期刊
DIABETES
卷 57, 期 2, 页码 415-423出版社
AMER DIABETES ASSOC
DOI: 10.2337/db07-0993
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资金
- Wellcome Trust [081958/Z/07/Z] Funding Source: Wellcome Trust
- Medical Research Council [G0401641] Funding Source: researchfish
- MRC [G0401641] Funding Source: UKRI
- Medical Research Council [G0401641] Funding Source: Medline
- Wellcome Trust [067081/Z/02/Z, 081958/Z/07/Z] Funding Source: Medline
OBJECTIVE-Apoptotic destruction of insulin-producing pancreatic beta-cells is involved in the etiology of both type 1 and type 2 diabetes. AMP-activated protein kinase (AMPK) is a sensor of cellular energy charge whose sustained activation has recently been implicated in pancreatic beta-cell apoptosis and in islet cell death posttransplantation. Here, we examine the importance of beta-cell AMPK in cytokine-induced apoptosis and in the cytotoxic action of CD8(+) T-cells. RESEARCH DESIGN AND METHODS-Clonal MIN6 P-cells or CD1 mouse pancreatic islets were infected with recombinant adenoviruses encoding enhanced green fluorescent protein (eGFP/null), constitutively active AMPK (AMPK-CA), or dominant-negative AMPK (AMPK-DN) and exposed or not to tumor necrosis facton-alpha, interleukin-1 beta, and interferon-gamma. Apoptosis was detected by monitoring the cleavage of caspase-3 and DNA fragmentation. The cytotoxic effect of CD8(+) purified T-cells was examined against pancreatic islets from NOD mice infected with either null or the AMPK-DN- expressing adenoviruses. RESULTS-Exposure to cytokines, or expression of AMPK-CA, induced apoptosis in clonal MIN6 P-cells and CD1 mouse pancreatic islets. By contrast, overexpression of AMPK-DN protected against the proapoptotic effect of these agents, in part by preventing decreases in cellular ATP, and lowered the cytotoxic effect of CD8(+) T-cells toward NOD mouse islets. CONCLUSIONS-Inhibition of AMPK activity enhances islet survival in the face of assault by either cytokines or T-cells. AMPK may therefore represent an interesting therapeutic target to suppress immuune-mediated beta-cell destruction and may increase the efficacy of islet allografts in type 1 diabetes.
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