Loss of the unique inhibitory G‐protein, Gαz, in the pancreatic β‐cell protects against diet‐induced glucose intolerance by enhancing insulin secretion, but is not β‐cell autonomous

Abstract

The α‐subunit of the heterotrimeric Gz protein, Gαz, is a member of the inhibitory subfamily of heterotrimeric G proteins. As such, it negatively regulates cyclic AMP (cAMP) production. In the insulin‐secreting β‐cell, cAMP potentiates glucose‐stimulated insulin secretion and β‐cell replication and survival. Previous work by our lab has determined that C57BL/6 mice lacking Gαz throughout the body are protected from developing fasting hyperglycemia and glucose intolerance when fed a high‐fat (45 kcal% fat) diet to induce obesity and insulin resistance. Gαz has a limited tissue distribution, but in addition to the pancreatic islets, it is expressed in the brain and platelets. To show the protection from metabolic dysfunction of the Gαz‐null mice is β‐cell autonomous, we created a β‐cell specific‐knockout of Gαz in the C57BL/6 background. Western Blot analysis for Gαz in the hypothalamus, platelets, islets, and kidney confirmed an islet‐specific loss of Gαz in the floxed/Cre‐positive mice as compared to all other genotypes. To characterize any diabetes protection of the β‐cell‐specific Gαz‐null mice, we placed 12‐week‐old mice on either a 45 kcal% high‐fat diet (HFD) or 10 kcal% fat control diet for 28 weeks. Pre‐diet glucose tolerance and insulin tolerance tests were performed, revealing no differences between genotypes. Weekly body weight and fasting blood glucose measurements were performed. Upon study completion, the β‐cell‐specific Gαz‐null mice showed no differences in body weight or insulin sensitivity as compared to their wild‐type counterparts, phenocopying results from the whole‐body Gαz‐null study. However, after glucose challenge, the glucose clearance of Gαz‐null mice fed the HFD was significantly better than wild‐type mice fed the HFD diet. Yet, this protection from glucose intolerance was not as complete as that observed in the whole‐body Gαznull mice, as the β‐cell‐specific Gαz‐null mice had worse glucose tolerance than control‐diet fed mice. Thus, it is possible that loss of Gαz in another cell type is required for full diabetes protection, and experiments are ongoing to confirm the hypothesis it is the α‐cell.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.