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Open Access 01-05-2016 | Article

ANT1-mediated fatty acid-induced uncoupling as a target for improving myocellular insulin sensitivity

Authors: Lauren M. Sparks, Anne Gemmink, Esther Phielix, Madeleen Bosma, Gert Schaart, Esther Moonen-Kornips, Johanna A. Jörgensen, Emmani B. M. Nascimento, Matthijs K. C. Hesselink, Patrick Schrauwen, Joris Hoeks

Published in: Diabetologia | Issue 5/2016

Abstract

Aims/hypothesis

Dissipating energy via mitochondrial uncoupling has been suggested to contribute to enhanced insulin sensitivity. We hypothesised that skeletal muscle mitochondria of endurance-trained athletes have increased sensitivity for fatty acid (FA)-induced uncoupling, which is driven by the mitochondrial protein adenine nucleotide translocase 1 (ANT1).

Methods

Capacity for FA-induced uncoupling was measured in endurance-trained male athletes (T) and sedentary young men (UT) in an observational study and also in isolated skeletal muscle mitochondria from Zucker diabetic fatty (ZDF) rats and C2C12 myotubes following small interfering RNA (siRNA)-mediated gene silencing of ANT1. Thus, fuelled by glutamate/succinate (fibres) or pyruvate (mitochondria and myotubes) and in the presence of oligomycin to block ATP synthesis, increasing levels of oleate (fibres) or palmitate (mitochondria and myotubes) were automatically titrated while respiration was monitored. Insulin sensitivity was measured by hyperinsulinaemic–euglycaemic clamp in humans and via insulin-stimulated glucose uptake in myotubes.

Results

Skeletal muscle from the T group displayed increased sensitivity to FA-induced uncoupling (p = 0.011) compared with muscle from the UT group, and this was associated with elevated insulin sensitivity (p = 0.034). ANT1 expression was increased in T (p = 0.013). Mitochondria from ZDF rats displayed decreased sensitivity for FA-induced uncoupling (p = 0.008). This difference disappeared in the presence of the adenine nucleotide translocator inhibitor carboxyatractyloside. Partial knockdown of ANT1 in C2C12 myotubes decreased sensitivity to the FA-induced uncoupling (p = 0.008) and insulin-stimulated glucose uptake (p = 0.025) compared with controls.

Conclusions/interpretation

Increased sensitivity to FA-induced uncoupling is associated with enhanced insulin sensitivity and is affected by ANT1 activity in skeletal muscle. FA-induced mitochondrial uncoupling may help to preserve insulin sensitivity in the face of a high supply of FAs.

Trial registration

www.trialregister.nl NTR2002

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Title: ANT1-mediated fatty acid-induced uncoupling as a target for improving myocellular insulin sensitivity
Authors: Lauren M. Sparks
Anne Gemmink
Esther Phielix
Madeleen Bosma
Gert Schaart
Esther Moonen-Kornips
Johanna A. Jörgensen
Emmani B. M. Nascimento
Matthijs K. C. Hesselink
Patrick Schrauwen
Joris Hoeks
Publication date: 01-05-2016
Publisher: Springer Berlin Heidelberg
Published in: Diabetologia / Issue 5/2016
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-016-3885-8

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ANT1-mediated fatty acid-induced uncoupling as a target for improving myocellular insulin sensitivity

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Trial registration

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Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Trial registration

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