Inhibition of AMP-Activated Protein Kinase Protects Pancreatic β-Cells From Cytokine-Mediated Apoptosis and CD8+ T-Cell–Induced Cytotoxicity

  1. Audrey Riboulet-Chavey1,
  2. Frédérique Diraison1,
  3. L. Khai Siew2,
  4. F. Susan Wong2 and
  5. Guy A. Rutter1
  1. 1Department of Cell Biology, Division of Medicine, Imperial College, London, U.K
  2. 2Department of Cellular and Molecular Medicine, University of Bristol, School of Medical Sciences, Bristol, U.K
  1. Address correspondence and reprint requests to Guy A. Rutter, PhD, Professor and Head of Department of Cell Biology, Division of Medicine, Sir Alexander Fleming Building, Imperial College, London, Exhibition Road, London SW7 2AZ, U.K. E-mail: g.rutter{at}


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+ 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-1β, and interferon-γ. 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 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+ 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.


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  1. Diabetes vol. 57 no. 2 415-423
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