Metabolic and endothelial effects of trimetazidine on forearm skeletal muscle in patients with type 2 diabetes and ischemic cardiomyopathy

Abstract

. Metabolic and endothelial effects of trimetazidine on forearm skeletal muscle in patients with type 2 diabetes and ischemic cardiomyopathy. Am J Physiol Endocrinol Metab 290: E54 -E59, 2006. First published September 20, 2005 doi:10.1152/ajpendo.00083.2005The aim of the present study was to evaluate the effect of prolonged inhibition of ␤-oxidation on glucose and lipid muscle forearm metabolism and cGMP and endothelin-1 forearm release in patients with type 2 diabetes mellitus and ischemic cardiomyopathy. Fifteen patients were randomly allocated in a double-blind cross-over parallel study with trimetazidine (20 mg tid) or placebo lasting 15 days. At the end of each period, all patients underwent euglycemic hyperinsulinemic clamps with forearm indirect calorimetry and endothelial balance of vasodilator and vasoconstricor factors. Compared with placebo, trimetazidine induced 1) an increase in insulin-induced forearm glucose uptake and glucose oxidation accompained by a reduction in forearm lipid oxidation and citrate release and 2) a decrease of endothelin-1 release paralleled by a significant increase in forearm cGMP release. Forearm glucose oxidation significantly correlated with cGMP release (r ϭ 0.37, P Ͻ 0.04), whereas forearm lipid oxidation positively correlated with endothelin-1 release (r ϭ 0.40, P Ͻ 0.03). In conclusion, for the first time, we demonstrated that insulin-induced forearm glucose oxidation and forearm cGMP release were increased whereas forearm endothelin-1 release was decreased during trimetazidine treatment. Muscle's metabolic and vascular effects of trimetazidine add new interest in the use of trimetazidine in type 2 diabetic patients with cardiovascular disease. endothelium; insulin resistance INSULIN RESISTANCE CHARACTERIZES type 2 diabetes. The impairment in insulin action in type 2 diabetes is multifaceted and has been found in both cardiac and skeletal muscle (29). Nuutila et al. (22) demonstrated that heart and arm skeletal muscle glucose uptakes are inversely related to serum free fatty acid (FFA) levels and increased FFA flux from adipose tissue to nonadipose tissue, resulting from abnormalities of fat metabolism, and participates in and amplifies many of the fundamental metabolic derangements that are characteristic of the insulin resistance syndrome and type 2 diabetes (17).In addition, new and interesting findings suggest that raised FFA levels not only impair glucose uptake in heart and skeletal muscle but also cause alterations in the metabolism of vascular endothelium, leading to premature cardiovascular disease (31).

Trimetazidine, a Metabolic Modulator, Has Cardiac and Extracardiac Benefits in Idiopathic Dilated Cardiomyopathy

“…47 Furthermore, improvement in whole-body insulin sensitivity by trimetazidine is accompanied by a metabolic shift from FFA to glucose oxidation in skeletal muscle during euglycemic hyperinsulinemia in diabetic HF patients. 48 Overall, we postulate that such extracardiac metabolic changes may indirectly improve myocardial glucose metabolism and glycolysis, amplifying the effects mediated by the modest decrease in FFA oxidation observed in the cardiac tissue. Of note, the substrate shift should not be drastic because excess rapid deprivation of FFA is potentially harmful in HF, as shown in our previous study, 8 whereas modest FFA inhibition, together with increased insulin sensitivity, as in the present study, appears more physiological and beneficial.…”

Human obesity is characterized by defective fat storage and enhanced muscle fatty acid oxidation, and trimetazidine gradually counteracts these abnormalities

“…The long-term metabolic effects of the partial inhibitor of ␤-oxidation trimetazidine were studied in a drug-naïve human model of moderately obese subjects in whom the still flexible stage of the disease is characterized by an increased FAO, and we performed all measurements during fasting to avoid the confounding suppressive effects of insulin on FA metabolism. One previous study, in which the modulation of FA and glucose metabolism by trimetazidine was simultaneously investigated in humans in an organ different from the myocardium (25) in diabetic patients with cardiomyopathy, showed that forearm lipid and glucose oxidation were reciprocally modulated during the insulin-stimulated state, but no changes occurred during the fasting state despite the higher FA turnover typical of fasting vs. insulin-stimulated conditions. Our present study extends previous findings in several regards, since 1) our human model discounts for the confounding actions of disease and multiple medications; 2) we prolonged the treatment period to 1 mo (vs. 15 days); 3) we adopted imaging techniques for the assessment of regional metabolism, thus targeting skeletal muscle and adipose tissue separately; and 4) by combining plasma tracer kinetics and indirect calorimetry, we estimated endogenous glucose production, hepatic insulin sensitivity, and whole body FA release and oxidation.…”

“…In cardiomyopathic patients with type 2 diabetes, trimetazidine has been shown to improve systemic glucose metabolism, as reflected by a reduction in fasting glycemia and an increase in forearm and whole body glucose uptake during hyperinsulinemic euglycemia (8). The effects on forearm lipid metabolism were investigated only in the short term (15 days), demonstrating a downregulation in lipid oxidation during insulin stimulation (25). The effects of trimetazidine on adipose tissue metabolism and adipokine secretion have not been investigated despite the dominant role played by this organ in the regulation of systemic FA disposal, and production of a variety of hormones and proinflammatory cytokines affecting insulin action, lipolysis, and oxidative stress (45).…”

Metabolic Modulators to Treat Cardiac Arrhythmias Induced by Ischemia and Reperfusion

“…These results suggest that trimetazidine is a useful adjunct to the current treatments for the patients with ischemic cardiomyopathy (Bertomeu-Gonzalez et al, 2006). Muscle's metabolic and vascular effects of trimetazidine add new interest in the use of trimetazidine in type 2 diabetic patients with ischemic cardiomyopathy (Monti et al, 2006). It has shown improvement in LV function, symptoms, glucose metabolism and endothelial function in such patients (Bhandari & Subramanian, 2007).…”