Acylcarnitines: reflecting or inflicting insulin resistance?

The incidence of obesity and insulin resistance is growing, and the increase in type 2 diabetes mellitus (DM2) constitutes one of the biggest challenges for our healthcare systems. Many theories are proposed for the induction of insulin resistance in glucose and lipid metabolism and its metabolic sequelae. One of these mechanisms is lipotoxicity (1–4): excess lipid supply and subsequent lipid accumulation in insulin-sensitive tissues such as skeletal muscle interfere with insulin-responsive metabolic pathways. Various lipid intermediates, like ceramides, gangliosides, diacylglycerol, and other metabolites, have been held responsible for insulin resistance (2,3,5–10). These intermediates can exert such effects because they are signaling molecules and building blocks of cellular membranes, which harbor the insulin receptor. In addition, lipids play an important role in energy homeostasis. Fatty acids (FA) can be metabolized via mitochondrial FA oxidation (FAO), which yields energy (11). As such, FAO competes with glucose oxidation in a process known as the glucose-FA, or Randle, cycle (12). Muoio and colleagues (1,13,14) proposed an alternative mechanism in which FAO rate outpaces the tricarboxylic acid cycle (TCA), thereby leading to the accumulation of intermediary metabolites such as acylcarnitines that may interfere with insulin sensitivity. This accumulation of acylcarnitines corroborates with some human studies showing that acylcarnitines are associated with insulin resistance (15–17). In addition, acylcarnitines have a long history in the diagnosis and neonatal screening of FAO defects and other inborn errors of metabolism (18). This knowledge may aid to understand the interaction between FAO and insulin resistance and fuel future research. In this review, we discuss the role of acylcarnitines in FAO and insulin resistance as emerging from animal and human studies. ### Carnitine biosynthesis and regulation of tissue carnitine content. To guarantee continuous energy supply, the human body oxidizes considerable amounts of fat besides glucose. …

[1]  R. Haller,et al.  Dynamic monitoring of carnitine and acetylcarnitine in the trimethylamine signal after exercise in human skeletal muscle by 7T 1H‐MRS , 2013, Magnetic resonance in medicine.

[2]  M. Westerterp-Plantenga,et al.  Augmenting muscle diacylglycerol and triacylglycerol content by blocking fatty acid oxidation does not impede insulin sensitivity , 2012, Proceedings of the National Academy of Sciences.

[3]  R. Wanders,et al.  Characterization of D-3-hydroxybutyrylcarnitine (ketocarnitine): an identified ketosis-induced metabolite. , 2012, Metabolism: clinical and experimental.

[4]  E. Ravussin,et al.  Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility. , 2012, Cell metabolism.

[5]  P. Neufer,et al.  Lipid-induced mitochondrial stress and insulin action in muscle. , 2012, Cell metabolism.

[6]  G. Shulman,et al.  Mechanisms for Insulin Resistance: Common Threads and Missing Links , 2012, Cell.

[7]  E. Parks,et al.  Postprandial changes in plasma acylcarnitine concentrations as markers of fatty acid flux in overweight and obesity. , 2012, Metabolism: clinical and experimental.

[8]  C. Gieger,et al.  Human metabolic individuality in biomedical and pharmaceutical research , 2011, Nature.

[9]  V. Mootha,et al.  Metabolite profiles and the risk of developing diabetes , 2011, Nature Medicine.

[10]  N. Fukagawa,et al.  Short‐Term Effects of Dietary Fatty Acids on Muscle Lipid Composition and Serum Acylcarnitine Profile in Human Subjects , 2011, Obesity.

[11]  W. Kraus,et al.  Effect of Caloric Restriction with and without Exercise on Metabolic Intermediates in Nonobese Men and Women. , 2011, Endocrinology.

[12]  Oliver Fiehn,et al.  Plasma Metabolomic Profiles Reflective of Glucose Homeostasis in Non-Diabetic and Type 2 Diabetic Obese African-American Women , 2010, PloS one.

[13]  W. Kraus,et al.  Exercise-Induced Changes in Metabolic Intermediates, Hormones, and Inflammatory Markers Associated With Improvements in Insulin Sensitivity , 2010, Diabetes Care.

[14]  F. Toledo,et al.  Increased Levels of Plasma Acylcarnitines in Obesity and Type 2 Diabetes and Identification of a Marker of Glucolipotoxicity , 2010, Obesity.

[15]  N. M. van den Broek,et al.  Increased mitochondrial content rescues in vivo muscle oxidative capacity in long‐term high‐fat‐diet‐fed rats , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[16]  Ruth C. R. Meex,et al.  Restoration of Muscle Mitochondrial Function and Metabolic Flexibility in Type 2 Diabetes by Exercise Training Is Paralleled by Increased Myocellular Fat Storage and Improved Insulin Sensitivity , 2009, Diabetes.

[17]  Louis Hue,et al.  The Randle cycle revisited: a new head for an old hat. , 2009, American journal of physiology. Endocrinology and metabolism.

[18]  O. Ilkayeva,et al.  Carnitine Insufficiency Caused by Aging and Overnutrition Compromises Mitochondrial Performance and Metabolic Control* , 2009, The Journal of Biological Chemistry.

[19]  William E. Kraus,et al.  Relationships Between Circulating Metabolic Intermediates and Insulin Action in Overweight to Obese, Inactive Men and Women , 2009, Diabetes Care.

[20]  C. Hoppel,et al.  Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women. , 2009, The Journal of nutrition.

[21]  Svati H Shah,et al.  A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. , 2009, Cell metabolism.

[22]  Geoffrey S Ginsburg,et al.  High heritability of metabolomic profiles in families burdened with premature cardiovascular disease , 2009, Molecular systems biology.

[23]  E. Fliers,et al.  Muscle acylcarnitines during short-term fasting in lean healthy men. , 2009, Clinical science.

[24]  J. Castle,et al.  ACC2 Is Expressed at High Levels Human White Adipose and Has an Isoform with a Novel N-Terminus , 2009, PloS one.

[25]  C. Hoppel,et al.  Quantification of carnitine and acylcarnitines in biological matrices by HPLC electrospray ionization-mass spectrometry. , 2008, Clinical chemistry.

[26]  N. Casals,et al.  CPT1c Is Localized in Endoplasmic Reticulum of Neurons and Has Carnitine Palmitoyltransferase Activity* , 2008, Journal of Biological Chemistry.

[27]  Piero Rinaldo,et al.  Acylcarnitine profile analysis , 2008, Genetics in Medicine.

[28]  Olga Ilkayeva,et al.  Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. , 2008, Cell metabolism.

[29]  D. Muoio,et al.  Lipid-induced metabolic dysfunction in skeletal muscle. , 2007, Novartis Foundation symposium.

[30]  I. Macdonald,et al.  Elevated free fatty acids attenuate the insulin-induced suppression of PDK4 gene expression in human skeletal muscle: potential role of intramuscular long-chain acyl-coenzyme A. , 2007, The Journal of clinical endocrinology and metabolism.

[31]  S. Ferdinandusse,et al.  PPAR alpha-activation results in enhanced carnitine biosynthesis and OCTN2-mediated hepatic carnitine accumulation. , 2007, Biochimica et biophysica acta.

[32]  K. Hoehn,et al.  Lipid mediators of insulin resistance. , 2007, Nutrition reviews.

[33]  R. Mahdavi,et al.  Determination of free L-carnitine levels in type II diabetic women with and without complications , 2007, European Journal of Clinical Nutrition.

[34]  R. Power,et al.  Carnitine revisited: potential use as adjunctive treatment in diabetes , 2007, Diabetologia.

[35]  F. Stephens,et al.  A threshold exists for the stimulatory effect of insulin on plasma L-carnitine clearance in humans. , 2007, American journal of physiology. Endocrinology and metabolism.

[36]  F. Stephens,et al.  An acute increase in skeletal muscle carnitine content alters fuel metabolism in resting human skeletal muscle. , 2006, The Journal of clinical endocrinology and metabolism.

[37]  K. Petersen,et al.  Molecular Mechanisms of Insulin Resistance in Humans and Their Potential Links With Mitochondrial Dysfunction , 2006, Diabetes.

[38]  G. Heigenhauser,et al.  Endurance training in obese humans improves glucose tolerance and mitochondrial fatty acid oxidation and alters muscle lipid content. , 2006, American journal of physiology. Endocrinology and metabolism.

[39]  A. Bonen,et al.  Identification of fatty acid translocase on human skeletal muscle mitochondrial membranes: essential role in fatty acid oxidation. , 2006, American journal of physiology. Endocrinology and metabolism.

[40]  F. Stephens,et al.  Insulin stimulates L‐carnitine accumulation in human skeletal muscle , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[41]  Ping Li,et al.  Peroxisome Proliferator-activated Receptor-γ Co-activator 1α-mediated Metabolic Remodeling of Skeletal Myocytes Mimics Exercise Training and Reverses Lipid-induced Mitochondrial Inefficiency* , 2005, Journal of Biological Chemistry.

[42]  David Millington,et al.  Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance , 2004, Nature Medicine.

[43]  K. Petersen,et al.  Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. , 2004, The New England journal of medicine.

[44]  L. Pochini,et al.  Reconstitution into liposomes and functional characterization of the carnitine transporter from renal cell plasma membrane. , 2004, Biochimica et biophysica acta.

[45]  D. Chace,et al.  Use of tandem mass spectrometry for multianalyte screening of dried blood specimens from newborns. , 2003, Clinical chemistry.

[46]  M. Daly,et al.  PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes , 2003, Nature Genetics.

[47]  A. Butte,et al.  Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[48]  W. Pories,et al.  Effect of weight loss on muscle lipid content in morbidly obese subjects. , 2003, American journal of physiology. Endocrinology and metabolism.

[49]  T. Ethofer,et al.  Validation of an ESI-MS/MS screening method for acylcarnitine profiling in urine specimens of neonates, children, adolescents and adults. , 2003, Clinica chimica acta; international journal of clinical chemistry.

[50]  R. Duclos,et al.  Interactions of acyl carnitines with model membranes DOI 10.1194/jlr.M200137-JLR200 , 2002, Journal of Lipid Research.

[51]  S. Eaton.  Control of mitochondrial beta-oxidation flux. , 2002, Progress in lipid research.

[52]  S. Eaton,et al.  Carnitine palmitoyl transferase I and the control of myocardial beta-oxidation flux. , 2001, Biochemical Society transactions.

[53]  F. R. van der Leij,et al.  Molecular enzymology of carnitine transfer and transport. , 2001, Biochimica et biophysica acta.

[54]  J. McGarry,et al.  Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats. , 2001, Diabetes.

[55]  G. Dohm,et al.  Lipid oxidation is reduced in obese human skeletal muscle. , 2000, American journal of physiology. Endocrinology and metabolism.

[56]  Simon C Watkins,et al.  Intramuscular lipid content is increased in obesity and decreased by weight loss. , 2000, Metabolism: clinical and experimental.

[57]  G. Shulman,et al.  On Diabetes: Insulin Resistance Cellular Mechanisms of Insulin Resistance , 2022 .

[58]  V. Zammit.  The malonyl-CoA-long-chain acyl-CoA axis in the maintenance of mammalian cell function. , 1999, The Biochemical journal.

[59]  M. Durán,et al.  Dynamic Changes of Plasma Acylcarnitine Levels Induced by Fasting and Sunflower Oil Challenge Test in Children , 1999, Pediatric Research.

[60]  Y. Siliğ,et al.  Carnitine deficiency in diabetes mellitus complications. , 1999, Journal of diabetes and its complications.

[61]  Demetrios Vavvas,et al.  Malonyl-CoA, fuel sensing, and insulin resistance. , 1999, American journal of physiology. Endocrinology and metabolism.

[62]  L. DiPietro,et al.  Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study , 1999, Diabetologia.

[63]  Yi-Chun Lu,et al.  Co-regulation of Tissue-specific Alternative Human Carnitine Palmitoyltransferase Iβ Gene Promoters by Fatty Acid Enzyme Substrate* , 1998, The Journal of Biological Chemistry.

[64]  D. Kelly,et al.  Fatty Acids Activate Transcription of the Muscle Carnitine Palmitoyltransferase I Gene in Cardiac Myocytes via the Peroxisome Proliferator-activated Receptor α* , 1998, The Journal of Biological Chemistry.

[65]  F. Hegardt,et al.  Control of Human Muscle-type Carnitine Palmitoyltransferase I Gene Transcription by Peroxisome Proliferator-activated Receptor* , 1998, The Journal of Biological Chemistry.

[66]  P. Ebeling,et al.  The association of acetyl-L-carnitine with glucose and lipid metabolism in human muscle in vivo: the effect of hyperinsulinemia. , 1997, Metabolism: clinical and experimental.

[67]  S. Lillioja,et al.  Skeletal Muscle Triglyceride Levels Are Inversely Related to Insulin Action , 1997, Diabetes.

[68]  V. Zammit,et al.  Flux control exerted by mitochondrial outer membrane carnitine palmitoyltransferase over beta-oxidation, ketogenesis and tricarboxylic acid cycle activity in hepatocytes isolated from rats in different metabolic states. , 1996, The Biochemical journal.

[69]  G. Lopaschuk,et al.  Regulation of fatty acid oxidation in the mammalian heart in health and disease. , 1994, Biochimica et biophysica acta.

[70]  C H Suelter,et al.  Quantitation of the efflux of acylcarnitines from rat heart, brain, and liver mitochondria. , 1986, The Journal of biological chemistry.

[71]  R. Chalmers,et al.  Urinary Excretion of l-Carnitine and Acylcarnitines by Patients with Disorders of Organic Acid Metabolism: Evidence for Secondary Insufficiency of l-Carnitine , 1984, Pediatric Research.

[72]  A. Delucia,et al.  Carnitine metabolism in Macaca arctoides: the effects of dietary change and fasting on serum triglycerides, unesterified carnitine, esterified (acyl) carnitine, and beta-hydroxybutyrate. , 1982, American Journal of Clinical Nutrition.

[73]  A. Bach.  [Carnitine biosynthesis in mammals]. , 1982, Reproduction, nutrition, developpement.

[74]  S. Genuth,et al.  Carnitine metabolism in normal-weight and obese human subjects during fasting. , 1980, The American journal of physiology.

[75]  J. McGarry,et al.  A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. , 1977, The Journal of clinical investigation.