The Inhibitory G Protein α-Subunit, Gαz, Promotes Type 1 Diabetes-Like Pathophysiology in NOD Mice. Endocrinology 2017 Jun 01;158(6):1645-1658
Date
04/19/2017Pubmed ID
28419211Pubmed Central ID
PMC5460933DOI
10.1210/en.2016-1700Scopus ID
2-s2.0-85020220292 (requires institutional sign-in at Scopus site) 17 CitationsAbstract
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.
Author List
Fenske RJ, Cadena MT, Harenda QE, Wienkes HN, Carbajal K, Schaid MD, Laundre E, Brill AL, Truchan NA, Brar H, Wisinski J, Cai J, Graham TE, Engin F, Kimple MEAuthor
Nathan A. Truchan PhD Research Scientist I in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Blood Glucose
Diabetes Mellitus, Experimental
Diabetes Mellitus, Type 1
Female
GTP-Binding Protein alpha Subunits
Insulin-Secreting Cells
Male
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Knockout
Mice, Transgenic
Streptozocin
