Beta‐cell‐specific loss of the inhibitory G protein, Gα _z , prevents development of Type 1 Diabetes in NOD mice.

The mechanisms that underlie the beta‐cell pathophysiology of Type 1 Diabetes (T1D) are not fully understood. Our lab has discovered a role for the unique inhibitory G‐protein, Gα z , in beta‐cell function, survival, and replication in both normal conditions and those of pathological stress. Gα z , when acting as a canonical inhibitory G‐protein, reduces production of cyclic adenosine monophosphate (cAMP) through inhibition of adenylate cyclase. cAMP acts as essential player in the amplification of glucose‐stimulated insulin secretion, while also mediating pathways that regulate beta‐cell death and replication. We've shown previously that removal of this inhibitory protein is sufficient to promote insulin secretion, beta‐cell growth and survival using chemically‐induced beta‐cell death and diabetes in C57BL/6J mice. Previous work in our lab has also shown that non‐obese diabetic (NOD) mice with global loss of Gα z are protected from developing T1D‐like hyperglycemia through a multi‐faceted maintenance of beta‐cell health. Whole body Gα z null animals exhibited a significant increase in beta‐cell function and replication and decreased beta‐cell death. Most interestingly, islets from Gα z ‐null NOD animals exhibited a marked decrease in immune infiltration. In order to determine if Gα z in the beta‐cell was responsible for the protected phenotype, we generated a beta‐cell‐specific Gα z knockout by breeding G z Flox/Flox mice with Rat Insulin Promoter (RIP) driven Cre Herr mice, on the NOD background. After 10 generations of backcrossing, we began by determining if loss of beta cell Gα z was sufficient to protect NOD animals from developing T1D‐like hyperglycemia. Weekly random‐fed blood glucose measurements were taken beginning at weaning. In the initial cohort, we saw a 12% penetrance of hyperglycemia in male Cre‐positive NOD mice and a 23% penetrance of hyperglycemia in female Cre‐positive NOD mice by 30 weeks of age. In contrast, Gα z β‐cell ‐KO males and females were entirely protected from developing hyperglycemia during this period. Despite this stark contrast, fasting blood glucose was no different between genotypes, grouped by sex, at either 12 or 28 weeks of age. Glucose tolerance was also not different between Cre‐positive NOD controls and Gα z β‐cell ‐KO animals. Experiments are ongoing to further investigate other facets of beta‐cell health, including function, replication and survival. Additionally, it will be crucial to evaluate the presence and extent of insulitis in our Gα z β‐cell ‐KO animals. Thus far, our results show a critical role for beta‐cell Gα z in promoting T1D pathophysiology, although the precise mechanism remains to be determined. Support or Funding Information NIH F31 DK109698 to RF This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .