Insulin-dependent H2O2 Production Is Higher in Muscle Fibers of Mice Fed With a High-Fat Diet

Int J Mol Sci. 2013 Jul 29;14(8):15740-54. doi: 10.3390/ijms140815740.

Abstract

Insulin resistance is defined as a reduced ability of insulin to stimulate glucose utilization. C57BL/6 mice fed with a high-fat diet (HFD) are a model of insulin resistance. In skeletal muscle, hydrogen peroxide (H2O2) produced by NADPH oxidase 2 (NOX2) is involved in signaling pathways triggered by insulin. We evaluated oxidative status in skeletal muscle fibers from insulin-resistant and control mice by determining H2O2 generation (HyPer probe), reduced-to-oxidized glutathione ratio and NOX2 expression. After eight weeks of HFD, insulin-dependent glucose uptake was impaired in skeletal muscle fibers when compared with control muscle fibers. Insulin-resistant mice showed increased insulin-stimulated H2O2 release and decreased reduced-to-oxidized glutathione ratio (GSH/GSSG). In addition, p47phox and gp91phox (NOX2 subunits) mRNA levels were also high (~3-fold in HFD mice compared to controls), while protein levels were 6.8- and 1.6-fold higher, respectively. Using apocynin (NOX2 inhibitor) during the HFD feeding period, the oxidative intracellular environment was diminished and skeletal muscle insulin-dependent glucose uptake restored. Our results indicate that insulin-resistant mice have increased H2O2 release upon insulin stimulation when compared with control animals, which appears to be mediated by an increase in NOX2 expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diet, High-Fat*
  • Glutathione / metabolism
  • Hydrogen Peroxide / metabolism*
  • Insulin / metabolism*
  • Insulin Resistance
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Muscle Fibers, Skeletal / metabolism*
  • NADPH Oxidase 2
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism
  • Oxidation-Reduction

Substances

  • Insulin
  • Membrane Glycoproteins
  • Hydrogen Peroxide
  • Cybb protein, mouse
  • NADPH Oxidase 2
  • NADPH Oxidases
  • neutrophil cytosolic factor 1
  • Glutathione