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

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

JOURNAL=Frontiers in Endocrinology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.693683

DOI=10.3389/fendo.2021.693683

ISSN=1664-2392

ABSTRACT=<p>The rs540467 SNP in the <italic>NDUFB6</italic> 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 (VO<sub>2</sub>AT) by spiroergometry and PA by questionnaires. Translational studies investigated insulin signaling and mitochondrial function in <italic>Ndufb6</italic> siRNA-treated C2C12 myotubes, with electronic pulse stimulation (EPS) to simulate exercising. PA levels were 10 and 6%, VO<sub>2</sub>AT 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 <italic>NDUFB6</italic> rs540467 SNP modifies PA-mediated changes in insulin sensitivity, body composition and liver fat estimates in type 2 diabetes. Silencing <italic>Ndufb6</italic> 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 <italic>NDUFB6</italic> gene, which may contribute to modulating mitochondrial function.</p><sec><title>Clinical Trial Registration</title><p>ClinicalTrials.gov, identifier NCT01055093. The trial was retrospectively registered on 25<sup>th</sup> of January 2010.</p></sec>