Inhibition of NADPH oxidase-1 preserves beta cell function

Diabetologia. 2015 Jan;58(1):113-21. doi: 10.1007/s00125-014-3398-2. Epub 2014 Oct 3.


Aims/hypothesis: Upregulation of the reactive oxygen species (ROS)-producing enzyme NADPH oxidase (NOX)-1 in islets and beta cells follows acute exposure to inflammatory cytokines and is concomitant with beta cell dysfunction. NOX-1 is a candidate mediator of inflammation-induced beta cell dysfunction. This study aimed to determine whether selective inhibition of NADPH oxidase-1 presents a new strategy to preserve beta cell function.

Methods: Induced beta cell dysfunction was studied in primary human donor islets, isolated mouse islets and murine beta cell lines. Islets and beta cells were stimulated with inflammatory cytokines (TNF-α, IL-1β, IFN-γ). NOX-1 activity was blocked by the selective inhibitor ML171.

Results: Cytokine induction of intracellular ROS was reduced 80% with 1 μmol/l ML171 in murine beta cell lines (p < 0.01). Cytokine-induced apoptosis, measured by caspase-3 activation or quantified fluorescence microscopy, was prevented in islets and beta cell lines up to 100% with ML171 in a concentration-dependent manner (p < 0.05). Functionally, glucose-stimulated insulin secretion was abolished by cytokine exposure but preserved by ML171 in isolated mouse islets and murine beta cell lines. A feed-forward regulation of NOX-1 in islets and beta cell lines was disrupted by ML171.

Conclusions/interpretation: Stimulation of NOX-1 activity is a major component of inflammatory cytokine-induced beta cell dysfunction. Significant protection of beta cells is conferred with selective inhibition of NOX-1. Suppression of NOX-1 activity may present a new therapeutic strategy to preserve and protect beta cell function in diabetes.

Publication types

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

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytoprotection / drug effects*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inflammation / prevention & control
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / physiology
  • Interferon-gamma / adverse effects
  • Interleukin-1beta / adverse effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NADH, NADPH Oxidoreductases / antagonists & inhibitors*
  • NADPH Oxidase 1
  • Phenothiazines / pharmacology*
  • Rats
  • Tumor Necrosis Factor-alpha / adverse effects


  • 2-acetylphenothiazine
  • Enzyme Inhibitors
  • Interleukin-1beta
  • Phenothiazines
  • TNF protein, human
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • NADH, NADPH Oxidoreductases
  • NADPH Oxidase 1