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Lisofylline, a Novel Antiinflammatory Agent, Protects Pancreatic ß-Cells from Proinflammatory Cytokine Damage by Promoting Mitochondrial Metabolism

Department of Medicine, University of Virginia Health System, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Jerry L. Nadler, M.D., Department of Medicine, Division of Endocrinology and Metabolism, University of Virginia Health System, P.O. Box 801405, Charlottesville, Virginia 22908-1405.

Proinflammatory cytokine-mediated pancreatic ß-cell dysfunction is a key pathological event in type I diabetes mellitus. Lisofylline (LSF), an anti-inflammatory agent, has been shown to protect pancreatic islets from IL-1ß-induced inhibitory effects on insulin release. However, the mechanism of LSF action is not known. Increasing evidence suggests that the mitochondria play an important role in regulating the ß-cell insulin release capacity and the control of cellular viability.

To examine the direct effects of LSF on ß-cells, insulin-secreting INS-1 cells were exposed to a combination of recombinant IL-1ß, TNF, and IFN with or without LSF for 18 h. Basal and glucose-stimulated static insulin release were measured using RIA. INS-1 cell viability was determined using in situ terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling and LIVE/DEAD dual fluorescence labeling. To evaluate INS-1 mitochondrial function, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) metabolism, change in mitochondrial membrane potential, and intracellular ATP levels were assessed.

Cytokine addition reduced basal (7.8 ± 0.30 vs. 10.0 ± 0.46 ng/ml•h; P < 0.005), glucose-stimulated insulin secretion (11.6 ± 0.86 vs. 17.4 ± 1.86 ng/ml•h; P < 0.005), and MTT metabolism in INS-1 cells. Over 40% of the cytokine-treated ß-cells exhibited nuclear DNA breakage, whereas the control cell death rate remained at 1–2%. Simultaneous application of LSF and cytokines to INS-1 cells restored insulin secretion, MTT metabolism, mitochondrial membrane potential, and cell viability to control levels. LSF increased ß-cell MTT metabolism as well as insulin release and glucose responsiveness.

In summary, proinflammatory cytokines lead to a reduction of glucose-induced insulin secretion, mitochondrial activity, and viability in INS-1 cells. LSF at concentrations achievable in vivo protected ß-cells from the cytokine effects. The mechanism of LSF-induced protection may be by promoting mitochondrial metabolism.

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