Sphingolipids in Obesity, Type 2 Diabetes, and Metabolic Disease

Part of the Handbook of Experimental Pharmacology book series (HEP, volume 216)


Metabolic disease, including obesity and type 2 diabetes, constitutes a major emerging health crisis in Western nations. Although the symptoms and clinical pathology and physiology of these conditions are well understood, the molecular mechanisms underlying the disease process have largely remained obscure. Sphingolipids, a lipid class with both signaling and structural properties, have recently emerged as key players in most major tissues affected by diabetes and are required components in the molecular etiology of this disease. Indeed, sphingolipids have been shown to mediate loss of insulin sensitivity, to promote the characteristic diabetic proinflammatory state, and to induce cell death and dysfunction in important organs such as the pancreas and heart. Furthermore, plasma sphingolipid levels are emerging as potential biomarkers for the decompensation of insulin resistance to frank type 2 diabetes. Despite these discoveries, the roles of specific sphingolipid species and sphingolipid metabolic pathways remain obscure, and newly developed experimental approaches must be employed to elucidate the detailed molecular mechanisms necessary for rational drug development and other clinical applications.


lipotoxicity cardiomyopathy insulin resistance 



This work was supported by Grant Number F30DK092125 from the NIDDK (to S.B.R.), GAANN fellowship in Lipidomics and Systems Biology (to J.S.R), a Merit Award from the Department of Veterans Affairs (to L.A.C.), and the NIH COBRE in Lipidomics and Pathobiology at MUSC (to L.A.C.).


  1. Aerts JM, Ottenhoff R, Powlson AS, Grefhorst A, van Eijk M, Dubbelhuis PF, Aten J, Kuipers F, Serlie MJ, Wennekes T, Sethi JK, O’Rahilly S, Overkleeft HS (2007) Pharmacological inhibition of glucosylceramide synthase enhances insulin sensitivity. Diabetes 56(5):1341PubMedCrossRefGoogle Scholar
  2. Amati F, Dube J, Alvarez-Carnero E, Edreira M, Chomentowski P, Coen P, Switzer G, Bickel P, Stefanovic-Racic M, Toledo F, Goodpaster B (2011) Skeletal muscle triglycerides, diacylglycerides, and ceramids in insulin resistance: another paradox in endurance-trained athletes? Diabetes 60(10):2588–2597PubMedCrossRefGoogle Scholar
  3. Auge N, Maupas-Schwalm F, Elbaz M, Thiers J, Waysbort A, Itohara S, Krell H, Salvayre R, Negre-Salvayre A (2004) Role for matrix metalloproteinase-2 in oxidized low-density lipoprotein-induced activation of sphingomyelin/ceramide pathway and smooth muscle cell proliferation. Circulation 110:571–578PubMedCrossRefGoogle Scholar
  4. Banegas JR, Lopez-Garcia E, Graciani A, Guallar-Castillon P, Gutierrez-Fisac JL, Alonso J, Rodriguez-Artalejo F (2007) Relationship between obesity, hypertension and diabetes, and health-related quality of life among the elderly. Eur J Cardiovasc Prev Rehabil 14(3):456–462PubMedCrossRefGoogle Scholar
  5. Baranowski M, Blachnio A, Zabielski P, Gorski J (2007) PPARalpha agonist induces the accumulation of ceramide in the heart of rats fed high-fat diet. J Physiol Pharmacol 58(1):57PubMedGoogle Scholar
  6. Baricos W, Cortez-Schwartz S, Shah S (1986) Renal neuraminidase. Characterization in normal rat kidney and measurement in experimentally induced nephrotic syndrome. Biochem J 239(3):705–710PubMedGoogle Scholar
  7. Barouch LA, Gao D, Chen L, Miller KL, Xu W, Phan AC, Kittleson MM, Minhas KM, Berkowitz DE, Wei C, Hare JM (2006) Cardiac myocyte apoptosis is associated with increased DNA damage and decreased survival in murine models of obesity. Circ Res 98(1):119PubMedCrossRefGoogle Scholar
  8. Baskin M, Ard J, Franklin F, Allison D (2005) Prevalence of obesity in the United States. Obes Rev 6:5–7PubMedCrossRefGoogle Scholar
  9. Bevilacqua S, Bonadonna R, Buzzigoli G, Boni C, Ciociaro D, Maccari F, Giorico MA, Ferrannini E (1987) Acute elevation of free fatty acid levels leads to hepatic insulin resistance in obese subjects. Metabolism 36(5):502PubMedCrossRefGoogle Scholar
  10. Bielawska AE, Shapiro JP, Jiang L, Melkonyan HS, Piot C, Wolfe CL, Tomei LD, Hannun YA, Umansky SR (1997) Ceramide is involved in triggering of cardiomyocyte apoptosis induced by ischemia and reperfusion. Am J Pathol 151(5):1257PubMedGoogle Scholar
  11. Bielawski J, Pierce JS, Snider J, Rembiesa B, Szulc ZM, Bielawska A (2010) Sphingolipid analysis by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Adv Exp Med Biol 688:46–59PubMedCrossRefGoogle Scholar
  12. Bijl N, Sokolovic M, Vrins C, Langeveld M, Moerland P, Ottenhoff R, Roomen Cv, Claessen N, Boot R, Aten J, Groen A, Aerts J, Eijk Mv (2009) Modulation of glycosphingolipid metabolism significantly improves hepatic insulin sensitivity and reverses hepatic steatosis in mice. Hepatology 50(5):1431–1441PubMedCrossRefGoogle Scholar
  13. Blomqvist M, Osterbye T, Mansson JE, Horn T, Buschard K, Fredman P (2003) Selective lack of the C16:0 fatty acid isoform of sulfatide in pancreas of type II diabetic animal models. Apmis 111(9):867PubMedCrossRefGoogle Scholar
  14. Blomqvist M, Carrier M, Andrews T, Pettersson K, Mansson JE, Rynmark BM, Fredman P, Buschard K (2005) In vivo administration of the C16:0 fatty acid isoform of sulfatide increases pancreatic sulfatide and enhances glucose-stimulated insulin secretion in Zucker fatty (fa/fa) rats. Diabetes Metab Res Rev 21(2):158PubMedCrossRefGoogle Scholar
  15. Boini K, Zhang C, Xia M, Poklis J, Li P (2010) Role of sphingolipid mediator ceramide in obesity and renal injury in mice fed a high-fat diet. J Pharmacol Exp Ther 334(3):839–846PubMedCrossRefGoogle Scholar
  16. Bonzon-Kulichenko E, Schwudke D, Gallardo N, Molto E, Fernandez-Agullo T, Shevchenko A, Andres A (2009) Central leptin regulates total ceramide content and sterol regulatory element binding protein-1C proteolytic maturation in rat white adipose tissue. Endocrinology 150(1):169–178PubMedCrossRefGoogle Scholar
  17. Boslem E, MacIntosh G, Preston AM, Bartley C, Busch AK, Fuller M, Laybutt DR, Meikle PJ, Biden TJ (2011) A lipidomic screen of palmitate-treated MIN6 beta-cells links sphingolipid metabolites with endoplasmic reticulum (ER) stress and impaired protein trafficking. Biochem J 435(1):267PubMedCrossRefGoogle Scholar
  18. Boudina S, Abel ED (2010) Diabetic cardiomyopathy, causes and effects. Rev Endocr Metab Disord 11(1):31PubMedCrossRefGoogle Scholar
  19. Brice SE, Cowart LA (2011) Sphingolipid metabolism and analysis in metabolic disease. Adv Exp Med Biol 721:1–17PubMedCrossRefGoogle Scholar
  20. Brown M, Goldstein J (2008) Selective versus total insulin resistance: a pathogenic paradox. Cell Metab 7:95–96PubMedCrossRefGoogle Scholar
  21. Bruce C, Kriketos A, Cooney G, Hawley J (2004) Disassociation of muscle triglyceride content and insulin sensitivity after exercise training in patients with type 2 diabetes. Diabetologia 47:23–30PubMedCrossRefGoogle Scholar
  22. Bruni P, Donati C (2008) Pleiotropic effects of sphingolipids in skeletal muscle. Cell Mol Life Sci 65:3725–3736PubMedCrossRefGoogle Scholar
  23. Buschard K, Hoy M, Bokvist K, Olsen HL, Madsbad S, Fredman P, Gromada J (2002) Sulfatide controls insulin secretion by modulation of ATP-sensitive K(+)-channel activity and Ca(2+)-dependent exocytosis in rat pancreatic beta-cells. Diabetes 51(8):2514PubMedCrossRefGoogle Scholar
  24. Buschard K, Blomqvist M, Mansson JE, Fredman P, Juhl K, Gromada J (2006) C16:0 sulfatide inhibits insulin secretion in rat beta-cells by reducing the sensitivity of KATP channels to ATP inhibition. Diabetes 55(10):2826PubMedCrossRefGoogle Scholar
  25. Cacicedo J, Benjachareowong S, Chou E, Ruderman N, Ido Y (2005) Palmitate-induced apoptosis in cultured bovine retinal pericytes: role for NAD(P)H oxidase, oxidant stress, and ceramide. Diabetes 54(6):1838–1845PubMedCrossRefGoogle Scholar
  26. Candiloros H, Zeghari N, Ziegler O, Donner M, Drouin P (1996) Hyperinsulinemia is related to erythrocyte phospholipid composition and membrane fluidity changes in obese nondiabetic women. J Clin Endocrinol Metab 81(8):2912PubMedCrossRefGoogle Scholar
  27. Cardenas A, Schadeck C, Bernard A, Lauwerys R (1991) Depletion of sialic acid without changes in sialidase activity in glmeruli of uninephrectomized diabetic rats. Biochem Med Metab Biol 46(3):416–421PubMedCrossRefGoogle Scholar
  28. Cavaghan MK, Ehrmann DA, Polonsky KS (2000) Interactions between insulin resistance and insulin secretion in the development of glucose intolerance. J Clin Invest 106(3):329PubMedCrossRefGoogle Scholar
  29. Chavez JA, Knotts TA, Wang LP, Li G, Dobrowsky RT, Florant GL, Summers SA (2003) A role for ceramide, but not diacylglycerol, in the antagonism of insulin signal transduction by saturated fatty acids. J Biol Chem 278:10297–10303PubMedCrossRefGoogle Scholar
  30. Christiansen T, Richelsen B, Bruun J (2005) Monocyte chemoattractant protein-1 is produced in isolated adipocytes, associated with adiposity and reduced after weight loss in morbid obese subjects. Int J Obes 29(1):146–150CrossRefGoogle Scholar
  31. Cnop M, Hannaert JC, Hoorens A, Eizirik DL, Pipeleers DG (2001) Inverse relationship between cytotoxicity of free fatty acids in pancreatic islet cells and cellular triglyceride accumulation. Diabetes 50(8):1771PubMedCrossRefGoogle Scholar
  32. Cohen-Forterre L, Mozere G, Andre J, Sternberg M (1984) Studies on kidney sialidase in normal and diabetic rats. Biochim Biophys Acta 800(1):138–145CrossRefGoogle Scholar
  33. Coleman R, Lee D (2004) Enzymes of triacylglycerol synthesis and their regulation. Prog Lipid Res 43:134–176PubMedCrossRefGoogle Scholar
  34. Constable PD, Smith GW, Rottinghaus GE, Tumbleson ME, Haschek WM (2003) Fumonisin-induced blockade of ceramide synthase in sphingolipid biosynthetic pathway alters aortic input impedance spectrum of pigs. Am J Physiol Heart Circ Physiol 284(6):H2034Google Scholar
  35. Davis S, Deo SH, Barlow M, Yoshishige D, Farias M, Caffrey JL (2006) The monosialosyl ganglioside GM-1 reduces the vagolytic efficacy of delta2-opioid receptor stimulation. Am J Physiol Heart Circ Physiol 291(5):H2318Google Scholar
  36. de Mello VD, Lankinen M, Schwab U, Kolehmainen M, Lehto S, Seppanen-Laakso T, Oresic M, Pulkkinen L, Uusitupa M, Erkkila AT (2009) Link between plasma ceramides, inflammation and insulin resistance: association with serum IL-6 concentration in patients with coronary heart disease. Diabetologia 52(12):2612PubMedCrossRefGoogle Scholar
  37. de Vries JE, Vork MM, Roemen TH, de Jong YF, Cleutjens JP, van der Vusse GJ, van Bilsen M (1997) Saturated but not mono-unsaturated fatty acids induce apoptotic cell death in neonatal rat ventricular myocytes. J Lipid Res 38(7):1384Google Scholar
  38. Deevska G, Rozenova K, Giltiay N, Chambers M, White J, Boyanovsky B, Wei J, Daugherty A, Smart E, Reid M, Merrill JAH, Nikolova-Karakashian M (2009) Acid sphingomyelinase deficiency prevents diet-induced hepatic triacylglycerol accumulation and hyperglycemia. J Biol Chem 284:8359–8368PubMedCrossRefGoogle Scholar
  39. Di Paola M, Zaccagnino P, Montedoro G, Cocco T, Lorusso M (2004) Ceramide induces release of pro-apoptotic proteins from mitochondria by either a Ca2+ −dependent or a Ca2+ −independent mechanism. J Bioenerg Biomembr 36(2):165PubMedCrossRefGoogle Scholar
  40. Dimitrios I, Drosatos K, Hiyama Y, Goldberg I, Zannis V (2010) MicroRNA-370 controls the expression of MicroRNA-122 and CPT1a and affects lipid metabolism. J Lipid Res 51(6):1513–1523CrossRefGoogle Scholar
  41. Dindo D, Dahm F, Szulc Z, Bielawska A, Obeid LM, Hannun YA, Graf R, Clavien PA (2006) Cationic long-chain ceramide LCL-30 induces cell death by mitochondrial targeting in SW403 cells. Mol Cancer Ther 5(6):1520–1529PubMedCrossRefGoogle Scholar
  42. Dinh W, Lankisch M, Nickl W, Scheyer D, Scheffold T, Kramer F, Krahn T, Klein RM, Barroso MC, Futh R (2010) Insulin resistance and glycemic abnormalities are associated with deterioration of left ventricular diastolic function: a cross-sectional study. Cardiovasc Diabetol 9:63PubMedCrossRefGoogle Scholar
  43. Dinh W, Lankisch M, Nickl W, Gies M, Scheyer D, Kramer F, Scheffold T, Krahns T, Sause A, Futh R (2011) Metabolic syndrome with or without diabetes contributes to left ventricular diastolic dysfunction. Acta Cardiol 66(2):167PubMedGoogle Scholar
  44. Dobrzyn P, Dobrzyn A, Miyazaki M, Ntambi JM (2010) Loss of stearoyl-CoA desaturase 1 rescues cardiac function in obese leptin-deficient mice. J Lipid Res 51(8):2202Google Scholar
  45. Drosatos K, Bharadwaj KG, Lymperopoulos A, Ikeda S, Khan R, Hu Y, Agarwal R, Yu S, Jiang H, Steinberg SF, Blaner WS, Koch WJ, Goldberg IJ (2011) Cardiomyocyte lipids impair beta-adrenergic receptor function via PKC activation. Am J Physiol Endocrinol Metab 300(3):E489PubMedCrossRefGoogle Scholar
  46. Dyntar D, Eppenberger-Eberhardt M, Maedler K, Pruschy M, Eppenberger HM, Spinas GA, Donath MY (2001) Glucose and palmitic acid induce degeneration of myofibrils and modulate apoptosis in rat adult cardiomyocytes. Diabetes 50(9):2105PubMedCrossRefGoogle Scholar
  47. El-Assaad W, Joly E, Barbeau A, Sladek R, Buteau J, Maestre I, Pepin E, Zhao S, Iglesias J, Roche E, Prentki M (2010) Glucolipotoxicity alters lipid partitioning and causes mitochondrial dysfunction, cholesterol, and ceramide deposition and reactive oxygen species production in INS832/13 ss-cells. Endocrinology 151(7):3061PubMedCrossRefGoogle Scholar
  48. Finck BN (2004) The role of the peroxisome proliferator-activated receptor alpha pathway in pathological remodeling of the diabetic heart. Curr Opin Clin Nutr Metab Care 7(4):391Google Scholar
  49. Fox T, Han X, Kelly S, Merrill JAH, Martin R, Anderson R, Gardner T, Kester M (2006) Diabetes alters sphingolipid metabolism in the retina: a potential mechanism of cell death in diabetic retinopathy. Diabetes 55(12):3573–3580PubMedCrossRefGoogle Scholar
  50. Fry J, Finley W (2005) The prevalence and costs of obesity in the EU. Proc Nutr Soc 64(3):359–362PubMedCrossRefGoogle Scholar
  51. Gault CR, Obeid LM, Hannun YA (2010) An overview of sphingolipid metabolism: from synthesis to breakdown. Adv Exp Med Biol 688:1–23PubMedCrossRefGoogle Scholar
  52. Gidwani A, Brown HA, Holowka D, Baird B (2003) Disruption of lipid order by short-chain ceramides correlates with inhibition of phospholipase D and downstream signaling by FcepsilonRI. J Cell Sci 116(Pt 15):3177PubMedCrossRefGoogle Scholar
  53. Goldkorn T, Balaban N, Shannon M, Chea V, Matsukuma K, Gilchrist D, Wang H, Chan C (1998) H2O2 acts on cellular membranes to generate ceramide signaling and initiate apoptosis in tracheobronchial epithelial cells. J Cell Sci 111(Pt 21):3209–3220PubMedGoogle Scholar
  54. Gonzalez-Pertusa JA, Dube J, Valle SR, Rosa TC, Takane KK, Mellado-Gil JM, Perdomo G, Vasavada RC, Garcia-Ocana A (2010) Novel proapoptotic effect of hepatocyte growth factor: synergy with palmitate to cause pancreatic {beta}-cell apoptosis. Endocrinology 151(4):1487PubMedCrossRefGoogle Scholar
  55. Goodpaster B, He J, Watkins S, Kelley D (2001) Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab 86:5755–5761PubMedCrossRefGoogle Scholar
  56. Gorski J, Dobrzyn A, Zendzian-Piotrowska M (2002) The sphingomyelin-signaling pathway in skeletal muscles and its role in regulation of glucose uptake. Ann NY Acad Sci 967:236–248PubMedCrossRefGoogle Scholar
  57. Grundy SM, Bryan Brewer JH, Cleeman JI, Sidney J, Smith C, Lenfant C (2004) Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 109:433–438PubMedCrossRefGoogle Scholar
  58. Guha A, Harmancey R, Taegtmeyer H (2008) Nonischemic heart failure in diabetes mellitus. Curr Opin Cardiol 23(3):241PubMedCrossRefGoogle Scholar
  59. Guo J, Qian Y, Xi X, Hu X, Zhu J, Han X (2010) Blockage of ceramide metabolism exacerbates palmitate inhibition of pro-insulin gene expression in pancreatic beta-cells. Mol Cell Biochem 338(1–2):283PubMedCrossRefGoogle Scholar
  60. Hajduch E, Alessi D, Hemmings B, Hundal H (1998) Constitutive activation of protein kinase B alpha by membrane targeting promotes glucose and system A amino acid transport, protein synthesis, and inactivation of glycogen synthase kinase 3 in L6 muscle cells. Diabetes 47:1006–1013PubMedCrossRefGoogle Scholar
  61. Hajduch E, LItherland G, Hundal H (2001) Protein kinase B (PKB/Akt)-a key regulator of glucose transport? FEBS Lett 492:199–203Google Scholar
  62. Hajer GR, Haeften TWv, Visseren FL (2008) Adipose tissue dysfunction in obesity, diabetes, and vascular disease. Eur Heart J 29:2959–2971Google Scholar
  63. Hannun YA, Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9(2):139–150PubMedCrossRefGoogle Scholar
  64. Haus JM, Kashyap SR, Kasumov T, Zhang R, Kelly KR, Defronzo RA, Kirwan JP (2009) Plasma ceramides are elevated in obese subjects with type 2 diabetes and correlate with the severity of insulin resistance. Diabetes 58(2):337PubMedCrossRefGoogle Scholar
  65. Hickson-Bick DL, Buja LM, McMillin JB (2000) Palmitate-mediated alterations in the fatty acid metabolism of rat neonatal cardiac myocytes. J Mol Cell Cardiol 32(3):511PubMedCrossRefGoogle Scholar
  66. Hirose H, Lee YH, Inman LR, Nagasawa Y, Johnson JH, Unger RH (1996) Defective fatty acid-mediated beta-cell compensation in Zucker diabetic fatty rats. Pathogenic implications for obesity-dependent diabetes. J Biol Chem 271(10):5633Google Scholar
  67. Ho KK, Pinsky JL, Kannel WB, Levy D (1993) The epidemiology of heart failure: the Framingham study. J Am Coll Cardiol 22(4 Suppl A):6AGoogle Scholar
  68. Hojjati M, Li Z, Zhou H, Tang S, Huan C, Ooi E, Lu S, Jiang X (2005) Effect of myriocin on plasma sphingolipid metabolism and atherosclerosis in apoE-deficient mice. J Biol Chem 280:10284–10289PubMedCrossRefGoogle Scholar
  69. Holland W, Brozinick J, Wang L, Hawkins E, Sargent S, Liu Y, Narra K, Hoehn K, Knotts T, Siesky A, Nelson D, Karathanasis S, Foentenot G, Birnbaum M, Summers S (2007) Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab 5:167–179PubMedCrossRefGoogle Scholar
  70. Holland WL, Miller RA, Wang ZV, Sun K, Barth BM, Bui HH, Davis KE, Bikman BT, Halberg N, Rutkowski JM, Wade MR, Tenorio VM, Kuo MS, Brozinick JT, Zhang BB, Birnbaum MJ, Summers SA, Scherer PE (2011) Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med 17(1):55PubMedCrossRefGoogle Scholar
  71. Hotamisligil G (2006) Inflammation and metabolic disorders. Nature 444(7121):860–867PubMedCrossRefGoogle Scholar
  72. Hu W, Bielawski J, Samad F, Merrill AH Jr, Cowart LA (2009) Palmitate increases sphingosine-1-phosphate in C2C12 myotubes via upregulation of sphingosine kinase message and activity. J Lipid Res 50(9):1852Google Scholar
  73. Hu W, Ross J, Geng T, Brice SE, Cowart LA (2011) Differential regulation of dihydroceramide desaturase by palmitate versus monounsaturated fatty acids: implications for insulin resistance. J Biol Chem 286(19):16596PubMedCrossRefGoogle Scholar
  74. Itani S, Ruderman N, Schmieder F, Boden G (2002) Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protien kinase C, and IkB-alpha. Diabetes 51:2005–2011PubMedCrossRefGoogle Scholar
  75. Jessup CF, Bonder CS, Pitson SM, Coates PT (2011) The sphingolipid rheostat: a potential target for improving pancreatic islet survival and function. Endocr Metab Immune Disord Drug Targets 11(4):262–272PubMedCrossRefGoogle Scholar
  76. Keller S, Lienhard G (1994) Insulin signalling the role of insulin receptor substrate 1. Trends Cell Biol 4:115–119PubMedCrossRefGoogle Scholar
  77. Kelpe CL, Moore PC, Parazzoli SD, Wicksteed B, Rhodes CJ, Poitout V (2003) Palmitate inhibition of insulin gene expression is mediated at the transcriptional level via ceramide synthesis. J Biol Chem 278(32):30015PubMedCrossRefGoogle Scholar
  78. Kolak M, Westerbacka J, Velagapudi V, Wagsater D, Yetukuri L, Makkonen J, Rissanen A, Hakkinen A, Lindell M, Bergholm R, Hamsten A, Eriksson P, Fisher R, Oresic M, Yki-Jarvinen H (2007) Adipose tissue inflammation and increased ceramide content characterize subjects with high liver fat content independent of obesity.". Diabetes 56(8):1960–1968PubMedCrossRefGoogle Scholar
  79. Kremer GJ, Atzpodien W, Schnellbacher E (1975) Plasma glycosphingolipids in diabetics and normals. Klin Wochenschr 53(13):637PubMedCrossRefGoogle Scholar
  80. Krown KA, Page MT, Nguyen C, Zechner D, Gutierrez V, Comstock KL, Glembotski CC, Quintana PJ, Sabbadini RA (1996) Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death. J Clin Invest 98(12):2854Google Scholar
  81. Kucharska-Newton AM, Couper DJ, Pankow JS, Prineas RJ, Rea TD, Sotoodehnia N, Chakravarti A, Folsom AR, Siscovick DS, Rosamond WD (2010) Diabetes and the risk of sudden cardiac death, the Atherosclerosis Risk in Communities study. Acta Diabetol 47(Suppl 1):161PubMedCrossRefGoogle Scholar
  82. Lam Y, Hatzinikolas G, Weir J, Janovska A, McAinch A, Game P, Meikle P, Wittert G (2011) Insulin-stimulated glucose uptake and pathways regulating energy metabolism in skeletal muscle cells: the effects of subcutaneous and visceral fat, and long-chain saturated, n-3 and n-6 polyunsaturated fatty acids. Biochim Biophys Acta 1811(7–8):468–475PubMedGoogle Scholar
  83. Laviad EL, Albee L, Pankova-Kholmyansky I, Epstein S, Park H, Merrill AH Jr, Futerman AH (2008) Characterization of ceramide synthase 2: tissue distribution, substrate specificity, and inhibition by sphingosine 1-phosphate. J Biol Chem 283(9):5677–5684PubMedCrossRefGoogle Scholar
  84. Leahy JL (2008) Pathogenesis of type 2 diabetes mellitus. In: Feinglos MN, Bethel MA (eds) Type 2 diabetes mellitus. Humana, Amstgerdam, p 17Google Scholar
  85. Lee Y, Hirose H, Ohneda M, Johnson JH, McGarry JD, Unger RH (1994) Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships. Proc Natl Acad Sci USA 91(23):10878Google Scholar
  86. Levy M, Castillo SS, Goldkorn T (2006) nSMase2 activation and trafficking are modulated by oxidative stress to induce apoptosis. Biochem Biophys Res Commun 344(3):900–905PubMedCrossRefGoogle Scholar
  87. Levy M, Khan E, Careaga M, Goldkorn T (2009) Neutral sphingomyelinase 2 is activated by cigarette smoke to augment ceramide-induced apoptosis in lung cell death. Am J Physiol Lung Cell Mol Physiol 297(1):L125–L133PubMedCrossRefGoogle Scholar
  88. Lipina C, Hundal H (2011) Sphingolipids: agents provoccateurs in the pathogenesis of insulin resistance. Diabetologia 54:1596–1607PubMedCrossRefGoogle Scholar
  89. Liu L, Shi X, Bharadwaj KG, Ikeda S, Yamashita H, Yagyu H, Schaffer JE, Yu YH, Goldberg IJ (2009) DGAT1 expression increases heart triglyceride content but ameliorates lipotoxicity. J Biol Chem 284(52):36312PubMedCrossRefGoogle Scholar
  90. Lupi R, Dotta F, Marselli L, Del Guerra S, Masini M, Santangelo C, Patane G, Boggi U, Piro S, Anello M, Bergamini E, Mosca F, Di Mario U, Del Prato S, Marchetti P (2002) Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes 51(5):1437PubMedCrossRefGoogle Scholar
  91. Ma MM, Chen JL, Wang GG, Wang H, Lu Y, Li JF, Yi J, Yuan YJ, Zhang QW, Mi J, Wang LS, Duan HF, Wu CT (2007) Sphingosine kinase 1 participates in insulin signalling and regulates glucose metabolism and homeostasis in KK/Ay diabetic mice. Diabetologia 50(4):891PubMedCrossRefGoogle Scholar
  92. Madrazo JA, Kelly DP (2008) The PPAR trio: regulators of myocardial energy metabolism in health and disease. J Mol Cell Cardiol 44(6):968PubMedCrossRefGoogle Scholar
  93. Maedler K, Spinas GA, Dyntar D, Moritz W, Kaiser N, Donath MY (2001) Distinct effects of saturated and monounsaturated fatty acids on beta-cell turnover and function. Diabetes 50(1):69PubMedCrossRefGoogle Scholar
  94. Maedler K, Oberholzer J, Bucher P, Spinas GA, Donath MY (2003) Monounsaturated fatty acids prevent the deleterious effects of palmitate and high glucose on human pancreatic beta-cell turnover and function. Diabetes 52(3):726PubMedCrossRefGoogle Scholar
  95. Maheux P, Jeppesen J, Sheu WH, Hollenbeck CB, Clinkingbeard C, Greenfield MS, Chen YD, Reaven GM (1994) Additive effects of obesity, hypertension, and type 2 diabetes on insulin resistance. Hypertension 24(6):695–698PubMedCrossRefGoogle Scholar
  96. Manchanayake J, Chitturi S, Nolan C, Farrell GC (2011) Postprandial hyperinsulinemia is universal in non-diabetic patients with nonalcoholic fatty liver disease. J Gastroenterol Hepatol 26(3):510PubMedCrossRefGoogle Scholar
  97. Martinez J, Kearney J, Kafatos A, Paquet S, Martinez-Gonzalez M (1999) Variables independently associated with self-reported obesity in the European Union. Public Health Nutr 2(1A):125–133PubMedCrossRefGoogle Scholar
  98. Mastrandrea LD, Sessanna SM, Laychock SG (2005) Sphingosine kinase activity and sphingosine-1 phosphate production in rat pancreatic islets and INS-1 cells: response to cytokines. Diabetes 54(5):1429PubMedCrossRefGoogle Scholar
  99. Mather A, Siskind LJ (2011) Glycosphingolipids and kidney disease. Adv Exp Med Biol 721:121–138PubMedCrossRefGoogle Scholar
  100. Maulik N, Das DK, Gogineni M, Cordis GA, Avrova N, Denisova N (1993) Reduction of myocardial ischemic reperfusion injury by sialylated glycosphingolipids, gangliosides. J Cardiovasc Pharmacol 22(1):74PubMedCrossRefGoogle Scholar
  101. Memon RA, Holleran WM, Moser AH, Seki T, Uchida Y, Fuller J, Shigenaga JK, Grunfeld C, Feingold KR (1998) Endotoxin and cytokines increase hepatic sphingolipid biosynthesis and produce lipoproteins enriched in ceramides and sphingomyelin. Arterioscler Thromb Vasc Biol 18(8):1257–1265PubMedCrossRefGoogle Scholar
  102. Merrill AH Jr, Nixon DW, Williams RD (1985) Activities of serine palmitoyltransferase (3-ketosphinganine synthase) in microsomes from different rat tissues. J Lipid Res 26(5):617Google Scholar
  103. Milburn JL Jr, Hirose H, Lee YH, Nagasawa Y, Ogawa A, Ohneda M, BeltrandelRio H, Newgard CB, Johnson JH, Unger RH (1995) Pancreatic beta-cells in obesity. Evidence for induction of functional, morphologic, and metabolic abnormalities by increased long chain fatty acids. J Biol Chem 270(3):1295Google Scholar
  104. Miyake Y, Kozutsumi Y, Nakamura S, Fujita T, Kawasaki T (1995) Serine palmitoyltransferase is the primary target of a sphingosine-like immunosuppressant, ISP-1/myriocin. Biochem Biophys Res Commun 211(2):396PubMedCrossRefGoogle Scholar
  105. Mohamed-Ali V, Goodrick S, Rawesh A, Katz D, Miles J, Yudkin J, Klein S, Coppack S (1997) Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab 82:4196–4200PubMedCrossRefGoogle Scholar
  106. Moro C, Bajpeyi S, Smith S (2008) Determinants of intramyocellular triglyceride turnover: implications for insulin sensitivity. Am J Physiol Endocrinol Metab 294:E203–E213PubMedCrossRefGoogle Scholar
  107. Mueller-Riemenschneider F, Reinhold T, Berghofer A, Willich S (2008) Health-economic burden of obesity in Europe. Eur J Epidemiol 23(8):499–509CrossRefGoogle Scholar
  108. Mullen TD, Jenkins RW, Clarke CJ, Bielawski J, Hannun YA, Obeid LM (2011a) Ceramide synthase-dependent ceramide generation and programmed cell death: involvement of salvage pathway in regulating postmitochondrial events. J Biol Chem 286(18):15929–15942PubMedCrossRefGoogle Scholar
  109. Mullen TD, Spassieva S, Jenkins RW, Kitatani K, Bielawski J, Hannun YA, Obeid LM (2011b) Selective knockdown of ceramide synthases reveals complex interregulation of sphingolipid metabolism. J Lipid Res 52(1):68–77PubMedCrossRefGoogle Scholar
  110. Nerpin E, Riserus U, Ingelsson E, Sundstrom J, Jobs M, Larsson A, Basu S, Arnlov J (2008) Insulin sensitivity measured with euglycemic clamp is independently associated with glomerular filtration rate in a community-based cohort. Diabetes Care 31(8):1550PubMedCrossRefGoogle Scholar
  111. Nussey S, Whitehead SA (2001) Endocrinology: an integrated approach. Bios, Oxford, UKCrossRefGoogle Scholar
  112. Nybond S, Bjorkqvist YJ, Ramstedt B, Slotte JP (2005) Acyl chain length affects ceramide action on sterol/sphingomyelin-rich domains. Biochim Biophys Acta 1718(1–2):61Google Scholar
  113. Osterbye T, Jorgensen KH, Fredman P, Tranum-Jensen J, Kaas A, Brange J, Whittingham JL, Buschard K (2001) Sulfatide promotes the folding of proinsulin, preserves insulin crystals, and mediates its monomerization. Glycobiology 11(6):473PubMedCrossRefGoogle Scholar
  114. Othman A, Rutti MF, Ernst D, Saely CH, Rein P, Drexel H, Porretta-Serapiglia C, Lauria G, Bianchi R, von Eckardstein A, Hornemann T (2011) Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome? Diabetologia 55(2):421–31PubMedCrossRefGoogle Scholar
  115. Park TS, Hu Y, Noh HL, Drosatos K, Okajima K, Buchanan J, Tuinei J, Homma S, Jiang XC, Abel ED, Goldberg IJ (2008) Ceramide is a cardiotoxin in lipotoxic cardiomyopathy. J Lipid Res 49(10):2101PubMedCrossRefGoogle Scholar
  116. Parra V, Eisner V, Chiong M, Criollo A, Moraga F, Garcia A, Hartel S, Jaimovich E, Zorzano A, Hidalgo C, Lavandero S (2008) Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis. Cardiovasc Res 77(2):387PubMedCrossRefGoogle Scholar
  117. Passa P (2002) Diabetes trends in Europe. Diabetes Metab Res Rev 18(Suppl 3):S3–S8PubMedCrossRefGoogle Scholar
  118. Pewzner-Jung Y, Ben-Dor S, Futerman AH (2006) When do Lasses (longevity assurance genes) become CerS (ceramide synthases)?: insights into the regulation of ceramide synthesis. J Biol Chem 281(35):25001–25005PubMedCrossRefGoogle Scholar
  119. Pick A, Clark J, Kubstrup C, Levisetti M, Pugh W, Bonner-Weir S, Polonsky KS (1998) Role of apoptosis in failure of beta-cell mass compensation for insulin resistance and beta-cell defects in the male Zucker diabetic fatty rat. Diabetes 47(3):358PubMedCrossRefGoogle Scholar
  120. Pontiroli AE, Camisasca R (2002) Additive effect of overweight and type 2 diabetes in the appearance of coronary heart disease but not of stroke: a cross-sectional study. Acta Diabetol 39(2):83–90PubMedCrossRefGoogle Scholar
  121. Pouliot MC, Despres JP, Nadeau A, Tremblay A, Moorjani S, Lupien PJ, Theriault G, Bouchard C (1990) Associations between regional body fat distribution, fasting plasma free fatty acid levels and glucose tolerance in premenopausal women. Int J Obes 14(4):293PubMedGoogle Scholar
  122. Preiss B, Sattar N (2008) Non-alcoholic fatty liver disease: an overview of prevalence, diagnosis, pathogenesis, and treatment considerations. Clin Sci 115:141–150PubMedCrossRefGoogle Scholar
  123. Prosdocimi M, Paro M, Travagli RA, Tessari F (1987) Alterations of the vegetative nervous system, experimental diabetes and pharmacological use of gangliosides. Funct Neurol 2(4):559PubMedGoogle Scholar
  124. Qiao Q, Nyamdorj R (2010) The optimal cutoff values and their performance of waist circumference and waist-to-hip ratio for diagnosing type II diabetes. Eur J Clin Nutr 64(1):23–29PubMedCrossRefGoogle Scholar
  125. Rijzewijk LJ, van der Meer RW, Smit JW, Diamant M, Bax JJ, Hammer S, Romijn JA, de Roos A, Lamb HJ (2008) Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J Am Coll Cardiol 52(22):1793PubMedCrossRefGoogle Scholar
  126. Robert P, Tsui P, Laville MP, Livi GP, Sarau HM, Bril A, Berrebi-Bertrand I (2001) EDG1 receptor stimulation leads to cardiac hypertrophy in rat neonatal myocytes. J Mol Cell Cardiol 33(9):1589PubMedCrossRefGoogle Scholar
  127. Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI (1996) Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 97(12):2859PubMedCrossRefGoogle Scholar
  128. Roeske-Nielsen A, Dalgaard LT, Mansson JE, Buschard K (2010) The glycolipid sulfatide protects insulin-producing cells against cytokine-induced apoptosis, a possible role in diabetes. Diabetes Metab Res Rev 26(8):631Google Scholar
  129. Rutti S, Ehses JA, Sibler RA, Prazak R, Rohrer L, Georgopoulos S, Meier DT, Niclauss N, Berney T, Donath MY, von Eckardstein A (2009) Low- and high-density lipoproteins modulate function, apoptosis, and proliferation of primary human and murine pancreatic beta-cells. Endocrinology 150(10):4521PubMedCrossRefGoogle Scholar
  130. Saito M, Cooper TB, Vadasz C (2005) Ethanol-induced changes in the content of triglycerides, ceramides, and glucosylceramides in cultured neurons. Alcohol Clin Exp Res 29(8):1374–1383PubMedCrossRefGoogle Scholar
  131. Samad F, Hester KD, Yang G, Hannun YA, Bielawski J (2006) Altered adipose and plasma sphingolipid metabolism in obesity: a potential mechanism for cardiovascular and metabolic risk. Diabetes 55:2579–2587PubMedCrossRefGoogle Scholar
  132. Samad F, Badeanlou L, Shah C, Yang G (2011) Adipose tissue and ceramide biosynthesis in the pathogenesis of obesity. Adv Exp Med Biol 721:67–86PubMedCrossRefGoogle Scholar
  133. Schmitz-Peiffer C, Craig D, Biden T (1999) Ceramide generation is sufficient to account for the inhibition of the insulin-stimulated PKB pathway in C2C12 skeletal muscle cells pretreated with palmitate. J Biol Chem 274:24202–24210PubMedCrossRefGoogle Scholar
  134. Senkal CE, Ponnusamy S, Bielawski J, Hannun YA, Ogretmen B (2010) Antiapoptotic roles of ceramide-synthase-6-generated C16-ceramide via selective regulation of the ATF6/CHOP arm of ER-stress-response pathways. FASEB J 24(1):296PubMedCrossRefGoogle Scholar
  135. Senkal CE, Ponnusamy S, Manevich Y, Meyers-Needham M, Saddoughi SA, Mukhopadyay A, Dent P, Bielawski J, Ogretmen B (2011) Alteration of ceramide synthase 6/C16-ceramide induces activating transcription factor 6-mediated endoplasmic reticulum (ER) stress and apoptosis via perturbation of cellular Ca2+ and ER/Golgi membrane network. J Biol Chem 286(49):42446PubMedCrossRefGoogle Scholar
  136. Serlie MJ, Meijer AJ, Groener JE, Duran M, Endert E, Fliers E, Aerts JM, Sauerwein HP (2007) Short-term manipulation of plasma free fatty acids does not change skeletal muscle concentrations of ceramide and glucosylceramide in lean and overweight subjects. J Clin Endocrinol Metab 92(4):1524PubMedCrossRefGoogle Scholar
  137. Shah C, Yang G, Lee I, Bielawski J, Hannun YA, Samad F (2008) Protection from high fat diet-induced increase in ceramide in mice lacking plaminogen activator inhibitor 1. J Biol Chem 283:13538–13548PubMedCrossRefGoogle Scholar
  138. Shimabukuro M, Zhou Y-T, Levi M, Unger R (1998) Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes. Proc Natl Acad Sci USA 95:2498–2502PubMedCrossRefGoogle Scholar
  139. Sparagna GC, Hickson-Bick DL, Buja LM, McMillin JB (2000) A metabolic role for mitochondria in palmitate-induced cardiac myocyte apoptosis. Am J Physiol Heart Circ Physiol 279(5):H2124PubMedGoogle Scholar
  140. Sultan I, Senkal CE, Ponnusamy S, Bielawski J, Szulc Z, Bielawska A, Hannun YA, Ogretmen B (2006) Regulation of the sphingosine-recycling pathway for ceramide generation by oxidative stress, and its role in controlling c-Myc/Max function. Biochem J 393(Pt 2):513–521PubMedGoogle Scholar
  141. Summers SA (2006) Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res 45:42–72PubMedCrossRefGoogle Scholar
  142. Summers S, Nelson D (2005) A role for sphingolipids in producting the common features of type 2 diabetes, metabolic syndrome X, and Cushing’s syndrome. Diabetes 54:591–602PubMedCrossRefGoogle Scholar
  143. Teruel T, Hernandez R, Lorenzo M (2001) Ceramide mediates insulin resistance by tumor necrosis factor-alpha in brown adipocytes by maintaining Akt in an inactive dephosphorylated state. Diabetes 50:2563–2571PubMedCrossRefGoogle Scholar
  144. Tessari F, Travagli RA, Zanoni R, Prosdocimi M (1988) Effects of long-term diabetes and treatment with gangliosides on cardiac sympathetic innervation: a biochemical and functional study in mice. J Diabet Complications 2(1):34PubMedCrossRefGoogle Scholar
  145. Theilmeier G, Schmidt C, Herrmann J, Keul P, Schafers M, Herrgott I, Mersmann J, Larmann J, Hermann S, Stypmann J, Schober O, Hildebrand R, Schulz R, Heusch G, Haude M, von Wnuck Lipinski K, Herzog C, Schmitz M, Erbel R, Chun J, Levkau B (2006) High-density lipoproteins and their constituent, sphingosine-1-phosphate, directly protect the heart against ischemia/reperfusion injury in vivo via the S1P3 lysophospholipid receptor. Circulation 114(13):1403PubMedCrossRefGoogle Scholar
  146. Turpin SM, Ryall JG, Southgate R, Darby I, Hevener AL, Febbraio MA, Kemp BE, Lynch GS, Watt MJ (2009) Examination of ‘lipotoxicity’ in skeletal muscle of high-fat fed and ob/ob mice. J Physiol 587(7):1598–1605CrossRefGoogle Scholar
  147. Utz W, Engeli S, Haufe S, Kast P, Hermsdorf M, Wiesner S, Pofahl M, Traber J, Luft FC, Boschmann M, Schulz-Menger J, Jordan J (2011) Myocardial steatosis, cardiac remodelling and fitness in insulin-sensitive and insulin-resistant obese women. Heart 97(19):1585PubMedCrossRefGoogle Scholar
  148. Vanhaesebroeck B, Alessi D (2000) The PI3K-PDK1 connection: more than just a road to PKB. Biochem J 346(3):561–576PubMedCrossRefGoogle Scholar
  149. Veluthakal R, Palanivel R, Zhao Y, McDonald P, Gruber S, Kowluru A (2005) Ceramide induces mitochondrial abnormalities in insulin-secreting INS-1 cells: potential mechanisms underlying ceramide-mediated metabolic dysfunction of the beta cell. Apoptosis 10(4):841PubMedCrossRefGoogle Scholar
  150. Veret J, Coant N, Berdyshev EV, Skobeleva A, Therville N, Bailbe D, Gorshkova I, Natarajan V, Portha B, Le Stunff H (2011) Ceramide synthase 4 and de novo production of ceramides with specific N-acyl chain lengths are involved in glucolipotoxicity-induced apoptosis of INS-1 beta-cells. Biochem J 438(1):177PubMedCrossRefGoogle Scholar
  151. Wang E, Norred WP, Bacon CW, Riley RT, Merrill AH Jr (1991) Inhibition of sphingolipid biosynthesis by fumonisins. Implications for diseases associated with Fusarium moniliforme. J Biol Chem 266(22):14486–14490PubMedGoogle Scholar
  152. Wang J, Zhen L, Klug MG, Wood D, Wu X, Mizrahi J (2000) Involvement of caspase 3- and 8-like proteases in ceramide-induced apoptosis of cardiomyocytes. J Card Fail 6(3):243PubMedCrossRefGoogle Scholar
  153. Wei GS, Coady SA, Goff DC Jr, Brancati FL, Levy D, Selvin E, Vasan RS, Fox CS (2011) Blood pressure and the risk of developing diabetes in african americans and whites: ARIC, CARDIA, and the framingham heart study. Diabetes Care 34(4):873–879PubMedCrossRefGoogle Scholar
  154. Whiteman E, Cho H, Birnbaum M (2002) Role of Akt/protein kinase B in metabolism. Trends Endocrinol Metab 13:444–451PubMedCrossRefGoogle Scholar
  155. Yagyu H, Chen G, Yokoyama M, Hirata K, Augustus A, Kako Y, Seo T, Hu Y, Lutz EP, Merkel M, Bensadoun A, Homma S, Goldberg IJ (2003) Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy. J Clin Invest 111(3):419PubMedGoogle Scholar
  156. Yosuke O, Seki E, Kodama Y, Suetsugu A, Miura K, Adachi M, Ito H, Shiratori Y, Banno Y, Olefsky J, Nagaki M, Moriwaki H, Brenner D, Seishima M (2011) Acid sphingomyelinase regulates glucose and lipid metabolism in hepatocytes through Akt activation and AMP-activated protein kinase suppression. FASEB J 25(4):1133–1144CrossRefGoogle Scholar
  157. Zeghari N, Younsi M, Meyer L, Donner M, Drouin P, Ziegler O (2000) Adipocyte and erythrocyte plasma membrane phospholipid composition and hyperinsulinemia: a study in nondiabetic and diabetic obese women. Int J Obes Relat Metab Disord 24(12):1600PubMedCrossRefGoogle Scholar
  158. Zhao H, Przybylska M, Wu I, Siegel C, Komarnitsky S, Yew N, Cheng S (2007) Inhibiting glycosphingolipid synthesis improves glycemic control and insulin sensitivity in animal models of type 2 diabetes. Diabetes 56(5):1210–1218PubMedCrossRefGoogle Scholar
  159. Zheng W, Kollmeyer J, Symolon H, Momin A, Munter E, Wang E, Kelly S, Allegood JC, Liu Y, Peng Q, Ramaraju H, Sullards MC, Cabot M, Merrill AH Jr (2006) Ceramides and other bioactive sphingolipid backbones in health and disease: lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autophagy. Biochim Biophys Acta 1758(12):1864–1884PubMedCrossRefGoogle Scholar

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© Springer-Verlag Wien 2013

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular Biology, Ralph H. Johnson VA Medical CenterThe Medical University of South CarolinaCharlestonUSA

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