The Inhibitory G Protein α-Subunit, Gαz, Promotes Type 1 Diabetes-Like Pathophysiology in NOD Mice

The alpha-subunit of the heterotrimeric G(z) protein, G alpha(z), promotes beta-cell death and inhibits beta-cell replication when pancreatic islets are challenged by stressors. Thus, we hypothesized that loss of Gaz protein would preserve functional beta-cell mass in the nonobese diabetic (NOD) model, protecting from overt diabetes. We saw that protection from diabetes was robust and durable up to 35 weeks of age in G alpha(z) knockout mice. By 17 weeks of age, G alpha(z)-null NOD mice had significantly higher diabetes-free survival than wild-type littermates. Islets from these mice had reduced markers of proinflammatory immune cell infiltration on both the histological and transcript levels and secreted more insulin in response to glucose. Further analyses of pancreas sections revealed significantly fewer terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive beta-cells in G alpha(z)-null islets despite similar immune infiltration in control mice. Islets from G alpha(z)-null mice also exhibited a higher percentage of Ki-67-positive beta-cells, a measure of proliferation, even in the presence of immune infiltration. Finally, beta-cell-specific G alpha(z)-nullmice phenocopy whole-body G alpha(z)-null mice in their protection from developing hyperglycemia after streptozotocin administration, supporting a beta-cell-centric role for G alpha(z) in diabetes pathophysiology. We propose that G alpha(z) plays a key role in beta-cell signaling that becomes dysfunctional in the type 1 diabetes setting, accelerating the death of beta-cells, which promotes further accumulation of immune cells in the pancreatic islets, and inhibiting a restorative proliferative response.