Loss of the Inhibitory G‐Protein, G α z , in the Cell Protects Against Spontaneous and Streptozotocin‐Induced Diabetes in NOD Mice

G α z is an inhibitory G protein that contributes to β‐cell death and diabetes pathogenesis. Loss of G α z in the nonobese diabetic (NOD) mouse model of type I diabetes mellitus (T1DM) results in protection from hyperglycemia and significantly higher diabetes‐free survival compared to wild‐type mice despite a similar initial immune infiltration profile. Wild type islets from histologically stained pancreas sections revealed a higher insulitis profile and lower insulin positive area than their G α z ‐null counterparts at 17 weeks of age, and the protected G α z null mice displayed significantly lower inflammation and immune infiltration. Loss of G α z also increased the percentage of ki‐67‐positive β‐cells, a marker of proliferation, and lead to a decrease in β‐cell death as measured by percentage of terminal deoxynucleotidyltransferase‐mediated dUTP nick end labeling (TUNEL)‐positive cells. These data suggest that G α z plays a central role in β‐cell survival and T1DM pathophysiology. Diabetes pathogenesis in the NOD model is initiated by immune infiltration into the pancreatic islet, followed by β‐cell death, which causes further recruitment of immune cells. To confirm the diabetes protection of Gα z ‐null NOD mice is due specifically to loss of Gα z in the β‐cell, and not the infiltrating immune cells, a β‐cell‐specific Gα z knockout mouse was created in the NOD background. The specificity of the knockout was confirmed in the C57Bl/6J model by western blot analysis, revealing specific loss of G α z from the pancreatic islets and wild‐type expression levels in other tissues. These mice were backcrossed for 10 generations into the NOD strain and were SNP genotyped to confirm that NOD loci were preserved. Preliminary data show a similar disease penetrance and diabetes‐free survival profile between whole‐body G α z‐ null and β‐cell‐specific G α z null NOD mice. To increase the penetrance and temporal control of the diabetes phenotype, we tested different dosing regimens of the β‐cell toxin, streptozotocin (STZ), designed to be less potent than the standard 5‐day, multiple low‐dose protocol normally applied to ensure rapid and severe diabetes development. A pilot study revealed 3 consecutive low doses at 9–10 weeks of age produced moderate and reliable hyperglycemia within 2 weeks of STZ administration. Supporting the β‐cell‐centric role of G α z in T1D pathophysiology, both the whole‐body G α z ‐null and β‐cell‐specific G α z ‐null NOD mice are protected from hyperglycemia after STZ administration as compared to the appropriate littermate controls. As the β‐cell‐specific NOD mice reach the study endpoint, pancreas samples will be collected and histologically stained. This data will allow us to confirm that it is solely β‐cell G α z responsible for differences in insulitis, immune infiltration, proliferation, and insulin positive area seen between wild‐type and G α z ‐null NOD mice. These data would support G α z as a strong target for therapeutics aimed to prevent or reverse insulitis and β‐cell death in early T1DM. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .