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Diabetologia
Published in: Diabetologia 3/2018

Open Access 01-03-2018 | Article

Skeletal muscle insulin resistance is induced by 4-hydroxy-2-hexenal, a by-product of n-3 fatty acid peroxidation

Authors: Christophe O. Soulage, Laura Sardón Puig, Laurent Soulère, Bader Zarrouki, Michel Guichardant, Michel Lagarde, Nicolas J. Pillon

Published in: Diabetologia | Issue 3/2018

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Abstract

Aims/hypothesis

Oxidative stress is involved in the pathophysiology of insulin resistance and its progression towards type 2 diabetes. The peroxidation of n-3 polyunsaturated fatty acids produces 4-hydroxy-2-hexenal (4-HHE), a lipid aldehyde with potent electrophilic properties able to interfere with many pathophysiological processes. The aim of the present study was to investigate the role of 4-HHE in the development of insulin resistance.

Methods

4-HHE concentration was measured in plasma from humans and rats by GC–MS. Insulin resistance was estimated in healthy rats after administration of 4-HHE using hyperinsulinaemic–euglycaemic clamps. In muscle cells, glucose uptake was measured using 2-deoxy-d-glucose and signalling pathways were investigated by western blotting. Intracellular glutathione was measured using a fluorimetric assay kit and boosted using 1,2-dithiole-3-thione (D3T).

Results

Circulating levels of 4-HHE in type 2 diabetic humans and a rat model of diabetes (obese Zucker diabetic fatty rats), were twice those in their non-diabetic counterparts (33 vs 14 nmol/l, p < 0.001), and positively correlated with blood glucose levels. During hyperinsulinaemic–euglycaemic clamps in rats, acute intravenous injection of 4-HHE significantly altered whole-body insulin sensitivity and decreased glucose infusion rate (24.2 vs 9.9 mg kg−1 min−1, p < 0.001). In vitro, 4-HHE impaired insulin-stimulated glucose uptake and signalling (protein kinase B/Akt and IRS1) in L6 muscle cells. Insulin-induced glucose uptake was reduced from 186 to 141.9 pmol mg−1 min−1 (p < 0.05). 4-HHE induced carbonylation of cell proteins and reduced glutathione concentration from 6.3 to 4.5 nmol/mg protein. Increasing intracellular glutathione pools using D3T prevented 4-HHE-induced carbonyl stress and insulin resistance.

Conclusions/interpretation

4-HHE is produced in type 2 diabetic humans and Zucker diabetic fatty rats and blunts insulin action in skeletal muscle. 4-HHE therefore plays a causal role in the pathophysiology of type 2 diabetes and might constitute a potential therapeutic target to taper oxidative stress-induced insulin resistance.
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Metadata
Title
Skeletal muscle insulin resistance is induced by 4-hydroxy-2-hexenal, a by-product of n-3 fatty acid peroxidation
Authors
Christophe O. Soulage
Laura Sardón Puig
Laurent Soulère
Bader Zarrouki
Michel Guichardant
Michel Lagarde
Nicolas J. Pillon
Publication date
01-03-2018
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 3/2018
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-017-4528-4

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