| First Author | Fenske RJ | Year | 2017 |
| Journal | Endocrinology | Volume | 158 |
| Issue | 6 | Pages | 1645-1658 |
| PubMed ID | 28419211 | Mgi Jnum | J:246053 |
| Mgi Id | MGI:5916618 | Doi | 10.1210/en.2016-1700 |
| Citation | Fenske RJ, et al. (2017) The Inhibitory G Protein alpha-Subunit, Galphaz, Promotes Type 1 Diabetes-Like Pathophysiology in NOD Mice. Endocrinology 158(6):1645-1658 |
| abstractText | The alpha-subunit of the heterotrimeric Gz protein, Galphaz, promotes beta-cell death and inhibits beta-cell replication when pancreatic islets are challenged by stressors. Thus, we hypothesized that loss of Galphaz 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 Galphaz knockout mice. By 17 weeks of age, Galphaz-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 Galphaz-null islets despite similar immune infiltration in control mice. Islets from Galphaz-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 Galphaz-null mice phenocopy whole-body Galphaz-null mice in their protection from developing hyperglycemia after streptozotocin administration, supporting a beta-cell-centric role for Galphaz in diabetes pathophysiology. We propose that Galphaz 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. |
