Carnitine revisited: potential use as adjunctive treatment in diabetes.
AIMS/HYPOTHESIS: This study examined the efficacy of supplemental L: -carnitine as an adjunctive diabetes therapy in mouse models of metabolic disease. We hypothesised that carnitine would facilitate fatty acid export from tissues in the form of acyl-carnitines, thereby alleviating lipid-induced insulin resistance. MATERIALS AND METHODS: Obese mice with genetic or diet-induced forms of insulin resistance were fed rodent chow +/- 0.5% L: -carnitine for a period of 1-8 weeks. Metabolic outcomes included insulin tolerance tests, indirect calorimetry and mass spectrometry-based profiling of acyl-carnitine esters in tissues and plasma. RESULTS: Carnitine supplementation improved insulin-stimulated glucose disposal in genetically diabetic mice and wild-type mice fed a high-fat diet, without altering body weight or food intake. In severely diabetic mice, carnitine supplementation increased average daily respiratory exchange ratio from 0.886 +/- 0.01 to 0.914 +/- 0.01 (p < 0.01), reflecting a marked increase in systemic carbohydrate oxidation. Similarly, under insulin-stimulated conditions, carbohydrate oxidation was higher and total energy expenditure increased from 172 +/- 10 to 210 +/- 9 kJ kg fat-free mass(-1) h(-1) in the carnitine-supplemented compared with control animals. These metabolic improvements corresponded with a 2.3-fold rise in circulating levels of acetyl-carnitine, which accounts for 86 and 88% of the total acyl-carnitine pool in plasma and skeletal muscle, respectively. Carnitine supplementation also increased several medium- and long-chain acyl-carnitine species in both plasma and tissues. CONCLUSIONS/INTERPRETATION: These findings suggest that carnitine supplementation relieves lipid overload and glucose intolerance in obese rodents by enhancing mitochondrial efflux of excess acyl groups from insulin-responsive tissues. Carefully controlled clinical trials should be considered.
Power, RA; Hulver, MW; Zhang, JY; Dubois, J; Marchand, RM; Ilkayeva, O; Muoio, DM; Mynatt, RL
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