Loss of the inhibitory G‐protein, Gz, protects against Type I Diabetes‐like hyperglycemia by stimulating islet signaling pathways that promote beta‐cell function and survival
Authors: Fenske Rachel J , Cadena Mark T , Brill Allison L , Truchan Nathan A , Kimple Michelle E 
Published: November 2023

Type I Diabetes (TID) is fundamentally characterized by insulitis and islet inflammation which, ultimately, leads to β‐cell death. The non‐obese diabetic (NOD) mouse is a well‐accepted model of TID as they exhibit insulitis, hyperglycemia and ultimately β‐cell failure. We have previously shown that loss of the catalytic alpha subunit of the inhibitory heterotrimeric G‐protein, Gz, Gαz, ameliorates streptozotocin (STZ)‐induced hyperglycemia, a chemically‐induced model of TID. We have gone on to confirm this protection in the NOD model and delineate the mechanisms by which this protection is conferred. After backcrossing the Gαz‐null mutation into the NOD background we tracked blood glucose and body weight for 17 weeks. Our results show that Gαz‐null mice were nearly completely protected from developing diabetes during this timeframe, whether expressed as mean blood glucose or disease‐free survival. At 4–5 weeks, when we expect apoptosis to be high, Gαz‐null mice exhibit significantly reduced terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)‐positive β‐cells. In correspondence, Gαz‐null mice have significantly increased insulin positive pancreas area as demonstrated by immunohistochemistry (IHC). We hypothesized that decreased apoptosis would result in decreased immune infiltration. Indeed, we found that islets from Gαz‐null mice exhibited a significant reduction in immune cell presence as analyzed by hematoxylin and eosin staining. Furthermore, Gαz‐null islets demonstrate significantly reduced pro‐inflammatory immune cell markers and cytokines at the transcript level as compared to wild‐type controls at 16 weeks of age. We also observed a significant increase in glucose‐stimulated insulin secretion compared to wild‐type controls at 16 weeks of age. Our current work is to delineate the mechanisms by which Gαz exerts a tonic inhibition on β‐cell function and survival. The canonical role for Gαz, upon activation, is inhibition of adenylyl cyclase, thereby reducing intracellular levels of the ubiquitous second messenger molecule cyclic adenosine monophosphate (cAMP). We, and others, have already shown that expression of the islet autocrine/paracrine peptide hormone, cholecystokinin (CCK) is regulated by cAMP‐responsive transcription factors, and that CCK promotes β‐cell function and survival. Interestingly, CCK mRNA expression is increased four‐fold in Gαz‐null NOD islets, whereas the mRNA expression of its receptor is increased 14‐fold. Our hypothesis is that Gαz regulation of cAMP interferes with the entire CCK synthesis and signaling pathway, negatively regulating β‐cell function and growth in the diabetic condition. Overall, our results confirm loss of Gαz protects NOD mice from the development of TID‐like islet pathogenesis and suggests that the Gαz signaling pathway may be a potential therapeutic target due to its multifaceted effects on β‐cell function and survival.