| First Author | Hennige AM | Year | 2010 |
| Journal | Diabetes | Volume | 59 |
| Issue | 1 | Pages | 119-27 |
| PubMed ID | 19826167 | Mgi Jnum | J:164168 |
| Mgi Id | MGI:4830834 | Doi | 10.2337/db09-0512 |
| Citation | Hennige AM, et al. (2010) Overexpression of kinase-negative protein kinase Cdelta in pancreatic beta-cells protects mice from diet-induced glucose intolerance and beta-cell dysfunction. Diabetes 59(1):119-27 |
| abstractText | OBJECTIVE: In vitro models suggest that free fatty acid-induced apoptotic beta-cell death is mediated through protein kinase C (PKC)delta. To examine the role of PKCdelta signaling in vivo, transgenic mice overexpressing a kinase-negative PKCdelta (PKCdeltaKN) selectively in beta-cells were generated and analyzed for glucose homeostasis and beta-cell survival. RESEARCH DESIGN AND METHODS: Mice were fed a standard or high-fat diet (HFD). Blood glucose and insulin levels were determined after glucose loads. Islet size, cleaved caspase-3, and PKCdelta expression were estimated by immunohistochemistry. In isolated islet cells apoptosis was assessed with TUNEL/TO-PRO3 DNA staining and the mitochondrial potential by rhodamine-123 staining. Changes in phosphorylation and subcellular distribution of forkhead box class O1 (FOXO1) were analyzed by Western blotting and immunohistochemistry. RESULTS: PKCdeltaKN mice were protected from HFD-induced glucose intolerance. This was accompanied by increased insulin levels in vivo, by an increased islet size, and by a reduced staining of beta-cells for cleaved caspase-3 compared with wild-type littermates. In accordance, long-term treatment with palmitate increased apoptotic cell death of isolated islet cells from wild-type but not from PKCdeltaKN mice. PKCdeltaKN overexpression protected islet cells from palmitate-induced mitochondrial dysfunction and inhibited nuclear accumulation of FOXO1 in mouse islet and INS-1E cells. The inhibition of nuclear accumulation of FOXO1 by PKCdeltaKN was accompanied by an increased phosphorylation of FOXO1 at Ser256 and a significant reduction of FOXO1 protein. CONCLUSIONS: Overexpression of PKCdeltaKN in beta-cells protects from HFD-induced beta-cell failure in vivo by a mechanism that involves inhibition of fatty acid-mediated apoptosis, inhibition of mitochondrial dysfunction, and inhibition of FOXO1 activation. |
