Cardiac mitochondrial alterations induced by insulin deficiency and hyperinsulinaemia in rats: targeting membrane homeostasis with trimetazidine.

Summary 1. The present study investigated the ability of trimetazidine (TMZ) to maintain cardiac mitochondrial function during the development of insulin deficiency and hyperinsulinaemia. The anti-ischaemic drug TMZ is known to increase phospholipid synthesis in cardiac membranes and to have a cardioprotective effect. 2. Insulin deficiency was obtained by streptozotocin injection and hyperinsulinaemia was achieved via a fructose diet. Trimetazidine was incorporated into the diet (7.8 mg/day) and mitochondrial function was evaluated in skinned cardiac fibres. 3. Insulin deficiency decreased mitochondrial affinity for ADP and the index of creatine kinase functional activity. This last alteration was partially prevented by TMZ treatment. Insulin deficiency strongly decreased n-3 polyunsaturated fatty acids, especially the docosahexaenoic acid (DHA) content, in cardiac and mitochondrial membranes, inducing a strong increase in the n-6/n-3 ratio. Trimetazidine treatment limited the increase in the n-6/n-3 ratio and prevented the decrease in DHA content in mitochondrial membranes. Insulin deficiency decreased glutamate- and palmitoylcarnitine-supported respiration. 4. Hyperinsulinaemia affected neither mitochondrial affinity for ADP nor the index of creatine kinase functional activity. Hyperinsulinaemia slightly and significantly affected mitochondrial fatty acid composition, by a small increase the n-6/n-3 ratio. Trimetazidine did not modify membrane-bound mitochondrial function but increased the n-6/n-3 ratio. Moreover, hyperinsulinaemia decreased glutamate-supported respiration. 5. In conclusion, modification of membrane homeostasis with TMZ partially prevented the alterations in fatty acid composition and function in cardiac mitochondria induced by insulin deficiency. Three months of hyperinsulinaemia did not modify membrane-bound mitochondrial function and had only slight effects on fatty acid composition.