|ISSN No. 1606-7754 Vol.16 No.1 April 2008|
Beneficial effects of levo-carnitine on lipid metabolism and cardiac function in neonatal streptozotocin rat model of diabetes
Jigneshkumar Patel, Ramesh Goyal, Parloop Bhatt
Department of Pharmacology, L. M. College of Pharmacy, Ahmedabad, India.
Levo-carnitine (L-carnitine) facilitates the transport of long chain fatty acyl co-enzyme A (CoA) across the mitochondrial membrane for eventual oxidation and energy production. Carnitine deficiency results in free fatty acid accumulation and contributes to cardiovascular complications in experimental diabetes. In this condition, oral carnitine supplementation provides cardio-protection by its various metabolic effects. The beneficial effects of six weeks treatment with L-carnitine (600 mg/kg day orally) were studied in neonatal streptozotocin (STZ) diabetic rats. STZ (90 mg/kg) was administered to five day old rats and after fourteen weeks of STZ administration, the rats showed hyperglycemia, hyperinsulinemia, hypercholesterolemia, hypertriglyceridemia and associated cardiac defects like hypertension and bradycardia. L-carnitine treatment for six weeks after induction of diabetes and associated complications significantly lowered cholesterol and triglyceride levels and normalized blood pressure and heart rate; however the treatment was not found to produce beneficial effects against hyperglycemia and hyperinsulinemia in diabetic rats. The L-carnitine treatment may have fulfilled the carnitine deficiency and have improved the lipid metabolism and subsequently the cardiac function in diabetic rats. The study suggest that long term treatment with L-carnitine not only prevents but also partially reverses the diabetes-associated lipid metabolism and cardiac function abnormalities in neonatal STZ diabetic rats.
Key words: L-carnitine; Diabetes mellitus; Lipid metabolism
Diabetes mellitus is a syndrome characterized by altered metabolism of lipids, carbohydrates, proteins and an increased risk of cardiovascular diseases. Several investigators have observed heart dysfunctions in both diabetic patients and experimental animal models of chronic diabetes.1 One of the cardiac defects in diabetes is the inability of the diabetic heart to utilize glucose as an energy substrate2 and hence its exclusive dependence on fatty acids for energy production.3 Extensive studies have shown that different membrane systems such as sarcolemma, sarcoplasmic reticulum and mitochondria as well as myofibrillar proteins are altered in the diabetic heart.4 The depression of sarcoplasmic reticular calcium pump is associated with an increased concentration of long chain fatty acyl derivatives.5,6 Changes in phospholipids composition and increase in the cholesterol content in sarcolemma have also been reported in diabetic cardiomyopathy.7 The carbohydrate and lipid metabolism abnormalities and free fatty acid accumulation is found to be an important contributor of these cardiac defects in diabetes.5,6
L-carnitine is an amino acid found in all living tissues and plays a vital role in fatty acid metabolism as well as in regulating many bodily functions.8,9 It is a water-soluble nutrient mainly present in non-vegetarian diet like beef and pork. It is synthesized endogenously in the liver10 and plays an important role in fatty acid metabolism. It facilitates the transport of long chain fatty acyl co-enzyme (CoA) across the mitochondrial membrane for eventual oxidation and energy production.11,12
Heart and skeletal muscle normally cover most of their energy needs by fatty acid oxidation.13,14 More than 90% of the total carnitine in the body is found in skeletal muscle and heart. 95% of the carnitine in normal cardiac muscle is located in cytosol and 95% of CoA is in mitochondrial matrix.15 These distributions in normal hearts are likely to cause activated fatty acids to be funneled toward oxidation rather than toward lipid synthesis. Diabetes is a condition associated with myocardial carnitine deficiency and this has been demonstrated in chemically induced diabetic rats.16-21 Myocardial carnitine deficiency is one of the causes of cardiac defects in experimental diabetes21-23 and L-carnitine supplementation is beneficial for the treatment and prevention of diabetes associated metabolic and cardiac defects.20,24-32 In all these studies, two major beneficial effects of L-carnitine have been observed; one is the improvement in lipid metabolism and second is improvement in glucose metabolism. However, majority of these experimental studies were carried out using STZ induced type 1 diabetes in Wistar rats in which diabetes was induced by cytotoxic actions of STZ on beta cells of pancreas. The beneficial effects of acute short term treatment with large dose of L-carnitine have been demonstrated in diabetes with mild cardiac defects. Studies demonstrating the effects of long term supplementation with L-carnitine in diabetes with metabolic and profound cardiac defects are still in demand. Whether treatment with L-carnitine produces any long term beneficial effect even after well developed metabolic and cardiac defects in diabetes is still a question. As L-carnitine could serve as a cardio-protective agent in diabetes, studies on neonatal STZ diabetic rat model which more closely resemble the human type 2 diabetes with associated cardiac defects would be more interesting. Hence, we have carried out an experimental study to investigate the beneficial effects of long term treatment with L-carnitine in neonatal STZ diabetic rats.