The Regulation of Energy Metabolism Pathways Through L-Carnitine Homeostasis

Diabetes mellitus is a widespread metabolic disease characterized by hyperglycemia and associated with severe complications, including cardiovascular disease and dyslipidemia. The cardiovascular risk is considerably increased in diabetic patients, and novel cardioprotective strategies are sought that could target both diabetic and cardiovascular outcomes. L-carnitine is a conditionally essential amino acid that plays an important role in cellular energy metabolism. Initial pharmacological studies suggest that preconditioninglike manipulation of substrate metabolism through the regulation of L-carnitine homeostasis could be an effective approach for the prevention of myocardial infarction and the treatment of heart failure, especially for patients with type 2 diabetes. Contradictory data exist concerning the pharmacological outcomes of L-carnitine treatment. It is known that Lcarnitine supplementation is beneficial and increases overall glucose utilisation in animals and humans. Interestingly, a state of limited L-carnitine availability also induces compensatory mechanisms that alter the pathways of energy metabolism. In some experimental studies, a decrease in L-carnitine concentration was achieved by the administration of 3-(2,2,2trimethylhydrazinium)-propionate (mildronate). In addition to its cardioprotective and antiatherosclerotic effects, it was shown recently that mildronate, by decreasing L-carnitine concentration, decreases fed and fasted blood glucose concentrations and prevents diabetic complications in an experimental model of type 2 diabetes, Goto-Kakizaki (GK) rats, and an obesity model using Zucker rats. Recently presented mildronate-induced gene expression profiles suggest the peroxisome proliferator-activated receptors (PPARs) as possible nuclear factors underlying the effects of mildronate and decreased L-carnitine availability on FA metabolism. The effects of mildronate might depend on dosing and the length of treatment, which could differentially compensate for the decreased L-carnitine availability and thereby inhibit FA metabolism by activating glucose utilisation. Thus, it is possible that a limited availability of tissue L-carnitine might improve the metabolic flexibility of muscle tissues and enhance the preconditioning-like adaptive responses.