NDUFB6 Polymorphism Is Associated With Physical Activity-Mediated Metabolic Changes in Type 2 Diabetes

Front Endocrinol (Lausanne). 2021 Sep 24;12:693683. doi: 10.3389/fendo.2021.693683. eCollection 2021.


The rs540467 SNP in the NDUFB6 gene, encoding a mitochondrial complex I subunit, has been shown to modulate adaptations to exercise training. Interaction effects with diabetes mellitus remain unclear. We assessed associations of habitual physical activity (PA) levels with metabolic variables and examined a possible modifying effect of the rs540467 SNP. Volunteers with type 2 (n=242), type 1 diabetes (n=250) or normal glucose tolerance (control; n=139) were studied at diagnosis and subgroups with type 1 (n=96) and type 2 diabetes (n=95) after 5 years. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamps, oxygen uptake at the ventilator threshold (VO2AT) by spiroergometry and PA by questionnaires. Translational studies investigated insulin signaling and mitochondrial function in Ndufb6 siRNA-treated C2C12 myotubes, with electronic pulse stimulation (EPS) to simulate exercising. PA levels were 10 and 6%, VO2AT was 31% and 8% lower in type 2 and type 1 diabetes compared to control. Within 5 years, 36% of people with type 2 diabetes did not improve their insulin sensitivity despite increasing PA levels. The NDUFB6 rs540467 SNP modifies PA-mediated changes in insulin sensitivity, body composition and liver fat estimates in type 2 diabetes. Silencing Ndufb6 in myotubes reduced mitochondrial respiration and prevented rescue from palmitate-induced insulin resistance after EPS. A substantial proportion of humans with type 2 diabetes fails to respond to rising PA with increasing insulin sensitivity. This may at least partly relate to a polymorphism of the NDUFB6 gene, which may contribute to modulating mitochondrial function.

Clinical trial registration: ClinicalTrials.gov, identifier NCT01055093. The trial was retrospectively registered on 25th of January 2010.

Keywords: diabetes mellitus; insulin sensitivity; mitochondrial function; physical activity; single nucleotide polymorphism.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Body Composition / genetics
  • Case-Control Studies
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Electron Transport Complex I / genetics*
  • Exercise / physiology*
  • Female
  • Follow-Up Studies
  • Genetic Association Studies
  • Germany
  • Glucose Clamp Technique
  • Humans
  • Longitudinal Studies
  • Male
  • Mice
  • Middle Aged
  • Muscle, Skeletal / metabolism
  • Polymorphism, Single Nucleotide
  • Young Adult


  • Electron Transport Complex I
  • NDUFB6 protein, human

Associated data

  • ClinicalTrials.gov/NCT01055093