The effects of Gαz signaling on pancreatic β‐cell function and mass

Abstract

Insufficient plasma insulin levels due to deficits in both pancreatic β‐cell function and mass (i.e., β‐cell decompensation) contribute to the pathogenesis of type 2 diabetes. The focus of our study was to define the role(s) of specific guanine nucleotide binding protein (G‐protein) signaling pathways in regulating β‐cell decompensation. We have previously demonstrated that the α‐subunit of the heterotrimeric Gz protein, Gαz, impairs insulin secretion by suppressing production of cyclic adenosine monophosphate (cAMP). Pancreatic islets from Gαz‐null mice also exhibit constitutively increased cAMP production and augmented glucose‐stimulated insulin secretion, suggesting that Gαz 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 Gαz are protected from developing glucose intolerance when fed a high‐fat (45 kcal%) diet. In these mice, a robust increase in β‐cell proliferation is correlated with significantly increased β‐cell mass. These results link signaling through Gαz to both major aspects of β‐cell decompensation: insufficient β‐cell function and mass. This work was supported by National Institutes of Health grants DK080845 (to MEK), DK042583 (to CBN), and DK076488 (to PJC).