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Polar lipid derangements in type 2 diabetes mellitus: potential pathological relevance of fatty acyl heterogeneity in sphingolipids

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Abstract

While pathological alterations in plasma neutral lipids with type 2 diabetes mellitus (T2DM) has been relatively well-characterized, only limited information is available on the variations in global polar lipidome (glycerophospholipids and sphingolipids) with the disease. To systematically identify polar lipid aberrations associated with early stage T2DM, we quantitatively profiled and compared changes in more than 300 plasma lipid species from distinct groups of T2DM patients against overtly healthy controls. Sphingolipid classes including ceramides, sphingomyelins, lactosylceramides (LacCer) and ganglioside GM3 (GM3) were significantly elevated in mild T2DM with a concomitant decrease in glucosylceramides (GluCer), suggesting the increased conversion of GluCer to LacCer in mild diabetes. Individual GM3 species were altered in T2DM according to their acyl chain lengths. While long-chain GM3s (fatty acyl carbon ≥18) were significantly increased in T2DM, the opposite was observed for GM3 18:1/16:0. Importantly, long-chain GM3 species were negatively correlated with HOMA2-%β and positively correlated with FBG; and could distinguish between healthy individuals and mildly diabetic patients with similar HOMA2-%β. The current study therefore identifies metabolic alterations in sphingolipid pathways as early events in T2DM pathogenesis, and provides hypothesis-generating new insights relevant for larger scale clinical studies aimed at identification of early molecular markers of T2DM.

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References

  1. Barber, M. N., Risis, S., Yang, C., et al. (2012). Plasma lysophosphatidylcholine levels are reduced in obesity and type 2 diabetes. PLoS ONE, 7, e41456.

  2. Bolin, D. J., & Jonas, A. (1994). Binding of lecithin:cholesterol acyltransferase to reconstituted high density lipoproteins is affected by their lipid but not apolipoprotein composition. Journal of Biological Chemistry, 269, 7429–7434.

  3. Boon, J., Hoy, A. J., Stark, R., et al. (2012). Ceramides contained in LDL are elevated in type 2 diabetes and promote inflammation and skeletal muscle insulin resistance. Diabetes, doi:10.2337/db12-0686.

  4. Brunham, L., Kruit, J., Verchere, C., et al. (2008). Cholesterol in islet dysfunction and type 2 diabetes. The Journal of Clinical Investigation, 118, 403–408.

  5. Chavez, J. A., & Summers, S. A. (2010). Lipid oversupply, selective insulin resistance, and lipotoxicity: molecular mechanisms. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 1801, 252–265.

  6. de Mello, V. D. F., Lankinen, M., Schwab, U., et al. (2009). Link between plasma ceramides, inflammation and insulin resistance: association with serum IL-6 concentration in patients with coronary heart disease. Diabetologia, 52, 2612–2615.

  7. Donath, M. Y., & Shoelson, S. E. (2011). Type 2 diabetes as an inflammatory disease. Nature Reviews Immunology, 11, 98–107.

  8. Drobnik, W., Liebisch, G., Audebert, F. X., et al. (2003). Plasma ceramide and lysophosphatidylcholine inversely correlate with mortality in sepsis patients. Journal of Lipid Research, 44, 754–761.

  9. Fuller, M. (2010). Sphingolipids: the nexus between gaucher disease and insulin resistance. Lipids in Health and Disease, 9, 113.

  10. Haus, J. M., Kashyap, S. R., Kasumov, T., et al. (2009). Plasma ceramides are elevated in obese subjects with type 2 diabetes and correlate with the severity of insulin resistance. Diabetes, 58, 337–343.

  11. Hill, M. J., Metcalfe, D., McTernan, P. G., et al. (2009). Obesity and diabetes: lipids, ‘nowhere to run to’. Clinical Science (London), 116, 113–123.

  12. Hiukka, A., Ståhlman, M., Pettersson, C., et al. (2009). ApoCIII-enriched LDL in type 2 diabetes displays altered lipid composition, increased susceptibility for sphingomyelinase, and increased binding to biglycan. Diabetes, 58, 2018–2026.

  13. Holland, W. L., Bikman, B. T., Wang, L. P., et al. (2011). Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. The Journal of Clinical Investigation, 121, 1858–1870.

  14. Holland, W. L., & Summers, S. A. (2008). Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocrine Reviews, 29, 381–402.

  15. Iwase, M., Sonoki, K., Sasaki, N., et al. (2008). Lysophosphatidylcholine contents in plasma LDL in patients with type 2 diabetes mellitus: relation with lipoprotein-associated phospholipase A2 and effects of simvastatin treatment. Atherosclerosis, 196, 931–936.

  16. Kabayama, K., Sato, T., Saito, K., et al. (2007). Dissociation of the insulin receptor and caveolin-1 complex by ganglioside GM3 in the state of insulin resistance. The Proceedings of the National Academy of Sciences of the United States of America, 104, 13678–13683.

  17. Kahn, S. E., Hull, R. L., Utzschneider, K. M., et al. (2006). Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature, 444, 840–846.

  18. Kaur, P., Rizk, N. M., Ibrahim, S., et al. (2012). iTRAQ-based quantitative protein expression profiling and MRM verification of markers in type 2 diabetes. Journal of Proteome Research, 11(11), 5527–5539.

  19. Kobayashi, T., Beuchat, M. H., Lindsay, M., et al. (1999). Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport. Nature Cell Biology, 1, 113–118.

  20. Kuniyasu, A., Tokunaga, M., Yamamoto, T., et al. (2011). Oxidized LDL and lysophosphatidylcholine stimulate plasminogen activator inhibitor-1 expression through reactive oxygen species generation and ERK1/2 activation in 3T3-L1 adipocytes. Biochimica et Biophysica Acta, 1811, 153–162.

  21. Lee, L. H. W., Tan, C. H., Lo, Y. L., et al. (2012). Brain lipid changes after repetitive transcranial magnetic stimulation: potential links to therapeutic effects? Metabolomics, 8, 19–33.

  22. Li, Z., Zhang, H., Liu, J., et al. (2011). Reducing plasma membrane sphingomyelin increases insulin sensitivity. Molecular and Cellular Biology, 31, 4205–4218.

  23. Lightle, S., Tosheva, R., Lee, A., et al. (2003). Elevation of ceramide in serum lipoproteins during acute phase response in humans and mice: role of serine-palmitoyl transferase. Archives of Biochemistry and Biophysics, 419, 120–128.

  24. McGarry, J. D. (1992). What if Minkowski had been ageusic? an alternative angle on diabetes. Science, 258, 766–770.

  25. Metz, S. (1986). Lysophosphatidylinositol, but not lysophosphatidic acid, stimulates insulin release: a possible role for phospholipase A2 but not de novo synthesis of lysophospholipid in pancreatic islet function. Biochemical and Biophysical Research Communications, 138, 720–727.

  26. Minehira, K., Young, S. G., Villanueva, C. J., et al. (2008). Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice. Journal of Lipid Research, 49, 2038–2044.

  27. Mitsutake, S., Zama, K., Yokota, H., et al. (2011). Dynamic modification of sphingomyelin in lipid microdomains controls development of obesity, fatty liver, and type 2 diabetes. Journal of Biological Chemistry, 286, 28544–28555.

  28. Mooradian, A. D. (2009). Dyslipidemia in type 2 diabetes mellitus. Nature Clinical Practice Endocrinology & Metabolism, 5, 150–159.

  29. Murtola, T., Vuorela, T. A., Hyvönen, M. T., et al. (2011). Low density lipoprotein: structure, dynamics, and interactions of apoB-100 with lipids. Soft Matter, 7, 8135–8141.

  30. Poitout, V., & Robertson, R. P. (2008). Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocrine Reviews, 29, 351–366.

  31. Quehenberger, O., Armando, A. M., Brown, A. H., et al. (2010). Lipidomics reveals a remarkable diversity of lipids in human plasma. The Journal of Lipid Research, 51, 3299–3305.

  32. Schmitz, G., & Ruebsaamen, K. (2010). Metabolism and atherogenic disease association of lysophosphatidylcholine. Atherosclerosis, 208, 10–18.

  33. Schuette, C. G., Doering, T., Kolter, T., et al. (1999). The glycosphingolipidoses: from disease to basic principles of metabolism. Biological chemistry, 380, 759–766.

  34. Shi, A. H., Yoshinari, M., Wakisaka, M., et al. (1999). Lysophosphatidylcholine molecular species in low density lipoprotein of type 2 diabetes. Hormone and Metabolic Research, 31, 283–286.

  35. Shui, G., Cheong, W. F., Jappar, I. A., et al. (2011a). Derivatization-independent cholesterol analysis in crude lipid extracts by liquid chromatography/mass spectrometry: applications to a rabbit model for atherosclerosis. Journal of Chromatography A, 1218, 4357–4365.

  36. Shui, G., Guan, X. L., Low, C. P., et al. (2010). Toward one step analysis of cellular lipidomes using liquid chromatography coupled with mass spectrometry: application to Saccharomyces cerevisiae and Schizosaccharomyces pombe lipidomics. Molecular BioSystems, 6, 1008–1017.

  37. Shui, G., Stebbins, J. W., Lam, B. D., et al. (2011b). Comparative plasma lipidome between human and cynomolgus monkey: Are plasma polar lipids good biomarkers for diabetic monkeys? PLoS ONE, 6, e19731.

  38. Skovbro, M., Baranowski, M., Skov-Jensen, C., et al. (2008). Human skeletal muscle ceramide content is not a major factor in muscle insulin sensitivity. Diabetologia, 51, 1253–1260.

  39. Sonnino, S., Mauri, L., Chigorno, V., et al. (2007). Gangliosides as components of lipid membrane domains. Glycobiology, 17, 1R–13R.

  40. Ståhlman, M., Pham, H. T., Adiels, M., et al. (2012). Clinical dyslipidaemia is associated with changes in the lipid composition and inflammatory properties of apolipoprotein-B-containing lipoproteins from women with type 2 diabetes. Diabetologia, 55, 1156–1166.

  41. Stratford, S., Hoehn, K. L., Liu, F., et al. (2004). Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. Journal of Biological Chemistry, 279, 36608–36615.

  42. Suhre, K., Meisinger, C., Döring, A., et al. (2010). Metabolic footprint of diabetes: a multiplatform metabolomics study in an epidemiological setting. PLoS ONE, 5, e13953.

  43. Summers, S. (2006). Ceramides in insulin resistance and lipotoxicity. Progress in Lipid Research, 45, 42–72.

  44. Tagami, S., Inokuchi Ji, J. I., Kabayama, K., et al. (2002). Ganglioside GM3 participates in the pathological conditions of insulin resistance. Journal of Biological Chemistry, 277, 3085–3092.

  45. Unger, R. (2003). Lipid overload and overflow: metabolic trauma and the metabolic syndrome. Trends in Endocrinology and Metabolism, 14, 398–403.

  46. Unger, R. H., Clark, G. O., Scherer, P. E., et al. (2010). Lipid homeostasis, lipotoxicity and the metabolic syndrome. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 1801, 209–214.

  47. van Eijk, M., Aten, J., Bijl, N., et al. (2009). Reducing glycosphingolipid content in adipose tissue of obese mice restores insulin sensitivity, adipogenesis and reduces inflammation. PLoS ONE, 4, e4723.

  48. Wang, T. J., Larson, M. G., Vasan, R. S., et al. (2011). Metabolite profiles and the risk of developing diabetes. Nature Medicine, 17, 448–453.

  49. Weir, G. C., & Bonner-Weir, S. (2004). Five stages of evolving beta-cell dysfunction during progression to diabetes. Diabetes, 53(Suppl 3), S16–S21.

  50. Wiesner, P., Leidl, K., Boettcher, A., et al. (2008). Lipid profiling of FPLC-separated lipoprotein fractions by electrospray ionization tandem mass spectrometry. The Journal of Lipid Research, 50, 574–585.

  51. Yamashita, T., Hashiramoto, A., Haluzik, M., et al. (2003). Enhanced insulin sensitivity in mice lacking ganglioside GM3. The Proceedings of the National Academy of Sciences of the United States of America, 100, 3445–3449.

  52. Yang, L. V., Radu, C. G., Wang, L., et al. (2005). Gi-independent macrophage chemotaxis to lysophosphatidylcholine via the immunoregulatory GPCR G2A. Blood, 105, 1127–1134.

  53. Zhao, H., Przybylska, M., Wu, I. H., et al. (2007). Inhibiting glycosphingolipid synthesis improves glycemic control and insulin sensitivity in animal models of type 2 diabetes. Diabetes, 56, 1210–1218.

  54. Zigmond, E., Zangen, S. W., Pappo, O., et al. (2008). Glycosphingolipids improve glucose intolerance and hepatic steatosis of the Cohen diabetic rat. The American Journal of Physiology-Endocrinology and Metabolism, 296, E72–E78.

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Correspondence to Guanghou Shui or Markus R. Wenk.

Additional information

Guanghou Shui and Sin Man Lam contributed equally to this study.

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Shui, G., Lam, S.M., Stebbins, J. et al. Polar lipid derangements in type 2 diabetes mellitus: potential pathological relevance of fatty acyl heterogeneity in sphingolipids. Metabolomics 9, 786–799 (2013). https://doi.org/10.1007/s11306-013-0494-0

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Keywords

  • T2DM
  • Ganglioside GM3
  • Sphingolipids
  • Lipidomics
  • Biomarkers
  • Mass spectrometry