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L-Carnitine Consumption, Its Metabolism by Intestinal Microbiota, and Cardiovascular Health

      In early April 2013, Koeth et al
      • Koeth R.A.
      • Wang Z.
      • Levison B.S.
      • et al.
      Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis.
      published in Nature Medicine an original article providing evidence that ingested L-carnitine can encourage the growth of intestinal microbiota capable of converting carnitine to trimethylamine; the latter compound, on absorption, can be oxidized in the liver to trimethylamine-N-oxide (TMAO), which the authors suggested was likely to be a key mediator of the adverse impact of red meat–rich diets on human vascular health. This report immediately gained attention in the nation’s media. For example, Koeth et al’s research was a highlighted story on the CBS Evening News With Scott Pelley on the evening of Friday, April 5, 2013, and by Sunday, April 7, Gina Kolata of the New York Times had cited this research in an article questioning the safety of carnitine.
      Within days of this report, Mayo Clinic Proceedings electronically published ahead of print a meta-analysis by DiNicolantonio et al
      • DiNicolantonio J.J.
      • Lavie C.J.
      • Fares H.
      • Menezes A.R.
      • O'Keefe J.H.
      L-Carnitine in the secondary prevention of cardiovascular disease: systematic review and meta-analysis.
      of 13 placebo-controlled clinical trials enrolling 3629 patients that had evaluated the clinical impact of L-carnitine administration (as a supplement, not in red meat) in patients who had previously experienced a myocardial infarction. This meta-analysis concluded that carnitine administration was associated with clinical benefit: decreased mortality and reduced onset of cardiac arrhythmias and angina.
      • DiNicolantonio J.J.
      • Lavie C.J.
      • Fares H.
      • Menezes A.R.
      • O'Keefe J.H.
      L-Carnitine in the secondary prevention of cardiovascular disease: systematic review and meta-analysis.
      The journal also issued a press release noting the findings of DiNicolantonio et al and their relevance to the report by Koeth et al. Other media sources seized on the seeming inconsistency of these reports, with websites such as Forbes.com, hearthealth.com, and junkscience.com offering commentary. This second wave of media reports was followed shortly thereafter by many hundreds of media stories on one or both of the L-carnitine studies.
      In publications focusing on choline, which, similar to carnitine, can be converted to trimethylamine by intestinal microbiota, Koeth and his colleagues
      • Wang Z.
      • Klipfell E.
      • Bennett B.J.
      • et al.
      Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.
      • Tang W.H.
      • Wang Z.
      • Levison B.S.
      • et al.
      Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk.
      have made a case that TMAO may be a mediating risk factor for atherosclerosis. They reported accelerated atherogenesis in genetically atheroma-prone mice fed high levels of TMAO and, more recently, they published a prospective epidemiologic study in which the highest quartile of plasma TMAO, compared with the bottom quartile, was associated with a 2.54-fold higher incidence of major cardiovascular events during 3-year follow-up.
      • Tang W.H.
      • Wang Z.
      • Levison B.S.
      • et al.
      Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk.
      This risk persisted after adjustment for (nondietary) traditional risk factors.
      However, it remains dubious whether ambient human levels of TMAO are mediators of atherogenesis. The plasma TMAO level achieved in the TMAO-fed mice averaged approximately 150 μM,
      • Wang Z.
      • Klipfell E.
      • Bennett B.J.
      • et al.
      Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.
      whereas the plasma TMAO level in the top quartile of patients in the epidemiologic analysis was 6.18 μM and higher; the median value of the whole group was 3.67 μM.
      • Tang W.H.
      • Wang Z.
      • Levison B.S.
      • et al.
      Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk.
      Hence, the values of TMAO achieved in the TMAO-fed mice were at least an order of magnitude higher than those occurring ambiently in humans. The TMAO could simply be functioning as a marker for habitual ingestion of foods rich in carnitine and choline, which include animal products such as red meat and eggs linked to increased vascular risk. Red meat is, by far, the richest dietary source of carnitine. Further, the chief sources of choline in the American diet, as assessed in the biethnic Atherosclerosis Risk in Communities study, are red meat, eggs, milk, and chicken.
      • Bidulescu A.
      • Chambless L.E.
      • Siega-Riz A.M.
      • Zeisel S.H.
      • Heiss G.
      Usual choline and betaine dietary intake and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study.
      Conversely, a low TMAO level could often be indicative of a predominantly plant-based diet.
      We should bear in mind the controversy regarding homocysteine and vascular health. The evident role of genetic homocystinuria in driving early atherogenesis led many to suspect that high-normal levels of homocysteine—about an order of magnitude lower than those in the genetic disorder—might be proatherogenic.
      • McCully K.S.
      Hyperhomocysteinemia and arteriosclerosis: historical perspectives.
      Epidemiologic evidence correlating high-normal homocysteine levels with increased vascular risk was largely consistent with this view.
      • Eikelboom J.W.
      • Lonn E.
      • Genest Jr., J.
      • Hankey G.
      • Yusuf S.
      Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence.
      However, the failure of subsequent clinical trials of homocysteine-lowering vitamin therapy to benefit cardiac health has demonstrated that a high-normal homocysteine level is not, in fact, a mediator of vascular risk; presumably, it is a marker for some other metabolic factor that is the true mediator of risk.
      • Albert C.M.
      • Cook N.R.
      • Gaziano J.M.
      • et al.
      Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial.
      The new reports regarding TMAO as a putative risk factor should be viewed in this context.
      Koeth et al’s discussion of carnitine and red meat omits a crucial consideration. Beefsteak contains no more than 350 mg of carnitine per pound, some minor fraction of which might be converted to TMAO after ingestion.
      • Rigault C.
      • Mazue F.
      • Bernard A.
      • Demarquoy J.
      • Le Borgne F.
      Changes in L-carnitine content of fish and meat during domestic cooking.
      In contrast, ocean fish contains approximately 1.7 g of preformed TMAO per pound; the TMAO content of deepwater fish is even higher.
      • Samerotte A.L.
      • Drazen J.C.
      • Brand G.L.
      • Seibel B.A.
      • Yancey P.H.
      Correlation of trimethylamine oxide and habitat depth within and among species of teleost fish: an analysis of causation.
      So, human exposure to TMAO will be approximately an order of magnitude higher from ingesting a given weight of fish than of beef; yet, as is well known, fish-rich diets are far more compatible with vascular health than those high in red meats. A pilot study published some years ago examined the impact of ingesting 46 different foods on urine levels of trimethylamine and TMAO and found that only fish and other sea products caused a significant increase.
      • Zhang A.Q.
      • Mitchell S.C.
      • Smith R.L.
      Dietary precursors of trimethylamine in man: a pilot study.
      The high content of TMAO in fish is not accidental; it functions as an osmolyte, likely helping fish to adapt to the pressure of ocean depths.
      • Samerotte A.L.
      • Drazen J.C.
      • Brand G.L.
      • Seibel B.A.
      • Yancey P.H.
      Correlation of trimethylamine oxide and habitat depth within and among species of teleost fish: an analysis of causation.
      The “fishy” odor of spoiled fish results from the bacterial reduction of TMAO to trimethylamine.
      • Barrett E.L.
      • Kwan H.S.
      Bacterial reduction of trimethylamine oxide.
      Curiously, people whose capacity for hepatic oxidation of trimethylamine is genetically impaired are prone to a “fish odor syndrome” when they ingest foods or supplements that can give rise to trimethylamine, including carnitine.
      • Rehman H.U.
      Fish odor syndrome.
      • Rocher F.
      • Caruba C.
      • Broly F.
      • Lebrun C.
      L-Carnitine treatment and fish odor syndrome: an unwaited adverse effect.
      Although these considerations do not entirely exonerate TMAO as a possible mediator of cardiovascular risk, they certainly call into question the magnitude of its impact in this regard at least in the concentrations achieved with natural diets, and they render absurd the contention that the vascular toxicity of red meat is largely mediated by TMAO. Those who genuinely believe that TMAO is an important driver of human vascular risk must necessarily recommend that fish consumption be abandoned in favor of fish oil capsules, a straightforward deduction that was notably missing in the media commentary regarding TMAO. A further conclusion is that in populations in which fish consumption is common, an elevated plasma TMAO level will often be a marker for ingestion of “heart healthy” fish, and, hence, TMAO may correlate poorly with vascular risk.
      To buttress their contention that dietary carnitine can be proatherogenic, Koeth et al
      • Koeth R.A.
      • Wang Z.
      • Levison B.S.
      • et al.
      Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis.
      reported that carnitine feeding could induce atheroma in atheroma-prone mice. In this study, they gave the mice 1.3% carnitine in their drinking water.
      • Koeth R.A.
      • Wang Z.
      • Levison B.S.
      • et al.
      Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis.
      In a human drinking 2 L of fluid daily, that would be equivalent to an intake of 26 g of carnitine daily, an order of magnitude higher than the recommended supplemental intake (2-4 g daily in most published clinical trials) and approximately two orders of magnitude higher than the amount that would be achieved from average omnivore diets. Koeth et al did not cite the two previously published studies in which supplemental carnitine or its propionyl ester was tested in animal models of atherogenesis. These studies reported that supplemental carnitine slowed or stopped the progression of atherosclerotic lesions in rabbits.
      • Spagnoli L.G.
      • Orlandi A.
      • Marino B.
      • Mauriello A.
      • De Angeles C.
      • Ramacci M.T.
      Propionyl-L-carnitine prevents the progression of atherosclerotic lesions in aged hyperlipemic rabbits.
      • Sayed-Ahmed M.M.
      • Khattab M.M.
      • Gad M.Z.
      • Mostafa N.
      L-Carnitine prevents the progression of atherosclerotic lesions in hypercholesterolaemic rabbits.
      Notably, these studies used more clinically pertinent doses of carnitine. It is entirely possible that these 2 seemingly opposite conclusions are reconcilable; optimal tissue concentrations of carnitine may indeed be anti-atherogenic–via favorable effects on endothelial function and by limiting cholesterol esterification in foam cells
      • Shankar S.S.
      • Mirzamohammadi B.
      • Walsh J.P.
      • Steinberg H.O.
      L-Carnitine may attenuate free fatty acid-induced endothelial dysfunction.
      • Bueno R.
      • Alvarez de Sotomayor M.
      • Perez-Guerrero C.
      • Gomez-Amores L.
      • Vazquez C.M.
      • Herrera M.D.
      L-carnitine and propionyl-L-carnitine improve endothelial dysfunction in spontaneously hypertensive rats: different participation of NO and COX-products.
      • Volek J.S.
      • Judelson D.A.
      • Silvestre R.
      • et al.
      Effects of carnitine supplementation on flow-mediated dilation and vascular inflammatory responses to a high-fat meal in healthy young adults.
      • De Marchi S.
      • Zecchetto S.
      • Rigoni A.
      • et al.
      Propionyl-L-carnitine improves endothelial function, microcirculation and pain management in critical limb ischemia.
      • Chinetti G.
      • Lestavel S.
      • Fruchart J.C.
      • Clavey V.
      • Staels B.
      Peroxisome proliferator-activated receptor alpha reduces cholesterol esterification in macrophages.
      –but at extreme levels of carnitine ingestion (ie, levels well beyond those achieved through a typical diet or even after routine ingestion of supplemental carnitine), very high production of TMAO may offset or counterbalance this protection.
      Numerous clinical studies have concluded that in patients with preexisting atherosclerosis, supplemental intake of carnitine or its esters can favorably impact angina, intermittent claudication, and congestive heart failure.
      • Cherchi A.
      • Lai C.
      • Onnis E.
      • et al.
      Propionyl carnitine in stable effort angina.
      • Cacciatore L.
      • Cerio R.
      • Ciarimboli M.
      • et al.
      The therapeutic effect of L-carnitine in patients with exercise-induced stable angina: a controlled study.
      • Brevetti G.
      • Chiariello M.
      • Ferulano G.
      • et al.
      Increases in walking distance in patients with peripheral vascular disease treated with L-carnitine: a double-blind, cross-over study.
      • Andreozzi G.M.
      Propionyl L-carnitine: intermittent claudication and peripheral arterial disease.
      • Anand I.
      • Chandrashekhan Y.
      • De Giuli F.
      • et al.
      Acute and chronic effects of propionyl-L-carnitine on the hemodynamics, exercise capacity, and hormones in patients with congestive heart failure.
      • Mancini M.
      • Rengo F.
      • Lingetti M.
      • Sorrentino G.P.
      • Nolfe G.
      Controlled study on the therapeutic efficacy of propionyl-L-carnitine in patients with congestive heart failure.
      • Arsenian M.A.
      Carnitine and its derivatives in cardiovascular disease.
      • Mingorance C.
      • Rodriguez-Rodriguez R.
      • Justo M.L.
      • Herrera M.D.
      • De Sotomayor M.A.
      Pharmacological effects and clinical applications of propionyl-L-carnitine.
      As noted previously herein, the recent meta-analysis by DiNicolantonio et al
      • DiNicolantonio J.J.
      • Lavie C.J.
      • Fares H.
      • Menezes A.R.
      • O'Keefe J.H.
      L-Carnitine in the secondary prevention of cardiovascular disease: systematic review and meta-analysis.
      published in the Proceedings concluded that supplemental carnitine is associated with decreased mortality and reduced onset of cardiac arrhythmias and angina in patients who have experienced myocardial infarction. Another meta-analysis confirmed that supplemental acetylcarnitine has a favorable effect on declining cognitive function in the elderly.
      • Montgomery S.A.
      • Thal L.J.
      • Amrein R.
      Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer's disease.
      In the fatigued elderly, supplemental carnitine can lessen physical and mental fatigue while decreasing body fat and increasing muscle mass.
      • Malaguarnera M.
      • Gargante M.P.
      • Cristaldi E.
      • et al.
      Acetyl L-carnitine (ALC) treatment in elderly patients with fatigue.
      • Malaguarnera M.
      • Cammalleri L.
      • Gargante M.P.
      • Vacante M.
      • Colonna V.
      • Motta M.
      L-Carnitine treatment reduces severity of physical and mental fatigue and increases cognitive functions in centenarians: a randomized and controlled clinical trial.
      Carnitine supplementation can modestly improve glycemic control and the lipid profile in individuals with type 2 diabetes.
      • Vidal-Casariego A.
      • Burgos-Pelaez R.
      • Martinez-Faedo C.
      • et al.
      Metabolic effects of L-carnitine on type 2 diabetes mellitus: systematic review and meta-analysis.
      Acetylcarnitine can increase the production of healthy mitochondria in aging animals by boosting peroxisome proliferator–activated receptor γ coactivator–1α activity, an effect that may be beneficial to bioenergetics and control of oxidative stress.
      • Pesce V.
      • Fracasso F.
      • Cassano P.
      • Lezza A.M.
      • Cantatore P.
      • Gadaleta M.N.
      Acetyl-L-carnitine supplementation to old rats partially reverts the age-related mitochondrial decay of soleus muscle by activating peroxisome proliferator-activated receptor γ coactivator-1α-dependent mitochondrial biogenesis.
      These varied benefits presumably reflect carnitine’s ability to transport and buffer fatty acyl and acetyl groups.
      Health experts generally acknowledge that the negative health impacts of diets rich in red meats are largely attributable to high intakes of saturated fat, heme iron, bioavailable phosphate, and carcinogens induced by cooking or interaction with nitrite preservatives. Ironically, in seeking to incriminate red meat’s carnitine content, Koeth et al may have pointed the finger at one of red meat’s few saving graces.
      The recent uncritical publicity given by the media to Koeth et al’s contentions will no doubt convince many people using supplemental carnitine, including many who were deriving genuine benefit from it, to discontinue it. This is deeply regrettable.

      Supplemental Online Material

      References

        • Koeth R.A.
        • Wang Z.
        • Levison B.S.
        • et al.
        Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis.
        Nat Med. 2013; 19: 576-585
        • DiNicolantonio J.J.
        • Lavie C.J.
        • Fares H.
        • Menezes A.R.
        • O'Keefe J.H.
        L-Carnitine in the secondary prevention of cardiovascular disease: systematic review and meta-analysis.
        Mayo Clin Proc. 2013; 88: 544-551
        • Wang Z.
        • Klipfell E.
        • Bennett B.J.
        • et al.
        Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.
        Nature. 2011; 472: 57-63
        • Tang W.H.
        • Wang Z.
        • Levison B.S.
        • et al.
        Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk.
        N Engl J Med. 2013; 368: 1575-1584
        • Bidulescu A.
        • Chambless L.E.
        • Siega-Riz A.M.
        • Zeisel S.H.
        • Heiss G.
        Usual choline and betaine dietary intake and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study.
        BMC Cardiovasc Disord. 2007; 7: 20
        • McCully K.S.
        Hyperhomocysteinemia and arteriosclerosis: historical perspectives.
        Clin Chem Lab Med. 2005; 43: 980-986
        • Eikelboom J.W.
        • Lonn E.
        • Genest Jr., J.
        • Hankey G.
        • Yusuf S.
        Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence.
        Ann Intern Med. 1999; 131: 363-375
        • Albert C.M.
        • Cook N.R.
        • Gaziano J.M.
        • et al.
        Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial.
        JAMA. 2008; 299: 2027-2036
        • Rigault C.
        • Mazue F.
        • Bernard A.
        • Demarquoy J.
        • Le Borgne F.
        Changes in L-carnitine content of fish and meat during domestic cooking.
        Meat Sci. 2008; 78: 331-335
        • Samerotte A.L.
        • Drazen J.C.
        • Brand G.L.
        • Seibel B.A.
        • Yancey P.H.
        Correlation of trimethylamine oxide and habitat depth within and among species of teleost fish: an analysis of causation.
        Physiol Biochem Zool. 2007; 80: 197-208
        • Zhang A.Q.
        • Mitchell S.C.
        • Smith R.L.
        Dietary precursors of trimethylamine in man: a pilot study.
        Food Chem Toxicol. 1999; 37: 515-520
        • Barrett E.L.
        • Kwan H.S.
        Bacterial reduction of trimethylamine oxide.
        Annu Rev Microbiol. 1985; 39: 131-149
        • Rehman H.U.
        Fish odor syndrome.
        Postgrad Med J. 1999; 75: 451-452
        • Rocher F.
        • Caruba C.
        • Broly F.
        • Lebrun C.
        L-Carnitine treatment and fish odor syndrome: an unwaited adverse effect.
        Rev Neurol (Paris). 2011; 167 ([in French]): 541-544
        • Spagnoli L.G.
        • Orlandi A.
        • Marino B.
        • Mauriello A.
        • De Angeles C.
        • Ramacci M.T.
        Propionyl-L-carnitine prevents the progression of atherosclerotic lesions in aged hyperlipemic rabbits.
        Atherosclerosis. 1995; 114: 29-44
        • Sayed-Ahmed M.M.
        • Khattab M.M.
        • Gad M.Z.
        • Mostafa N.
        L-Carnitine prevents the progression of atherosclerotic lesions in hypercholesterolaemic rabbits.
        Pharmacol Res. 2001; 44: 235-242
        • Shankar S.S.
        • Mirzamohammadi B.
        • Walsh J.P.
        • Steinberg H.O.
        L-Carnitine may attenuate free fatty acid-induced endothelial dysfunction.
        Ann N Y Acad Sci. 2004; 1033: 189-197
        • Bueno R.
        • Alvarez de Sotomayor M.
        • Perez-Guerrero C.
        • Gomez-Amores L.
        • Vazquez C.M.
        • Herrera M.D.
        L-carnitine and propionyl-L-carnitine improve endothelial dysfunction in spontaneously hypertensive rats: different participation of NO and COX-products.
        Life Sci. 2005; 77: 2082-2097
        • Volek J.S.
        • Judelson D.A.
        • Silvestre R.
        • et al.
        Effects of carnitine supplementation on flow-mediated dilation and vascular inflammatory responses to a high-fat meal in healthy young adults.
        Am J Cardiol. 2008; 102: 1413-1417
        • De Marchi S.
        • Zecchetto S.
        • Rigoni A.
        • et al.
        Propionyl-L-carnitine improves endothelial function, microcirculation and pain management in critical limb ischemia.
        Cardiovasc Drugs Ther. 2012; 26: 401-408
        • Chinetti G.
        • Lestavel S.
        • Fruchart J.C.
        • Clavey V.
        • Staels B.
        Peroxisome proliferator-activated receptor alpha reduces cholesterol esterification in macrophages.
        Circ Res. 2003; 92: 212-217
        • Cherchi A.
        • Lai C.
        • Onnis E.
        • et al.
        Propionyl carnitine in stable effort angina.
        Cardiovasc Drugs Ther. 1990; 4: 481-486
        • Cacciatore L.
        • Cerio R.
        • Ciarimboli M.
        • et al.
        The therapeutic effect of L-carnitine in patients with exercise-induced stable angina: a controlled study.
        Drugs Exp Clin Res. 1991; 17: 225-235
        • Brevetti G.
        • Chiariello M.
        • Ferulano G.
        • et al.
        Increases in walking distance in patients with peripheral vascular disease treated with L-carnitine: a double-blind, cross-over study.
        Circulation. 1988; 77: 767-773
        • Andreozzi G.M.
        Propionyl L-carnitine: intermittent claudication and peripheral arterial disease.
        Expert Opin Pharmacother. 2009; 10: 2697-2707
        • Anand I.
        • Chandrashekhan Y.
        • De Giuli F.
        • et al.
        Acute and chronic effects of propionyl-L-carnitine on the hemodynamics, exercise capacity, and hormones in patients with congestive heart failure.
        Cardiovasc Drugs Ther. 1998; 12: 291-299
        • Mancini M.
        • Rengo F.
        • Lingetti M.
        • Sorrentino G.P.
        • Nolfe G.
        Controlled study on the therapeutic efficacy of propionyl-L-carnitine in patients with congestive heart failure.
        Arzneimittelforschung. 1992; 42: 1101-1104
        • Arsenian M.A.
        Carnitine and its derivatives in cardiovascular disease.
        Prog Cardiovasc Dis. 1997; 40: 265-286
        • Mingorance C.
        • Rodriguez-Rodriguez R.
        • Justo M.L.
        • Herrera M.D.
        • De Sotomayor M.A.
        Pharmacological effects and clinical applications of propionyl-L-carnitine.
        Nutr Rev. 2011; 69: 279-290
        • Montgomery S.A.
        • Thal L.J.
        • Amrein R.
        Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer's disease.
        Int Clin Psychopharmacol. 2003; 18: 61-71
        • Malaguarnera M.
        • Gargante M.P.
        • Cristaldi E.
        • et al.
        Acetyl L-carnitine (ALC) treatment in elderly patients with fatigue.
        Arch Gerontol Geriatr. 2008; 46: 181-190
        • Malaguarnera M.
        • Cammalleri L.
        • Gargante M.P.
        • Vacante M.
        • Colonna V.
        • Motta M.
        L-Carnitine treatment reduces severity of physical and mental fatigue and increases cognitive functions in centenarians: a randomized and controlled clinical trial.
        Am J Clin Nutr. 2007; 86: 1738-1744
        • Vidal-Casariego A.
        • Burgos-Pelaez R.
        • Martinez-Faedo C.
        • et al.
        Metabolic effects of L-carnitine on type 2 diabetes mellitus: systematic review and meta-analysis.
        Exp Clin Endocrinol Diabetes. 2013; 121: 234-239
        • Pesce V.
        • Fracasso F.
        • Cassano P.
        • Lezza A.M.
        • Cantatore P.
        • Gadaleta M.N.
        Acetyl-L-carnitine supplementation to old rats partially reverts the age-related mitochondrial decay of soleus muscle by activating peroxisome proliferator-activated receptor γ coactivator-1α-dependent mitochondrial biogenesis.
        Rejuvenation Res. 2010; 13: 148-151