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- Title
Inhibition of AMP-Activated Protein Kinase Protects Pancreatic β-Cells From Cytokine-Mediated Apoptosis and CD8<sup>+</sup> T-Cell--Induced Cytotoxicity.
- Authors
Riboulet-Chavey, Audrey; Diraison, Frédérique; Siew, L. Khai; Wong, F. Susan; Rutter, Guy A.
- Abstract
OBJECTIVE--Apoptotic destruction of insulin-producing pancreatic β-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 β-cell apoptosis and in islet cell death posttransplantation. Here, we examine the importance of β-cell AMPK in cytokine-induced apoptosis and in the cytotoxic action of CD8[sup +] T-cells. RESEARCH DESIGN AND METHODS--Clonal MIN6 β-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 factor-α, interleukin-lβ, and interferon-γ. Apoptosis was detected by monitoring the cleavage of caspase-3 and DNA fragmentation. The cytotoxic effect of CD8[sup +] 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 β-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[sup +] 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 immune-mediated β-cell destruction and may increase the efficacy of islet allografts in type 1 diabetes. Diabetes 57:415-423, 2008
- Subjects
TYPE 2 diabetes; DIABETES; ETIOLOGY of diseases; LABORATORY rats; ENDOCRINE diseases; APOPTOSIS
- Publication
Diabetes, 2008, Vol 57, Issue 2, p415
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db07-0993