Abstract
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.
Highlights
Exercise training improves insulin sensitivity and ameliorates the risk of diabetes onset and cardiovascular mortality in type 2 diabetes (T2D) [1,2,3], but may be beneficial for type 1 diabetes (T1D) [4]
This study shows that (i) habitual physical activity (PA) is lower in T1D and T2D within the first year after diagnosis, (ii) increases in habitual PA over 5 years do not associate with improvements of insulin sensitivity in 36% of individuals with T2D, (iii) rs540467 single nucleotide polymorphism (SNP) of the NADH dehydrogenase beta subcomplex subunit 6 (NDUFB6) gene is associated with PA-mediated changes in insulin sensitivity, body composition and liver fat estimates (iv) silencing NDUFB6 in myotubes lowers mitochondrial respiration and inhibits the contraction-mediated rescue from palmitateinduced insulin resistance
These findings suggest that a polymorphism related to mitochondrial function could contribute to modulating the effect of PA on important metabolic endpoints in T2D
Summary
Exercise training improves insulin sensitivity and ameliorates the risk of diabetes onset and cardiovascular mortality in type 2 diabetes (T2D) [1,2,3], but may be beneficial for type 1 diabetes (T1D) [4]. The effects of structured exercise training, i.e. aerobic or resistance training, vary considerably [5], with up to 63% of participants being nonresponders with regard to improvements of glucose homeostasis or cardiovascular outcomes [5, 6] This phenomenon and its causes have not yet been addressed in a prospective manner in newly-diagnosed diabetes. Presence of the G/G genotype (rs540467) was associated with exercise-mediated increases in muscle ATP synthase flux [7] and insulin sensitivity [9] with responders to exercise being more frequently carriers of the G allele of the NDUFB6 rs540467 polymorphism These associations remain unclear in patients with diabetes mellitus
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
