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

• Published in: Diabetologia 2018-03, Vol.61 (3), p.688-699
• Main Authors: Soulage, Christophe O., Sardón Puig, Laura, Soulère, Laurent, Zarrouki, Bader, Guichardant, Michel, Lagarde, Michel, Pillon, Nicolas J.
• Format: Article
• Language: English
• Subjects: Adult; AKT protein; Aldehydes - pharmacology; Animals; Biochemistry; Biochemistry, Molecular Biology; Blood glucose; Blood Glucose - drug effects; Blotting, Western; Diabetes mellitus; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - metabolism; Endocrinology and metabolism; Fatty Acids, Omega-3 - blood; Female; Gas Chromatography-Mass Spectrometry; Glucose; Glutathione; Human health and pathology; Human Physiology; Humans; Insulin; Insulin - blood; Insulin - pharmacology; Insulin resistance; Insulin Resistance - physiology; Internal Medicine; Intracellular; Intracellular signalling; Intravenous administration; Kinases; Life Sciences; Lipid peroxidation; Lipid Peroxidation - drug effects; Male; Medicine; Medicine & Public Health; Metabolic Diseases; Middle Aged; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Oxidative stress; Oxidative Stress - drug effects; Polyunsaturated fatty acids; Rats; Rats, Zucker; Rodents; Signal transduction; Skeletal muscle; Thiones - pharmacology; Thiophenes - pharmacology; Western blotting
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-017-4528-4

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