Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress

Endocrinology. 2004 Nov;145(11):5087-96. doi: 10.1210/en.2004-0478. Epub 2004 Aug 5.


Apoptosis is probably the main form of beta-cell death in both type 1 diabetes mellitus (T1DM) and T2DM. In T1DM, cytokines contribute to beta-cell destruction through nuclear factor-kappaB (NF-kappaB) activation. Previous studies suggested that in T2DM high glucose and free fatty acids (FFAs) are beta-cell toxic also via NF-kappaB activation. The aims of this study were to clarify whether common mechanisms are involved in FFA- and cytokine-induced beta-cell apoptosis and determine whether TNFalpha, an adipocyte-derived cytokine, potentiates FFA toxicity through enhanced NF-kappaB activation. Apoptosis was induced in insulinoma (INS)-1E cells, rat islets, and fluorescence-activated cell sorting-purified beta-cells by oleate, palmitate, and/or cytokines (IL-1beta, interferon-gamma, TNFalpha). Palmitate and IL-1beta induced a similar percentage of apoptosis in INS-1E cells, whereas oleate was less toxic. TNFalpha did not potentiate FFA toxicity in primary beta-cells. The NF-kappaB-dependent genes inducible nitric oxide synthase and monocyte chemoattractant protein-1 were induced by IL-1beta but not by FFAs. Cytokines activated NF-kappaB in INS-1E and beta-cells, but FFAs did not. Moreover, FFAs did not enhance NF-kappaB activation by TNFalpha. Palmitate and oleate induced C/EBP homologous protein, activating transcription factor-4, and immunoglobulin heavy chain binding protein mRNAs, X-box binding protein-1 alternative splicing, and activation of the activating transcription factor-6 promoter in INS-1E cells, suggesting that FFAs trigger an endoplasmic reticulum (ER) stress response. We conclude that apoptosis is the main mode of FFA- and cytokine-induced beta-cell death but the mechanisms involved are different. Whereas cytokines induce NF-kappaB activation and ER stress (secondary to nitric oxide formation), FFAs activate an ER stress response via an NF-kappaB- and nitric oxide-independent mechanism. Our results argue against a unifying hypothesis for the mechanisms of beta-cell death in T1DM and T2DM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Carcinogens / pharmacology
  • Cell Line, Tumor
  • Cytokines / pharmacology*
  • Drug Synergism
  • Endoplasmic Reticulum / metabolism*
  • Fatty Acids, Nonesterified / toxicity*
  • Flow Cytometry
  • Insulinoma
  • Interferon-gamma / pharmacology
  • Interleukin-1 / pharmacology
  • Islets of Langerhans / cytology*
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Male
  • NF-kappa B / metabolism*
  • Oleic Acid / toxicity
  • Palmitates / toxicity
  • Pancreatic Neoplasms
  • Rats
  • Rats, Wistar
  • Thapsigargin / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology


  • Carcinogens
  • Cytokines
  • Fatty Acids, Nonesterified
  • Interleukin-1
  • NF-kappa B
  • Palmitates
  • Tumor Necrosis Factor-alpha
  • Oleic Acid
  • Thapsigargin
  • Interferon-gamma