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Endocrinology. 2017 Jun 1;158(6):1645-1658. doi: 10.1210/en.2016-1700.

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

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Interdisciplinary Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53705.
Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705.
Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin 53705.
Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53705.
Molecular Medicine Program, Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, Department of Nutrition, and Department of Biological Chemistry, University of Utah School of Medicine, Salt Lake City, Utah 84112.
George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah 84112.
Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin 53705.


The α-subunit of the heterotrimeric Gz protein, Gαz, promotes β-cell death and inhibits β-cell replication when pancreatic islets are challenged by stressors. Thus, we hypothesized that loss of Gαz protein would preserve functional β-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 Gαz knockout mice. By 17 weeks of age, Gαz-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 β-cells in Gαz-null islets despite similar immune infiltration in control mice. Islets from Gαz-null mice also exhibited a higher percentage of Ki-67-positive β-cells, a measure of proliferation, even in the presence of immune infiltration. Finally, β-cell-specific Gαz-null mice phenocopy whole-body Gαz-null mice in their protection from developing hyperglycemia after streptozotocin administration, supporting a β-cell-centric role for Gαz in diabetes pathophysiology. We propose that Gαz plays a key role in β-cell signaling that becomes dysfunctional in the type 1 diabetes setting, accelerating the death of β-cells, which promotes further accumulation of immune cells in the pancreatic islets, and inhibiting a restorative proliferative response.

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