Therapeutic Strategies for Diabetes and Complications: A Role for Sphingolipids?

  • Todd E. Fox
  • Mark Kester
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 688)


Diabetes is a debilitating chronic disease that has no cure and can only be managed by pharmaceutical or nutritional interventions. Worldwide, the incidence of diabetes and diabetic complications is dramatically increasing. This may reflect the incomplete knowledge base underlying the role of inflammatory or nutritional stresses to exacerbate diabetic complications. Despite the knowledge that hyperlipidemia is a cardinal feature of both Type 1 and 2 diabetes, the actual lipid species that contribute to complications such as diabetic nephropathy, retinopathy, neuropathy and cardiovascular disease have not been well defined, or have not elucidated new treatment strategies. Sphingolipids comprise only a fraction of total lipids but a body of evidence has now identified dysfunctional sphingolipid metabolism and/or generation of specific sphingolipid metabolites as contributors to diabetic complications. This review suggests that pharmacological therapies that target dysfunctional sphingolipid metabolism and/or signaling may prove beneficial in decreasing the chronic pathology of hyperglycemia and hyperlipidemia. Moreover, the review suggests that these treatment options may also prove beneficial to ameliorate or delay pancreatic beta cell failure.


Diabetic Retinopathy Sphingosine Kinase Nonobese Diabetic Mouse Ceramide Level Ceramide Content 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Diabetes Atlas, Third Edition: International Diabetes Federation; 2007.Google Scholar
  2. 2.
    Muoio DM, Newgard CB. Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes. Nat Rev Mol Cell Biol 2008; 9(3):193–205.PubMedCrossRefGoogle Scholar
  3. 3.
    Greenbaum CJ. Insulin resistance in type 1 diabetes. Diabetes Metab Res Rev 2002; 18(3):192–200.PubMedCrossRefGoogle Scholar
  4. 4.
    Chaturvedi N, Sjoelie AK, Porta M et al. Markers of insulin resistance are strong risk factors for retinopathy incidence in type 1 diabetes. Diabetes Care 2001; 24(2):284–289.PubMedCrossRefGoogle Scholar
  5. 5.
    De Block CE, De Leeuw IH, Van Gaal LF. Impact of overweight on chronic microvascular complications in type 1 diabetic patients. Diabetes Care 2005; 28(7):1649–1655.PubMedCrossRefGoogle Scholar
  6. 6.
    McGill M, Molyneaux L, Twigg SM et al. The metabolic syndrome in type 1 diabetes: does it exist and does it matter? J Diabetes Complications 2008; 22(1):18–23.PubMedCrossRefGoogle Scholar
  7. 7.
    Kilpatrick ES, Rigby AS, Atkin SL. Insulin resistance, the metabolic syndrome and complication risk in type 1 diabetes: “double diabetes” in the Diabetes Control and Complications Trial. Diabetes Care 2007; 30(3):707–712.PubMedCrossRefGoogle Scholar
  8. 8.
    Balkau B, Tichet J, Caces E et al. Insulin dose and cardiovascular risk factors in type 1 diabetic children and adolescents. Diabetes Metab 1998; 24(2):143–150.PubMedGoogle Scholar
  9. 9.
    Won JS, Singh I. Sphingolipid signaling and redox regulation. Free Radic Biol Med 2006; 40(11):1875–1888.PubMedCrossRefGoogle Scholar
  10. 10.
    Fox TE, Han X, Kelly S et al. Diabetes alters sphingolipid metabolism in the retina: a potential mechanism of cell death in diabetic retinopathy. Diabetes 2006; 55(12):3573–3580.PubMedCrossRefGoogle Scholar
  11. 11.
    Kralik SF, Liu P, Leffler BJ et al. Ceramide and glucosamine antagonism of alternate signaling pathways regulating insulin-and osmotic shock-induced glucose transporter 4 translocation. Endocrinology 2002; 143(1):37–46.PubMedCrossRefGoogle Scholar
  12. 12.
    El Alwani M, Wu BX, Obeid LM et al. Bioactive sphingolipids in the modulation of the inflammatory response. Pharmacol Ther 2006; 112(1):171–183.PubMedCrossRefGoogle Scholar
  13. 13.
    Natalizio A, Ruggiero D, Lecomte M et al. Glycosphingolipid changes induced by advanced glycation end-products. Biochem Biophys Res Commun 2001; 281(1):78–83.PubMedCrossRefGoogle Scholar
  14. 14.
    Geoffroy K, Wiernsperger N, Lagarde M et al. Bimodal effect of advanced glycation end products on mesangial cell proliferation is mediated by neutral ceramidase regulation and endogenous sphingolipids. J Biol Chem 2004; 279(33):34343–34352.PubMedCrossRefGoogle Scholar
  15. 15.
    Masson E, Troncy L, Ruggiero D et al. a-Series gangliosides mediate the effects of advanced glycation end products on pericyte and mesangial cell proliferation: a common mediator for retinal and renal microangiopathy? Diabetes 2005; 54(1):220–227.PubMedCrossRefGoogle Scholar
  16. 16.
    Nilsson J, Bengtsson E, Fredrikson GN et al. Inflammation and immunity in diabetic vascular complications. Curr Opin Lipidol 2008; 19(5):519–524.PubMedCrossRefGoogle Scholar
  17. 17.
    Schenk S, Saberi M, Olefsky JM. Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest 2008; 118(9):2992–3002.PubMedCrossRefGoogle Scholar
  18. 18.
    Basta G, Schmidt AM, De Caterina R. Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovasc Res 2004; 63(4):582–592.PubMedCrossRefGoogle Scholar
  19. 19.
    Holland WL, Summers SA. Sphingolipids, insulin resistance and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocr Rev 2008; 29(4):381–402.PubMedCrossRefGoogle Scholar
  20. 20.
    Holland WL, Brozinick JT, Wang LP et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-and obesity-induced insulin resistance. Cell Metab 2007; 5(3):167–179.PubMedCrossRefGoogle Scholar
  21. 21.
    Deevska GM, Rozenova KA, Giltiay NV et al. Acid sphingomyelinase deficiency prevents diet-induced hepatic triacylglycerol accumulation and hyperglycemia in mice. J Biol Chem 2008.Google Scholar
  22. 22.
    Yetukuri L, Katajamaa M, Medina-Gomez G et al. Bioinformatics strategies for lipidomics analysis: characterization of obesity related hepatic steatosis. BMC Syst Biol 2007; 1:12.PubMedCrossRefGoogle Scholar
  23. 23.
    Aerts JM, Ottenhoff R, Powlson AS et al. Pharmacological inhibition of glucosylceramide synthase enhances insulin sensitivity. Diabetes 2007; 56(5):1341–1349.PubMedCrossRefGoogle Scholar
  24. 24.
    Tagami S, Inokuchi Ji J, Kabayama K et al. Ganglioside GM3 participates in the pathological conditions of insulin resistance. J Biol Chem 2002; 277(5):3085–3092.PubMedCrossRefGoogle Scholar
  25. 25.
    Zhao H, Przybylska M, Wu IH et al. Inhibiting glycosphingolipid synthesis improves glycemic control and insulin sensitivity in animal models of type 2 diabetes. Diabetes 2007; 56(5):1210–1218.PubMedCrossRefGoogle Scholar
  26. 26.
    Grigsby RJ, Dobrowsky RT. Inhibition of ceramide production reverses TNF-induced insulin resistance. Biochem Biophys Res Commun 2001; 287(5):1121–1124.PubMedCrossRefGoogle Scholar
  27. 27.
    Kabayama K, Sato T, Kitamura F et al. TNFalpha-induced insulin resistance in adipocytes as a membrane microdomain disorder: involvement of ganglioside GM3. Glycobiology 2005; 15(1):21–29.PubMedCrossRefGoogle Scholar
  28. 28.
    Yamashita T, Hashiramoto A, Haluzik M et al. Enhanced insulin sensitivity in mice lacking ganglioside GM3. Proc Natl Acad Sci USA 2003; 100(6):3445–3449.PubMedCrossRefGoogle Scholar
  29. 29.
    De Maria R, Lenti L, Malisan F et al. Requirement for GD3 ganglioside in CD95-and ceramide-induced apoptosis. Science 1997; 277(5332):1652–1655.PubMedCrossRefGoogle Scholar
  30. 30.
    Abregu AV, Genta SB, Sanchez Riera AN et al. Immunohistochemical detection of hepatic GM1 and GM2 gangliosides in streptozotocin-induced diabetic rats. Hepatol Res 2002; 24(3):256.PubMedCrossRefGoogle Scholar
  31. 31.
    Sanchez SS, Abregu AV, Aybar MJ et al. Changes in liver gangliosides in streptozotocin-induced diabetic rats. Cell Biol Int 2000; 24(12):897–904.PubMedCrossRefGoogle Scholar
  32. 32.
    Saito M, Ito M, Sugiyama K. A specific loss of C-series gangliosides in pancreas of streptozotocin-induced diabetic rats. Life Sci 1999; 64(20):1803–1810.PubMedCrossRefGoogle Scholar
  33. 33.
    Samad F, Hester KD, Yang G et al. Altered adipose and plasma sphingolipid metabolism in obesity: a potential mechanism for cardiovascular and metabolic risk. Diabetes 2006; 55(9):2579–2587.PubMedCrossRefGoogle Scholar
  34. 34.
    Adams JM, 2nd, Pratipanawatr T, Berria R et al. Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. Diabetes 2004; 53(1):25–31.PubMedCrossRefGoogle Scholar
  35. 35.
    Straczkowski M, Kowalska I, Nikolajuk A et al. Relationship between insulin sensitivity and sphingomyelin signaling pathway in human skeletal muscle. Diabetes 2004; 53(5):1215–1221.PubMedCrossRefGoogle Scholar
  36. 36.
    Turinsky J, O’Sullivan DM, Bayly BP. 1,2-Diacylglycerol and ceramide levels in insulin-resistant tissues of the rat in vivo. J Biol Chem 1990; 265(28):16880–16885.PubMedGoogle Scholar
  37. 37.
    Gorska M, Dobrzyn A, Zendzian-Piotrowska M et al. Effect of streptozotocin-diabetes on the functioning of the sphingomyelin-signalling pathway in skeletal muscles of the rat. Horm Metab Res 2004; 36(1):14–21.PubMedCrossRefGoogle Scholar
  38. 38.
    Skovbro M, Baranowski M, Skov-Jensen C et al. Human skeletal muscle ceramide content is not a major factor in muscle insulin sensitivity. Diabetologia 2008; 51(7):1253–1260.PubMedCrossRefGoogle Scholar
  39. 39.
    Gorska M, Dobrzyn A, Baranowski M. Concentrations of sphingosine and sphinganine in plasma of patients with type 2 diabetes. Med Sci Monit 2005; 11(1):CR35–38.PubMedGoogle Scholar
  40. 40.
    Buschard K, Fredman P, Bog-Hansen E et al. Low serum concentration of sulfatide and presence of sulfated lactosylceramid are associated with Type 2 diabetes. The Skaraborg Project. Diabet Med 2005; 22(9):1190–1198.PubMedCrossRefGoogle Scholar
  41. 41.
    Shimabukuro M, Higa M, Zhou YT et al. Lipoapoptosis in beta-cells of obese prediabetic fa/fa rats. Role of serine palmitoyltransferase overexpression. J Biol Chem 1998; 273(49):32487–32490.PubMedCrossRefGoogle Scholar
  42. 42.
    Shimabukuro M, Zhou YT, Levi M et al. Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes. Proc Natl Acad Sci USA 1998; 95(5):2498–2502.PubMedCrossRefGoogle Scholar
  43. 43.
    Kelpe CL, Moore PC, Parazzoli SD et al. Palmitate inhibition of insulin gene expression is mediated at the transcriptional level via ceramide synthesis. J Biol Chem 2003; 278(32):30015–30021.PubMedCrossRefGoogle Scholar
  44. 44.
    Maedler K, Oberholzer J, Bucher P et al. Monounsaturated fatty acids prevent the deleterious effects of palmitate and high glucose on human pancreatic beta-cell turnover and function. Diabetes 2003; 52(3):726–733.PubMedCrossRefGoogle Scholar
  45. 45.
    Tanaka Y, Gleason CE, Tran PO et al. Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. Proc Natl Acad Sci USA 1999; 96(19):10857–10862.PubMedCrossRefGoogle Scholar
  46. 46.
    Shimizu H, Okajima F, Kimura T et al. Sphingosine 1-phosphate stimulates insulin secretion in HIT-T 15 cells and mouse islets. Endocr J 2000; 47(3):261–269.PubMedCrossRefGoogle Scholar
  47. 47.
    Laychock SG, Sessanna SM, Lin MH et al. Sphingosine 1-phosphate affects cytokine-induced apoptosis in rat pancreatic islet beta-cells. Endocrinology 2006; 147(10):4705–4712.PubMedCrossRefGoogle Scholar
  48. 48.
    Blomqvist M, Osterbye T, Mansson JE et al. Selective lack of the C16:0 fatty acid isoform of sulfatide in pancreas of type II diabetic animal models. APMIS 2003; 111(9):867–877.PubMedCrossRefGoogle Scholar
  49. 49.
    Blomqvist M, Carrier M, Andrews T et al. 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 2005; 21(2):158–166.PubMedCrossRefGoogle Scholar
  50. 50.
    Buschard K, Hoy M, Bokvist K et al. Sulfatide controls insulin secretion by modulation of ATP-sensitive K(+)-channel activity and Ca(2+)-dependent exocytosis in rat pancreatic beta-cells. Diabetes 2002; 51(8):2514–2521.PubMedCrossRefGoogle Scholar
  51. 51.
    Osterbye T, Jorgensen KH, Fredman P et al. Sulfatide promotes the folding of proinsulin, preserves insulin crystals and mediates its monomerization. Glycobiology 2001; 11(6):473–479.PubMedCrossRefGoogle Scholar
  52. 52.
    Misasi R, Dionisi S, Farilla L et al. Gangliosides and autoimmune diabetes. Diabetes Metab Rev 1997; 13(3):163–179.PubMedCrossRefGoogle Scholar
  53. 53.
    Morano S, Tiberti C, Cristina G et al. Autoimmune markers and neurological complications in non-insulin-dependent diabetes mellitus. Hum Immunol 1999; 60(9):848–854.PubMedCrossRefGoogle Scholar
  54. 54.
    Milicevic Z, Newlon PG, Pittenger GL et al. Anti-ganglioside GM1 antibody and distal symmetric “diabetic polyneuropathy” with dominant motor features. Diabetologia 1997; 40(11):1364–1365.PubMedCrossRefGoogle Scholar
  55. 55.
    Mata S, Betti E, Masotti G et al. Motor nerve damage is associated with anti-ganglioside antibodies in diabetes. J Peripher Nerv Syst 2004; 9(3):138–143.PubMedCrossRefGoogle Scholar
  56. 56.
    Deutschman DH, Carstens JS, Klepper RL et al. Predicting obstructive coronary artery disease with serum sphingosine-1-phosphate. Am Heart J 2003; 146(1):62–68.PubMedCrossRefGoogle Scholar
  57. 57.
    Wang L, Xing XP, Holmes A et al. Activation of the sphingosine kinase-signaling pathway by high glucose mediates the proinflammatory phenotype of endothelial cells. Circ Res 2005; 97(9):891–899.PubMedCrossRefGoogle Scholar
  58. 58.
    Whetzel AM, Bolick DT, Srinivasan S et al. Sphingosine-1 phosphate prevents monocyte/endothelial interactions in type 1 diabetic NOD mice through activation of the S1P1 receptor. Circ Res 2006; 99(7):731–739.PubMedCrossRefGoogle Scholar
  59. 59.
    Ma MM, Chen JL, Wang GG et al. Sphingosine kinase 1 participates in insulin signalling and regulates glucose metabolism and homeostasis in KK/Ay diabetic mice. Diabetologia 2007; 50(4):891–900.PubMedCrossRefGoogle Scholar
  60. 60.
    Kawanabe T, Kawakami T, Yatomi Y et al. Sphingosine 1-phosphate accelerates wound healing in diabetic mice. J Dermatol Sci 2007; 48(1):53–60.PubMedCrossRefGoogle Scholar
  61. 61.
    Gorska M, Baranczuk E, Dobrzyn A. Secretory Zn2+-dependent sphingomyelinase activity in the serum of patients with type 2 diabetes is elevated. Horm Metab Res 2003; 35(8):506–507.PubMedCrossRefGoogle Scholar
  62. 62.
    Marathe S, Kuriakose G, Williams KJ et al. Sphingomyelinase, an enzyme implicated in atherogenesis, is present in atherosclerotic lesions and binds to specific components of the subendothelial extracellular matrix. Arterioscler Thromb Vasc Biol 1999; 19(11):2648–2658.PubMedGoogle Scholar
  63. 63.
    Argaud L, Prigent AF, Chalabreysse L et al. Ceramide in the antiapoptotic effect of ischemic preconditioning. Am J Physiol Heart Circ Physiol 2004; 286(1):H246–251.PubMedCrossRefGoogle Scholar
  64. 64.
    Merrill AH, Jr., Lingrell S, Wang E et al. Sphingolipid biosynthesis de novo by rat hepatocytes in culture. Ceramide and sphingomyelin are associated with, but not required for, very low density lipoprotein secretion. J Biol Chem 1995; 270(23):13834–13841.PubMedCrossRefGoogle Scholar
  65. 65.
    Charles R, Sandirasegarane L, Yun J et al. Ceramide-coated balloon catheters limit neointimal hyperplasia after stretch injury in carotid arteries. Circ Res 2000; 87(4):282–288.PubMedGoogle Scholar
  66. 66.
    O’Neill SM, Olympia DK, Fox TE et al. C6-ceramide-coated catheters promote re-endothelialization of stretch-injured arteries. Vasc Dis Prev 2008; 5(3):200–210.PubMedCrossRefGoogle Scholar
  67. 67.
    Sun Y, Fox T, Adhikary G et al. Inhibition of corneal inflammation by liposomal delivery of short-chain, C-6 ceramide. J Leukoc Biol 2008; 83(6):1512–1521.PubMedCrossRefGoogle Scholar
  68. 68.
    Zador IZ, Deshmukh GD, Kunkel R et al. A role for glycosphingolipid accumulation in the renal hypertrophy of streptozotocin-induced diabetes mellitus. J Clin Invest 1993; 91(3):797–803.PubMedCrossRefGoogle Scholar
  69. 69.
    Kwak DH, Rho YI, Kwon OD et al. Decreases of ganglioside GM3 in streptozotocin-induced diabetic glomeruli of rats. Life Sci 2003; 72(17):1997–2006.PubMedCrossRefGoogle Scholar
  70. 70.
    Geoffroy K, Troncy L, Wiernsperger N et al. Glomerular proliferation during early stages of diabetic nephropathy is associated with local increase of sphingosine-1-phosphate levels. FEBS Lett 2005; 579(5):1249–1254.PubMedCrossRefGoogle Scholar
  71. 71.
    Gardner TW, Antonetti DA, Barber AJ et al. Diabetic retinopathy: more than meets the eye. Surv Ophthalmol 2002; 47 Suppl 2:S253–262.CrossRefGoogle Scholar
  72. 72.
    Reiter CE, Sandirasegarane L, Wolpert EB et al. Characterization of insulin signaling in rat retina in vivo and ex vivo. Am J Physiol Endocrinol Metab 2003; 285(4):E763–774.PubMedGoogle Scholar
  73. 73.
    Reiter CE, Wu X, Sandirasegarane L et al. Diabetes reduces basal retinal insulin receptor signaling: reversal with systemic and local insulin. Diabetes 2006; 55(4):1148–1156.PubMedCrossRefGoogle Scholar
  74. 74.
    Barber AJ, Antonetti DA, Kern TS et al. The Ins2Akita mouse as a model of early retinal complications in diabetes. Invest Ophthalmol Vis Sci 2005; 46(6):2210–2218.PubMedCrossRefGoogle Scholar
  75. 75.
    Barber AJ, Lieth E, Khin SA et al. Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. J Clin Invest 1998; 102(4):783–791.PubMedCrossRefGoogle Scholar
  76. 76.
    Rajala A, Tanito M, Le YZ et al. Loss of neuroprotective survival signal in mice lacking insulin receptor gene in rod photoreceptor cells. J Biol Chem 2008; 283(28):19781–19792.PubMedCrossRefGoogle Scholar
  77. 77.
    Pelled D, Shogomori H, Futerman AH. The increased sensitivity of neurons with elevated glucocerebroside to neurotoxic agents can be reversed by imiglucerase. J Inherit Metab Dis 2000; 23(2):175–184.PubMedCrossRefGoogle Scholar
  78. 78.
    Ambati J, Chalam KV, Chawla DK et al. Elevated gamma-aminobutyric acid, glutamate and vascular endothelial growth factor levels in the vitreous of patients with proliferative diabetic retinopathy. Arch Ophthalmol 1997; 115(9):1161–1166.PubMedGoogle Scholar
  79. 79.
    Maines LW, French KJ, Wolpert EB et al. Pharmacologic manipulation of sphingosine kinase in retinal endothelial cells: implications for angiogenic ocular diseases. Invest Ophthalmol Vis Sci 2006; 47(11):5022–5031.PubMedCrossRefGoogle Scholar
  80. 80.
    Skoura A, Sanchez T, Claffey K et al. Essential role of sphingosine 1-phosphate receptor 2 in pathological angiogenesis of the mouse retina. J Clin Invest 2007; 117(9):2506–2516.PubMedCrossRefGoogle Scholar
  81. 81.
    Xie B, Shen J, Dong A et al. Blockade of sphingosine-1-phosphate reduces macrophage influx and retinal and choroidal neovascularization. J Cell Physiol 2009; 218(1):192–198.PubMedCrossRefGoogle Scholar
  82. 82.
    Oshima Y, Takahashi K, Oshima S et al. Intraocular gutless adenoviral-vectored VEGF stimulates anterior segment but not retinal neovascularization. J Cell Physiol 2004; 199(3):399–411.PubMedCrossRefGoogle Scholar
  83. 83.
    Bijl N, van Roomen CP, Triantis V et al. Reduction of glycosphingolipid biosynthesis stimulates biliary lipid secretion in mice. Hepatology 2008.Google Scholar
  84. 84.
    Vieira KP, de Almeida e Silva Lima Zollner AR, Malaguti C et al. Ganglioside GM1 effects on the expression of nerve growth factor (NGF), Trk-A receptor, proinflammatory cytokines and on autoimmune diabetes onset in non-obese diabetic (NOD) mice. Cytokine 2008; 42(1):92–104.PubMedCrossRefGoogle Scholar
  85. 85.
    Buschard K, Hanspers K, Fredman P et al. Treatment with sulfatide or its precursor, galactosylceramide, prevents diabetes in NOD mice. Autoimmunity 2001; 34(1):9–17.PubMedCrossRefGoogle Scholar
  86. 86.
    Mizuno M, Masumura M, Tomi C et al. Synthetic glycolipid OCH prevents insulitis and diabetes in NOD mice. J Autoimmun 2004; 23(4):293–300.PubMedCrossRefGoogle Scholar
  87. 87.
    Wang B, Geng YB, Wang CR. CD1-restricted NK T-cells protect nonobese diabetic mice from developing diabetes. J Exp Med 2001; 194(3):313–320.PubMedCrossRefGoogle Scholar
  88. 88.
    Naumov YN, Bahjat KS, Gausling R et al. Activation of CD1d-restricted T-cells protects NOD mice from developing diabetes by regulating dendritic cell subsets. Proc Natl Acad Sci USA 2001; 98(24):13838–13843.PubMedCrossRefGoogle Scholar
  89. 89.
    Sharif S, Arreaza GA, Zucker P et al. Activation of natural killer T-cells by alpha-galactosylceramide treatment prevents the onset and recurrence of autoimmune Type 1 diabetes. Nat Med 2001; 7(9):1057–1062.PubMedCrossRefGoogle Scholar
  90. 90.
    Hong S, Wilson MT, Serizawa I et al. The natural killer T-cell ligand alpha-galactosylceramide prevents autoimmune diabetes in non-obese diabetic mice. Nat Med 2001; 7(9):1052–1056.PubMedCrossRefGoogle Scholar
  91. 91.
    Chiba K. FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors. Pharmacol Ther 2005; 108(3):308–319.PubMedCrossRefGoogle Scholar
  92. 92.
    Popovic J, Kover KL, Moore WV. The effect of immunomodulators on prevention of autoimmune diabetes is stage dependent: FTY720 prevents diabetes at three different stages in the diabetes-resistant biobreeding rat. Pediatr Diabetes 2004; 5(1):3–9.PubMedCrossRefGoogle Scholar
  93. 93.
    Maki T, Gottschalk R, Monaco AP. Prevention of autoimmune diabetes by FTY720 in nonobese diabetic mice. Transplantation 2002; 74(12):1684–1686.PubMedCrossRefGoogle Scholar
  94. 94.
    Maki T, Gottschalk R, Ogawa N et al. Prevention and cure of autoimmune diabetes in nonobese diabetic mice by continuous administration of FTY720. Transplantation 2005; 79(9):1051–1055.PubMedCrossRefGoogle Scholar
  95. 95.
    Yang Z, Chen M, Fialkow LB et al. The immune modulator FYT720 prevents autoimmune diabetes in nonobese diabetic mice small star, filled. Clin Immunol 2003; 107(1):30–35.PubMedCrossRefGoogle Scholar
  96. 96.
    Hering BJ, Wijkstrom M, Graham ML et al. Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nat Med 2006; 12(3):301–303.PubMedCrossRefGoogle Scholar
  97. 97.
    Liu L, Wang C, He X et al. Long-term effect of FTY720 on lymphocyte count and islet allograft survival in mice. Microsurgery 2007; 27(4):300–304.PubMedCrossRefGoogle Scholar
  98. 98.
    Truong W, Emamaullee JA, Merani S et al. Human islet function is not impaired by the sphingosine-1-phosphate receptor modulator FTY720. Am J Transplant 2007; 7(8):2031–2038.PubMedCrossRefGoogle Scholar
  99. 99.
    Fu F, Hu S, Deleo J et al. Long-term islet graft survival in streptozotocin-and autoimmune-induced diabetes models by immunosuppressive and potential insulinotropic agent FTY720. Transplantation 2002; 73(9):1425–1430.PubMedCrossRefGoogle Scholar
  100. 100.
    Payne SG, Oskeritzian CA, Griffiths R et al. The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors. Blood 2007; 109(3):1077–1085.PubMedCrossRefGoogle Scholar
  101. 101.
    Berdyshev EV, Gorshkova I, Skobeleva A et al. FTY720 inhibits ceramide synthases and upregulates dihydrosphingosine-1-phosphate formation in human lung endothelial cells. J Biol Chem 2009.Google Scholar
  102. 102.
    Planavila A, Alegret M, Sanchez RM et al. Increased Akt protein expression is associated with decreased ceramide content in skeletal muscle of troglitazone-treated mice. Biochem Pharmacol 2005; 69(8):1195–1204.PubMedCrossRefGoogle Scholar
  103. 103.
    Todd MK, Watt MJ, Le J et al. Thiazolidinediones enhance skeletal muscle triacylglycerol synthesis while protecting against fatty acid-induced inflammation and insulin resistance. Am J Physiol Endocrinol Metab 2007; 292(2):E485–493.PubMedCrossRefGoogle Scholar
  104. 104.
    Zendzian-Piotrowska M, Baranowski M, Zabielski P et al. Effects of pioglitazone and high-fat diet on ceramide metabolism in rat skeletal muscles. J Physiol Pharmacol 2006; 57 Suppl 10:101–114.PubMedGoogle Scholar
  105. 105.
    Zhou YT, Grayburn P, Karim A et al. Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci USA 2000; 97(4):1784–1789.PubMedCrossRefGoogle Scholar
  106. 106.
    Baranowski M, Blachnio A, Zabielski P et al. Pioglitazone induces de novo ceramide synthesis in the rat heart. Prostaglandins Other Lipid Mediat 2007; 83(1–2):99–111.PubMedCrossRefGoogle Scholar
  107. 107.
    Wilson KD, Li Z, Wagner R et al. Transcriptome alteration in the diabetic heart by rosiglitazone: implications for cardiovascular mortality. PLoS ONE 2008; 3(7):e2609.PubMedCrossRefGoogle Scholar
  108. 108.
    Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356(24):2457–2471.PubMedCrossRefGoogle Scholar
  109. 109.
    Smith AC, Mullen KL, Junkin KA et al. Metformin and exercise reduce muscle FAT/CD36 and lipid accumulation and blunt the progression of high-fat diet-induced hyperglycemia. Am J Physiol Endocrinol Metab 2007; 293(1):E172–181.PubMedCrossRefGoogle Scholar

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© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  1. 1.Department of PharmacologyPenn State College of MedicineHersheyUSA

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