Deletion of GαZ Protein Protects against Diet-induced Glucose Intolerance via Expansion of β-Cell Mass

Insufficient plasma insulin levels caused by deficits in both pancreatic beta-cell function and mass contribute to the pathogenesis of type 2 diabetes. This loss of insulin-producing capacity is termed beta-cell decompensation. Our work is focused on defining the role(s) of guanine nucleotide-binding protein (G protein) signaling pathways in regulating beta-cell decompensation. We have previously demonstrated that the alpha-subunit of the hetero-trimeric G(z) protein, G alpha(z), impairs insulin secretion by suppressing production of cAMP. Pancreatic islets from G alpha(z)-null mice also exhibit constitutively increased cAMP production and augmented glucose-stimulated insulin secretion, suggesting that G alpha(z) is a tonic inhibitor of adenylate cyclase, the enzyme responsible for the conversion of ATP to cAMP. In the present study, we show that mice genetically deficient for G alpha(z) are protected from developing glucose intolerance when fed a high fat (45 kcal%) diet. In these mice, a robust increase in beta-cell proliferation is correlated with significantly increased beta-cell mass. Further, an endogenous G alpha(z) signaling pathway, through circulating prostaglandin E activating the EP3 isoform of the E prostanoid receptor, appears to be up-regulated in insulin-resistant, glucose-intolerant mice. These results, along with those of our previous work, link signaling through G alpha(z) to both major aspects of beta-cell decompensation: insufficient beta-cell function and mass.