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

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The a-subunit of the heterotrimeric G z protein, Ga z , promotes b-cell death and inhibits b-cell replication when pancreatic islets are challenged by stressors.Thus, we hypothesized that loss of Ga z protein would preserve functional b-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 Ga z knockout mice.By 17 weeks of age, Ga 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 b-cells in Ga z -null islets despite similar immune infiltration in control mice.Islets from Ga z -null mice also exhibited a higher percentage of Ki-67-positive b-cells, a measure of proliferation, even in the presence of immune infiltration.Finally, b-cell-specific Ga z -null mice phenocopy whole-body Ga z -null mice in their protection from developing hyperglycemia after streptozotocin administration, supporting a b-cell-centric role for Ga z in diabetes pathophysiology.We propose that Ga z plays a key role in b-cell signaling that becomes dysfunctional in the type 1 diabetes setting, accelerating the death of b-cells, which promotes further accumulation of immune cells in the pancreatic islets, and inhibiting a restorative proliferative response.(Endocrinology 158: 1645-1658, 2017) T ype 1 diabetes mellitus (T1DM) is a result of insulin deficiency arising from immune-mediated b-cell destruction.In the US population alone, it is expected that the prevalence will increase more than 144% by 2050, which means that T1DM will be diagnosed in more than 500,000 individuals in the next 35 years (1, 2).

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