Frontiers in Endocrinology (Sep 2021)

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

  • Dominik Pesta,
  • Dominik Pesta,
  • Dominik Pesta,
  • Dominik Pesta,
  • Dominik Pesta,
  • Tomas Jelenik,
  • Tomas Jelenik,
  • Oana-Patricia Zaharia,
  • Oana-Patricia Zaharia,
  • Pavel Bobrov,
  • Pavel Bobrov,
  • Sven Görgens,
  • Sven Görgens,
  • Kálmán Bódis,
  • Kálmán Bódis,
  • Kálmán Bódis,
  • Yanislava Karusheva,
  • Yanislava Karusheva,
  • Nina Krako Jakovljevic,
  • Nina Krako Jakovljevic,
  • Nebojsa M. Lalic,
  • Daniel F. Markgraf,
  • Daniel F. Markgraf,
  • Volker Burkart,
  • Volker Burkart,
  • Karsten Müssig,
  • Karsten Müssig,
  • Karsten Müssig,
  • Birgit Knebel,
  • Birgit Knebel,
  • Jörg Kotzka,
  • Jörg Kotzka,
  • Jürgen Eckel,
  • Jürgen Eckel,
  • Klaus Strassburger,
  • Klaus Strassburger,
  • Julia Szendroedi,
  • Julia Szendroedi,
  • Julia Szendroedi,
  • Michael Roden,
  • Michael Roden,
  • Michael Roden

DOI
https://doi.org/10.3389/fendo.2021.693683
Journal volume & issue
Vol. 12

Abstract

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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 RegistrationClinicalTrials.gov, identifier NCT01055093. The trial was retrospectively registered on 25th of January 2010.

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