final product of carnitine. The last of these 4 enzymes is gamma-butyrobetaine dioxygenase (GBB), which hydroxylates butyrobetaine into carnitine. The main cardioprotective effects of meldonium are mediated by the inhibition of GBB. By subsequently inhibiting carnitine biosynthesis, fatty acid transport is reduced and the accumulation of cytotoxic intermediate products of fatty acid beta-oxidation in ischemic tissues to produce energy is prevented, therefore blocking this highly oxygen-consuming process. Treatment with meldonium therefore shifts the myocardial energy metabolism from fatty acid oxidation to the more favorable oxidation of glucose, or glycolysis, under conditions where oxygen is limited. It also reduces the formation of trimethylamine N-oxide (TMAO), a product of carnitine breakdown that has been implicated in the pathogenesis of atherosclerosis and congestive heart failure. In fatty acid (FA) metabolism, long chain fatty acids in the cytosol cannot cross the mitochondrial membrane because they are negatively charged. The process in which they move into the mitochondria is called the carnitine shuttle. Long chain FA are first activated via esterification with coenzyme A to produce a fatty acid-coA complex which can then cross the external mitochondrial border. The co-A is then exchanged with carnitine (via the enzyme carnitine palmitoyltransferase I) to produce a fatty acid-carnitine complex. This complex is then transported through the inner mitochondrial membrane via a transporter protein called carnitine-acylcarnitine translocase. Once inside, carnitine is liberated (catalysed by the enzyme carnitine palmitoyltransferase II) and transported back outside so the process can occur again. Acylcarnitines like palmitoylcarnitine are produced as intermediate products of the carnitine shuttle. In the mitochondria themselves, meldonium also competitively inhibits the carnitine shuttle protein SLC22A5. This results in reduced transportation and metabolism of long-chain fatty acids in the mitochondria (this burden is shifted more to peroxisomes). The final effect is a decreased risk of mitochondrial injury from fatty acid oxidation and a reduction of the production of acylcarnitines, which has been implicated in the development of insulin resistance. Because of its inhibitory effects on L-carnitine biosynthesis and its subsequent glycolytic effects as well as reduced acylcarnitine production, meldonium has been indicated for use in diabetic patients. In animal models and a very small clinical trial, meldonium has been shown to reduce blood glucose concentrations, exhibit cardioprotective effects and prevent or reduce the severity of diabetic complications. Long-term treatment has also been shown to attenuate the development of atherosclerosis in the heart. Meldonium's vasodilatory effects are thought to be due