Lisofylline, a novel antiinflammatory agent, protects pancreatic beta-cells from proinflammatory cytokine damage by promoting mitochondrial metabolism

Endocrinology. 2002 Jun;143(6):2341-8. doi: 10.1210/endo.143.6.8841.


Proinflammatory cytokine-mediated pancreatic beta-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-1 beta-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 beta-cell insulin release capacity and the control of cellular viability. To examine the direct effects of LSF on beta-cells, insulin-secreting INS-1 cells were exposed to a combination of recombinant IL-1 beta, TNF alpha, and IFN gamma 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 beta-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 beta-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 beta-cells from the cytokine effects. The mechanism of LSF-induced protection may be by promoting mitochondrial metabolism.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cytokines / antagonists & inhibitors*
  • Cytokines / toxicity
  • DNA Damage
  • Fluorescent Dyes
  • In Situ Nick-End Labeling
  • Insulin / metabolism
  • Insulin Secretion
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism
  • Membrane Potentials / drug effects
  • Membranes / drug effects
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Pentoxifylline / analogs & derivatives
  • Pentoxifylline / pharmacology*
  • Rats
  • Stimulation, Chemical
  • Tetrazolium Salts
  • Thiazoles


  • Anti-Inflammatory Agents, Non-Steroidal
  • Cytokines
  • Fluorescent Dyes
  • Insulin
  • Tetrazolium Salts
  • Thiazoles
  • Adenosine Triphosphate
  • thiazolyl blue
  • lisofylline
  • Pentoxifylline