucial role in modulating beta-cell function and offers protection against high-fat diet-induced diabetes. The altered gene expression pattern in islets from HFD-fed G alpha(z) KO mice compared to WT mice suggests a secretion-specific mechanism is involved in this protection. Additionally, G alpha(z) couples with the prostaglandin EP3 receptor in pancreatic beta cells to regulate cAMP production and downstream beta-cell function.