The work of Christophe Soulage from CarMeN team 3 in collaboration with the team 5, have just highlighted the role of 4-hydroxy-2-hexénal (4-HHE) suggesting future avenues for improving blood glucose levels in diabetic patients.
Oxidative stress is involved in the development of insulin resistance and its progression toward type 2 diabetes (T2D). The peroxidation of omega-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. In context of an increased consumption of omega-3, we investigated the specific role of 4-HHE in the development of insulin resistance. In T2D humans and rats, circulating levels 4-HHE were twice the level of healthy controls and positively correlated with glycaemia. During hyperinsulinemic euglycaemic clamps in rats, acute intravenous injection of 4-HHE significantly altered whole body insulin sensitivity and decreased glucose infusion rate. In vitro, 4-HHE impaired insulin-stimulated glucose uptake and signalling in L6 muscle cells. 4-HHE induced carbonylation of cell proteins and reduced glutathione concentration. Increasing intracellular glutathione pools prevented 4-HHE-induced carbonyl stress and insulin resistance. 4-HHE is produced under diabetic conditions and impairs insulin action in skeletal muscle. 4-HHE therefore plays a causal role in the pathophysiology of T2D and might constitute a potential therapeutic target to taper oxidative stress-induced insulin resistance.
Soulage CO, Sardón Puig L, Soulère L, Zarrouki B, Guichardant M, Lagarde M, Pillon NJ.
Diabetologia. 2018 Mar;61(3):688-699. doi: 10.1007/s00125-017-4528-4. Epub 2018 Jan 3.