Overexpression of kinase-negative protein kinase Cδ in pancreatic β-cells protects mice from diet-induced glucose intolerance and β-cell dysfunction

Anita M. Hennige, Felicia Ranta, Isabel Heinzelmann, Martina Düfer, Diana Michael, Heidi Braumüller, Stefan Z. Lutz, Reiner Lammers, Gisela Drews, Fatima Bosch, Hans Ulrich Häring, Susanne Ullrich

Research output: Contribution to journalArticleResearchpeer-review

49 Citations (Scopus)


OBJECTIVE - In vitro models suggest that free fatty acid-induced apoptotic β-cell death is mediated through protein kinase C (PKC)δ. To examine the role of PKCδ signaling in vivo, transgenic mice overexpressing a kinase-negative PKCδ (PKCδKN) selectively in β-cells were generated and analyzed for glucose homeostasis and β-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 PKCδ 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 - PKCδKN 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 β-cells for cleaved caspase-3 compared with wild-type litter-mates. In accordance, long-term treatment with palmitate increased apoptotic cell death of isolated islet cells from wild-type but not from PKCδKN mice. PKCδKN 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 PKCδKN was accompanied by an increased phosphorylation of FOXO1 at Ser256 and a significant reduction of FOXO1 protein. CONCLUSIONS - Overexpression of PKCδKN in β-cells protects from HFD-induced β-cell failure in vivo by a mechanism that involves inhibition of fatty acid-mediated apoptosis, inhibition of mitochondrial dysfunction, and inhibition of FOXO1 activation. © 2010 by the American Diabetes Association.
Original languageEnglish
Pages (from-to)119-127
Publication statusPublished - 1 Jan 2010


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