Journal
JOURNAL OF MOLECULAR ENDOCRINOLOGY
Volume 46, Issue 3, Pages 193-204Publisher
BIOSCIENTIFICA LTD
DOI: 10.1530/JME-10-0117
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Funding
- Canadian Diabetes Association [OG-1-09-2689-CC]
- Canadian Institutes for Health Research [MOP 43987]
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Mutations in the uncoupling protein 2 (Ucp2) gene are linked to type-2 diabetes. Here, a potential mechanism by which lack of UCP2 is cytoprotective in pancreatic beta-cells was investigated. Nitric oxide (NO) production was elevated in Ucp2(-/-) islets. Proliferation (cyclin D2, Ccnd2) and anti-apoptosis (Tnfaip3) genes had increased expression in Ucp2(-/-) islets, whereas the mRNA of pro-apoptosis genes (Jun, Myc) was reduced. TNFAIP3 cellular localization was detected in both alpha- and beta-cells of Ucp2(-/-) islets but in neither alpha- nor beta-cells of UCP2(+/+) islets, where it was detected in pancreatic polypeptide-expressing cells. TNFAIP3 distribution was not markedly altered 14 days after streptozotocin treatment. Basal apoptosis was attenuated in Ucp2(-/-) beta-cells, while the nuclear factor kappa B (NF-kappa B) pathway was transactivated after islet isolation. Ucp2(+/+) and Ucp2(-/-) islets were treated with cytokines for 24 h. Cytokines did not increase NF-kappa B transactivation or apoptosis in Ucp2(-/-) islets and TNFAIP3 was more strongly induced in Ucp2(-/-) islets. Inhibition of NO production strongly reduced NF-kappa B activation and apoptosis. These data show that null expression of Ucp2 induces transactivation of NF-kappa B in isolated islets, possibly due to NO-dependent up-regulation of inhibitor of kappa B kinase beta activity. NF-kappa B transactivation appears to result in altered expression of genes that enhance a pro-survival phenotype basally and when beta-cells are exposed to cytokines. TNFAIP3 is of particular interest because of its ability to regulate NF-kappa B signaling pathways.
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