The novel NADPH oxidase 4 inhibitor GLX351322 counteracts glucose intolerance in high-fat diet-treated C57BL/6 mice

Free Radic Res. 2015;49(11):1308-18. doi: 10.3109/10715762.2015.1067697. Epub 2015 Jul 30.


In type 2 diabetes, it has been proposed that pancreatic beta-cell dysfunction is promoted by oxidative stress caused by NADPH oxidase (NOX) overactivity. Five different NOX enzymes (NOX1-5) have been characterized, among which NOX1 and NOX2 have been proposed to negatively affect beta-cells, but the putative role of NOX4 in type 2 diabetes-associated beta-cell dysfunction and glucose intolerance is largely unknown. Therefore, we presently investigated the importance of NOX4 for high-fat diet or HFD-induced glucose intolerance using male C57BL/6 mice using the new NOX4 inhibitor GLX351322, which has relative NOX4 selectivity over NOX2. In HFD-treated male C57BL/6 mice a two-week treatment with GLX351322 counteracted non-fasting hyperglycemia and impaired glucose tolerance. This effect occurred without any change in peripheral insulin sensitivity. To ascertain that NOX4 also plays a role for the function of human beta-cells, we observed that glucose- and sodium palmitate-induced insulin release from human islets in vitro was increased in response to NOX4 inhibitors. In long-term experiments (1-3 days), high-glucose-induced human islet cell reactive oxygen species (ROS) production and death were prevented by GLX351322. We propose that while short-term NOX4-generated ROS production is a physiological requirement for beta-cell function, persistent NOX4 activity, for example, during conditions of high-fat feeding, promotes ROS-mediated beta-cell dysfunction. Thus, selective NOX inhibition may be a therapeutic strategy in type 2 diabetes.

Keywords: NADPH oxidase; NOX inhibitor; beta-cell death; glucose intolerance; human islet; insulin release; reactive oxygen radical.

MeSH terms

  • Animals
  • Diet, High-Fat / adverse effects*
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / pharmacology*
  • Glucose Intolerance / drug therapy*
  • High-Throughput Screening Assays
  • Humans
  • Hyperglycemia / drug therapy
  • Hyperglycemia / etiology
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NADPH Oxidase 4
  • NADPH Oxidases / antagonists & inhibitors*
  • NADPH Oxidases / metabolism
  • Piperazines / pharmacology
  • Reactive Oxygen Species / metabolism
  • Thiophenes / pharmacology


  • Enzyme Inhibitors
  • Piperazines
  • Reactive Oxygen Species
  • Thiophenes
  • NADPH Oxidase 4
  • NADPH Oxidases
  • Nox4 protein, mouse