Abstract
Aims/hypothesisOxidative 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.Methods4-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).ResultsCirculating 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/interpretation4-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.
Highlights
Oxidative stress is involved in the pathophysiology of many chronic diseases and in particular contributes to the development of insulin resistance and its progression towards type 2 diabetes [1,2,3]
Diabetes is associated with increased oxidative stress in metabolic tissues and excessive production of reactive oxygen species negatively affects insulin responses [2]
Lipid peroxidation byproducts are long-lived and may spread from their site of production to exert their effects throughout the whole organism
Summary
Oxidative stress is involved in the pathophysiology of many chronic diseases and in particular contributes to the development of insulin resistance and its progression towards type 2 diabetes [1,2,3]. Peroxidation of n-6 polyunsaturated fatty acids (PUFA) leads to the production of 4-hydroxy-2-nonenal (4HNE), while 4-hydroxy-2-hexenal (4-HHE) is released during the oxidation of n-3-PUFA [4] These lipid aldehydes are major by-products of lipid peroxidation of PUFA and exhibit potent electrophilic properties allowing them to form covalent adducts with phospholipids, proteins and nucleotides [5, 6]. Because of their relative stability and high reactivity, these aldehydes are thought to interfere with crucial physiological processes such as cell cycle, apoptosis or metabolic pathways [7,8,9]. The production of 4-hydroxyalkenals is associated with hindered insulin responses: 4-HNE-adducts accumulate in liver and pancreatic beta cells of diabetic rats [10,11,12], impairs glucose-induced insulin secretion in isolated beta cells [13] and blunts insulin action in 3T3-L1 adipocytes and L6 muscle cells [14, 15]
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