Risks and Benefits of Carnitine Supplementation in Diabetes

Abstract

L-carnitine is a very popular food supplement due to its safety profile, antioxidant-type activity and suggested effects on energy metabolism pathways. L-carnitine participates in both fatty acid transport pathways and the export of acetyl groups out of the mitochondria. However, contradictory data exist concerning the pharmacological outcomes of L-carnitine treatment in diabetes mellitus, which is a highly prevalent metabolic disease characterised by hyperglycemia and associated with severe complications, including cardiovascular disease and dyslipidemia. Recently, the L-carnitine-derived metabolites, acylcarnitines and trimethylamine-N-oxide, have been associated with increased cardio-metabolic risks. This review aims to highlight the possible risks and benefits of L-carnitine supplementation.

Key words

L-carnitine - diabetes - food supplement

• References

• 1 Gulewitsch W, Krimberg R. Zur Kenntnis der Extraktivstoffe der Muskeln. II. Mitteilung: Über das Carnitin. Zeitschrift für Physiologische Chemie 1905; 45: 5
• 2 Saper RB, Eisenberg DM, Phillips RS. Common dietary supplements for weight loss. Am Fam Physician 2004; 70: 1731-1738
• 3 Huang A, Owen K. Role of supplementary L-carnitine in exercise and exercise recovery. Med Sport Sci 2012; 59: 135-142
• 4 Koves TR, Ussher JR, Noland RC et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 2008; 7: 45-56
• 5 Kuhajda FP, Ronnett GV. Modulation of carnitine palmitoyltransferase-1 for the treatment of obesity. Curr Opin Investig Drugs 2007; 8: 312-317
• 6 Bremer J. Carnitine-metabolism and functions. Physiol Rev 1983; 63: 1420-1480
• 7 Stephens FB, Constantin-Teodosiu D, Greenhaff PL. New insights concerning the role of carnitine in the regulation of fuel metabolism in skeletal muscle. J Physiol 2007; 581: 431-444
• 8 Ramsay RR, Gandour RD, van der Leij FR. Molecular enzymology of carnitine transfer and transport. Biochim Biophys Acta 2001; 1546: 21-43
• 9 Lopaschuk GD. Optimizing cardiac energy metabolism: how can fatty acid and carbohydrate metabolism be manipulated?. Coron Artery Dis 2001; 12 (Suppl. 01) S8-S11
• 10 Rebouche CJ. Kinetics, pharmacokinetics, and regulation of L-carnitine and acetyl-L-carnitine metabolism. Ann N Y Acad Sci 2004; 1033: 30-41
• 11 Strijbis K, Vaz FM, Distel B. Enzymology of the carnitine biosynthesis pathway. IUBMB Life 2010; 62: 357-362
• 12 Liepinsh E, Konrade I, Skapare E et al. Mildronate treatment alters gamma-butyrobetaine and l-carnitine concentrations in healthy volunteers. J Pharm Pharmacol 2011; 63: 1195-1201
• 13 D’Argenio G, Petillo O, Margarucci S et al. Colon OCTN2 gene expression is up-regulated by peroxisome proliferator-activated receptor gamma in humans and mice and contributes to local and systemic carnitine homeostasis. J Biol Chem 2010; 285: 27078-27087
• 14 Koch A, Konig B, Luci S et al. Dietary oxidised fat up regulates the expression of organic cation transporters in liver and small intestine and alters carnitine concentrations in liver, muscle and plasma of rats. Br J Nutr 2007; 98: 882-889
• 15 Tamai I, China K, Sai Y et al. Na(+)-coupled transport of L-carnitine via high-affinity carnitine transporter OCTN2 and its subcellular localization in kidney. Biochim Biophys Acta 2001; 1512: 273-284
• 16 Brass EP. Pivalate-generating prodrugs and carnitine homeostasis in man. Pharmacol Rev 2002; 54: 589-598
• 17 Liepinsh E, Makrecka M, Kuka J et al. Selective inhibition of OCTN2 is more effective than inhibition of gamma-butyrobetaine dioxygenase to decrease the availability of l-carnitine and to reduce myocardial infarct size. Pharmacol Res 2014; 85: 33-38
• 18 Pochini L, Scalise M, Galluccio M et al. OCTN cation transporters in health and disease: role as drug targets and assay development. J Biomol Screen 2013; 18: 851-867
• 19 Bieber LL. Carnitine. Annu Rev Biochem 1988; 57: 261-283
• 20 Liepinsh E, Skapare E, Vavers E et al. High L-carnitine concentrations do not prevent late diabetic complications in type 1 and 2 diabetic patients. Nutr Res 2012; 32: 320-327
• 21 Hathcock JN, Shao A. Risk assessment for carnitine. Regul Toxicol Pharmacol 2006; 46: 23-28
• 22 Pregant P, Schernthaner G, Legenstein E et al. Decreased plasma carnitine in Type I diabetes mellitus. Klin Wochenschr 1991; 69: 511-516
• 23 Soltesz G, Melegh B, Sandor A. The relationship between carnitine and ketone body levels in diabetic children. Acta Paediatr Scand 1983; 72: 511-515
• 24 Winter SC, Simon M, Zorn EM et al. Relative carnitine insufficiency in children with type I diabetes mellitus. Am J Dis Child 1989; 143: 1337-1339
• 25 Poorabbas A, Fallah F, Bagdadchi J et al. Determination of free L-carnitine levels in type II diabetic women with and without complications. Eur J Clin Nutr 2007; 61: 892-895
• 26 Tamamogullari N, Silig Y, Icagasioglu S et al. Carnitine deficiency in diabetes mellitus complications. J Diabetes Complications 1999; 13: 251-253
• 27 Okuda Y, Kawai K, Murayama Y et al. Postprandial changes in plasma ketone body and carnitine levels in normal and non-insulin-dependent diabetic subjects. Endocrinol Jpn 1987; 34: 415-422
• 28 Pregant P, Kaiser E, Schernthaner G. No effect of insulin treatment or glycemic improvement on plasma carnitine levels in type 2 diabetic patients. Clin Investig 1993; 71: 610-612
• 29 Jacobson JD, Midyett LK, Garg U et al. Biochemical Evidence for Reduced Carnitine Palmitoyl Transferase 1(CPT-1) Activity in Type 1 Diabetes Mellitus. Journal of Diabetes & Metabolism 2011; 02: 5
• 30 Stanley CA. Carnitine deficiency disorders in children. Ann N Y Acad Sci 2004; 1033: 42-51
• 31 Chen Y, Abbate M, Tang L et al. L-Carnitine supplementation for adults with end-stage kidney disease requiring maintenance hemodialysis: a systematic review and meta-analysis. Am J Clin Nutr 2014; 99: 408-422
• 32 Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila) 2009; 47: 101-111
• 33 Kerner W, Bruckel J. Definition, classification and diagnosis of diabetes mellitus. Exp Clin Endocrinol Diabetes 2014; 122: 384-386
• 34 Matteucci E, Giampietro O. Epidemiology of cardiovascular disease in patients with type 1 diabetes: European perspective. Exp Clin Endocrinol Diabetes 2014; 122: 208-214
• 35 Yang Z, Xing X, Xiao J et al. Prevalence of cardiovascular disease and risk factors in the Chinese population with impaired glucose regulation: the 2007–2008 China national diabetes and metabolic disorders study. Exp Clin Endocrinol Diabetes 2013; 121: 372-374
• 36 Capaldo B, Napoli R, Di Bonito P et al. Carnitine improves peripheral glucose disposal in non-insulin-dependent diabetic patients. Diabetes Res Clin Pract 1991; 14: 191-195
• 37 De Gaetano A, Mingrone G, Castagneto M et al. Carnitine increases glucose disposal in humans. J Am Coll Nutr 1999; 18: 289-295
• 38 Molfino A, Cascino A, Conte C et al. Caloric restriction and L-carnitine administration improves insulin sensitivity in patients with impaired glucose metabolism. JPEN J Parenter Enteral Nutr 2010; 34: 295-299
• 39 Vidal-Casariego A. The administration of L-carnitine in type 2 diabetes mellitus is associated with an improvement in glycaemia and plasma lipids. Exp Clin Endocrinol Diabetes 2013; 121: 5
• 40 Csiky B, Nyul Z, Toth G et al. L-carnitine supplementation and adipokines in patients with end-stage renal disease on regular hemodialysis. Exp Clin Endocrinol Diabetes 2010; 118: 735-740
• 41 Golbidi S, Ebadi SA, Laher I. Antioxidants in the treatment of diabetes. Curr Diabetes Rev 2011; 7: 106-125
• 42 Gonzalez-Ortiz M, Hernandez-Gonzalez SO, Hernandez-Salazar E et al. Effect of oral L-carnitine administration on insulin sensitivity and lipid profile in type 2 diabetes mellitus patients. Ann Nutr Metab 2008; 52: 335-338
• 43 Ringseis R, Keller J, Eder K. Role of carnitine in the regulation of glucose homeostasis and insulin sensitivity: evidence from in vivo and in vitro studies with carnitine supplementation and carnitine deficiency. Eur J Nutr 2012; 51: 1-18
• 44 Ferrari R, Merli E, Cicchitelli G et al. Therapeutic effects of L-carnitine and propionyl-L-carnitine on cardiovascular diseases: a review. Ann N Y Acad Sci 2004; 1033: 79-91
• 45 Cui J, Das DK, Bertelli A et al. Effects of L-carnitine and its derivatives on postischemic cardiac function, ventricular fibrillation and necrotic and apoptotic cardiomyocyte death in isolated rat hearts. Mol Cell Biochem 2003; 254: 227-234
• 46 Diaz R, Lorita J, Soley M et al. Carnitine worsens both injury and recovery of contractile function after transient ischemia in perfused rat heart. J Physiol Biochem 2008; 64: 1-8
• 47 Tarantini G, Scrutinio D, Bruzzi P et al. Metabolic treatment with L-carnitine in acute anterior ST segment elevation myocardial infarction. A randomized controlled trial. Cardiology 2006; 106: 215-223
• 48 Dinicolantonio JJ, Niazi AK, McCarty MF et al. L-carnitine for the treatment of acute myocardial infarction. Rev Cardiovasc Med 2014; 15: 52-62
• 49 DiNicolantonio JJ, Lavie CJ, Fares H et al. L-carnitine in the secondary prevention of cardiovascular disease: systematic review and meta-analysis. Mayo Clin Proc 2013; 88: 544-551
• 50 Shang R, Sun Z, Li H. Effective dosing of L-carnitine in the secondary prevention of cardiovascular disease: a systematic review and meta-analysis. BMC Cardiovasc Disord 2014; 14: 88
• 51 Makrecka M, Kuka J, Volska K et al. Long-chain acylcarnitine content determines the pattern of energy metabolism in cardiac mitochondria. Mol Cell Biochem 2014; 395: 1-10
• 52 Ashour B, Hansford RG. Effect of fatty acids and ketones on the activity of pyruvate dehydrogenase in skeletal-muscle mitochondria. Biochem J 1983; 214: 725-736
• 53 Hansford RG. Studies on inactivation of pyruvate dehydrogenase by palmitoylcarnitine oxidation in isolated rat heart mitochondria. J Biol Chem 1977; 252: 1552-1560
• 54 Smith SJ, Saggerson ED. Regulation of pyruvate dehydrogenase activity in white adipocyte mitochondria by palmitoyl carnitine and citrate. Int J Biochem 1979; 10: 785-790
• 55 Bell JA, Reed MA, Consitt LA et al. Lipid partitioning, incomplete fatty acid oxidation, and insulin signal transduction in primary human muscle cells: effects of severe obesity, fatty acid incubation, and fatty acid translocase/CD36 overexpression. J Clin Endocrinol Metab 2010; 95: 3400-3410
• 56 Koves TR, Li P, An J et al. Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency. J Biol Chem 2005; 280: 33588-33598
• 57 Muoio DM, Neufer PD. Lipid-induced mitochondrial stress and insulin action in muscle. Cell Metab 2012; 15: 595-605
• 58 Tominaga H, Katoh H, Odagiri K et al. Different effects of palmitoyl-L-carnitine and palmitoyl-CoA on mitochondrial function in rat ventricular myocytes. Am J Physiol Heart Circ Physiol 2008; 295: H105-H112
• 59 Abdul-Ghani MA, Muller FL, Liu Y et al. Deleterious action of FA metabolites on ATP synthesis: possible link between lipotoxicity, mitochondrial dysfunction, and insulin resistance. Am J Physiol Endocrinol Metab 2008; 295: E678-E685
• 60 Seifert EL, Estey C, Xuan JY et al. Electron transport chain-dependent and -independent mechanisms of mitochondrial H2O2 emission during long-chain fatty acid oxidation. J Biol Chem 2010; 285: 5748-5758
• 61 Shug AL, Thomsen JH, Folts JD et al. Changes in tissue levels of carnitine and other metabolites during myocardial ischemia and anoxia. Arch Biochem Biophys 1978; 187: 25-33
• 62 Clarke B, Wyatt KM, May GR et al. On the roles of long-chain acyl carnitine accumulation and impaired glucose utilization in ischaemic contracture development and tissue damage in the guinea-pig heart. J Mol Cell Cardiol 1996; 28: 171-181
• 63 Ford DA, Han X, Horner CC et al. Accumulation of unsaturated acylcarnitine molecular species during acute myocardial ischemia: metabolic compartmentalization of products of fatty acyl chain elongation in the acylcarnitine pool. Biochemistry 1996; 35: 7903-7909
• 64 Rutkowsky JM, Knotts TA, Ono-Moore KD et al. Acylcarnitines activate proinflammatory signaling pathways. Am J Physiol Endocrinol Metab 2014; 306: E1378-E1387
• 65 Bugger H, Abel ED. Mitochondria in the diabetic heart. Cardiovasc Res 2010; 88: 229-240
• 66 Martins AR, Nachbar RT, Gorjao R et al. Mechanisms underlying skeletal muscle insulin resistance induced by fatty acids: importance of the mitochondrial function. Lipids Health Dis 2012; 11: 30
• 67 Viscarra JA, Ortiz RM. Cellular mechanisms regulating fuel metabolism in mammals: role of adipose tissue and lipids during prolonged food deprivation. Metabolism 2013; 62: 889-897
• 68 Soeters MR, Sauerwein HP, Duran M et al. Muscle acylcarnitines during short-term fasting in lean healthy men. Clin Sci (Lond) 2009; 116: 585-592
• 69 Liepinsh E, Skapare E, Kuka J et al. Activated peroxisomal fatty acid metabolism improves cardiac recovery in ischemia-reperfusion. Naunyn Schmiedebergs Arch Pharmacol 2013; 386: 541-550
• 70 Liepinsh E, Vilskersts R, Zvejniece L et al. Protective effects of mildronate in an experimental model of type 2 diabetes in Goto-Kakizaki rats. Br J Pharmacol 2009; 157: 1549-1556
• 71 Koeth RA, Wang Z, Levison BS et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013; 19: 576-585
• 72 Wang Z, Tang WH, Buffa JA et al. Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. Eur Heart J 2014; 35: 904-910
• 73 Bain MA, Fornasini G, Evans AM. Trimethylamine: metabolic, pharmacokinetic and safety aspects. Curr Drug Metab 2005; 6: 227-240
• 74 Ussher JR, Lopaschuk GD, Arduini A. Gut microbiota metabolism of L-carnitine and cardiovascular risk. Atherosclerosis 2013; 231: 456-461
• 75 Li X, Chen Y, Liu J et al. Serum metabolic variables associated with impaired glucose tolerance induced by high-fat-high-cholesterol diet in Macaca mulatta. Exp Biol Med (Maywood) 2012; 237: 1310-1321
• 76 Gao X, Liu X, Xu J et al. Dietary trimethylamine N-oxide exacerbates impaired glucose tolerance in mice fed a high fat diet. J Biosci Bioeng 2014;
• 77 Wang Z, Klipfell E, Bennett BJ et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011; 472: 57-63