The Inhibitory G‐protein, Gz, Accelerates the Progression of Insulitis and Hyperglycemia in a Type 1 Diabetes Mouse Model

Abstract

In type 1 diabetes (T1D), an autoimmune insulitis leads to β‐cell death. The non‐obese diabetic (NOD) mouse model mimics these facets of the human disease. Our laboratory has previously shown that mice deficient in the alpha subunit of the heterotrimeric G protein, Gz (Gαz), were protected from developing chemically induced diabetes via decreased β‐cell apoptosis and increased replication. We aimed to confirm this in the NOD model, as well as delineate the mechanisms of any protection. Between 4‐16 weeks of age, weekly blood glucose levels were monitored in wild‐type and Gαz‐null NOD mice. As compared to wild‐type mice, Gαz‐null mice were completely protected from developing hyperglycemia. Pancreas histologic analysis showed that Gαz‐null pancreata had significantly lower insulitis scores at 16 weeks as compared to wild‐type mice. We hypothesized that decreased immune infiltration increased β‐cell survival. To test our hypothesis, we calculated beta‐cell fractional area, and found it was increased in Gαz‐null NOD mice. New cohorts of mice were sacrificed at 4, 8, and 12 weeks of age. At 4 weeks, immune infiltration was already observed in the wild‐type islets, correlating with apoptotic beta‐cells in islet regions immediately surrounding the invading immune cells. As the first step in delineating mechanism, we showed that islets from Gαz‐null NOD mice have significantly less IL‐1β and IL‐6 cytokine expression; pro‐inflammatory cytokines that have been linked with β‐cell death. Overall, our results further strengthen our claim that Gαz has a protective effect in maintaining β‐cell regeneration and survival, and that the Gαz signaling pathway may be a valid therapeutic target for T1D.