Highlights
- •Low levels of VLC lactoceramides predicted progression of macroalbuminuria in DM.
- •Lactoceramide levels are not significantly associated with reduced eGFR.
- •Hexosylceramides are not significantly associated with progression of macroalbuminuria.
- •Increase of C18:1H, a minor hexosylceramide, is associated with reduced eGFR.
Background
Glycosphingolipids are important components of cell membranes, modulators of cell-cell
interactions and cell recognition, and have recently emerged as bioactive molecules
and important players in nearly all cell biological processes. We previously have
shown that decreased plasma levels of long and very long species of ceramides were
able to predict the development of macroalbuminuria (MA) in type 1 diabetes.
Objective
This study proposed to examine whether plasma glycosphingolipids could predict development
of diabetic nephropathy, assessed as MA or chronic kidney disease (CKD).
Methods
Measurement of plasma hexosylceramides (H) and lactosylceramides (L) were conducted
in the Lipidomics Core Facility of our Institution in a subcohort of 432 patients
from the DCCT/Epidemiology of Diabetes Interventions and Complications cohort in plasma
collected at entry into the study. Inverse probability weighted Cox proportional hazards
regression models were used to assess the effect of glycosphingolipids levels on the
risk of developing MA (albumin excretion rate ≥300 mg/24 hours) or CKD (glomerular
filtration rate <60 mL/min) over a period of 21 to 28 years.
Results
Decreases of several long and very long chain lactosylceramides were significantly
associated with increased risk of progression to MA but not CKD. Among the hexosylceramides,
the only significant association observed was between one of its minor species C18:1–H
and CKD.
Conclusion
Our findings showed that decreased levels of long and very long lactosylceramides
were able to predict the development of MA in type 1 diabetes. This finding is similar
to previous findings showing that low levels of long and very long ceramides were
also able to predict development of MA in the same cohort. Further studies are needed
to determine the changes in sphingolipid metabolism leading to the development of
complications.
Keywords
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References
- KDOQI clinical practice guidelines for diabetes and CKD: 2012 update.Am J Kidney Dis. 2012; 60: 850-886
- Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals.JAMA. 2001; 286: 421-426
- Dyslipidemia associated with chronic kidney disease.Open Cardiovasc Med J. 2011; 5: 41-48
- Diabetic nephropathy induces alterations in the glomerular and tubule lipid profiles.J Lipid Res. 2014; 55: 1375-1385
- Therapeutic strategies for diabetes and complications: a role for sphingolipids.Adv Exp Med Biol. 2010; 688: 206-216
- ELOVL4-mediated production of very long-chain ceramides stabilizes tight junctions and prevents diabetes-induced retinal vascular permeability.Diabetes. 2018; 67: 769-781
- Sphingolipids: second messengers, mediators and raft constituents in signaling.Immunol Today. 2000; 21: 555-560
- Sphingolipids and their metabolism in physiology and disease.Nat Rev Mol Cell Biol. 2018; 19: 175-191
- Sphingolipids and redox signaling in renal regulation and chronic kidney diseases.Antioxid Redox Signal. 2018; https://doi.org/10.1089/ars.2017.7129
- Roles of glycosphingolipids in cell signaling: adhesion, migration, and proliferation.Methods Enzymol. 2003; 363: 300-312
- Glycosphingolipids and mitochondria: role in apoptosis and disease.Glycoconj J. 2004; 20: 579-588
- Glycosphingolipids–nature, function, and pharmacological modulation.Angew Chem Int Ed Engl. 2009; 48: 8848-8869
- Sphingolipids and insulin resistance: the five Ws.Curr Opin Lipidol. 2010; 21: 128-135
- Ceramides as modulators of cellular and whole-body metabolism.J Clin Invest. 2011; 121: 4222-4230
- Review: glycosphingolipids in health and disease.Ann Clin Lab Sci. 2014; 34: 3-13
- Glycosphingolipids and kidney disease.Adv Exp Med Biol. 2011; 721: 121-138
- Blood sphingolipids in homeostasis and pathobiology.Adv Exp Med Biol. 2011; 721: 57-66
- Specific Hepatic Sphingolipids relate to Insulin Resistance, oxidative stress and inflammation in non-alcoholic steatohepatitis.Diabetes Care. 2018; 41: 1235-1243
- Reconsideration of hydrophobic lipid distributions in lipoprotein particles.Chem Phys Lipids. 2008; 155: 57-62
- Sphingosine 1-phosphate distribution in human plasma: associations with lipid profiles.J Lipids. 2012; 2012: 180705
- Sphingolipids and lipoproteins in health and metabolic disorders.Trends Endocrinol Metab. 2017; 28: 506-518
- Blood sphingolipidomics in healthy humans: impact of sample collection and methodology.J Lipid Res. 2010; 51: 3074-3087
- Metabolism of very long chain fatty acids: genes and pathophysiology.Biomol Ther (Seoul). 2014; 22: 83-92
- Microsomal triglyceride transfer protein transfers and determines plasma concentrations of ceramide and sphingomyelin but not glycosylceramide.J Biol Chem. 2015; 290: 25863-25875
- ATP binding cassette family A protein 1 determines hexosylceramide and sphingomyelin levels in human and mouse plasma.J Lipid Res. 2018; 59: 2084-2097
- A role for glycosphingolipid accumulation in the renal hypertrophy of streptozotocin-induced diabetes mellitus.J Clin Invest. 1993; 91: 797-803
- Kidney glycosphingolipids are elevated early in diabetic nephropathy and mediate hypertrophy of mesangial cells.Am J Physiol Renal Physiol. 2015; 309: F204-F215
- Decreased plasma levels of select very long chain ceramides species are associated with the development of nephropathy in type 1 diabetes.Metabolism. 2014; 63: 1287-1295
- Sphingomyelin is associated with kidney disease in type 1 diabetes (The FinnDiane Study).Metabolomics. 2012; 8: 369-375
- The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.N Engl J Med. 1993; 329: 977-986
- Epidemiology of Diabetes Interventions and Complications. Design, implementation, and preliminary results of a long-term follow-up of the diabetes control and complications trial cohort.Diabetes Care. 1999; 22: 99-111
- HDL3, but not HDL2, stimulates plasminogen activator inhibitor-1 release from adipocytes: the role of sphingosine-1-phosphate.J Lipid Res. 2010; 51: 2619-2628
- Sphingosine 1-phosphate distribution in plasma: associations with atypical lipoprotein profiles.J Lipids. 2012; 2012: 180705
- A new equation to estimate glomerular filtration rate.Ann Intern Med. 2009; 150: 604-612
- Controlling the false discovery rate: a practical and powerful approach to multiple testing.J R Stat Soc Series B Stat Methodol. 1995; 57: 289-300
- Renal glycosphingolipid metabolism is dysfunctional in lupus nephritis.J Am Soc Nephrol. 2015; 26: 1402-1413
- Suramin: a potential therapy for diabetic nephropathy.PLoS One. 2013; 8: e73655
- Regulation of neutral sphingomyelinase-2 by GSH: a new insight to the role of oxidative stress in aging-associated inflammation.J Lipid Res. 2007; 48: 2443-2452
- Connection of lipid peroxide oxidation with the sphingomyelin pathway in the development of Alzheimer’s disease.Biochem Soc Trans. 2004; 32: 144-146
- Neutral and acidic glycosphingolipids in glucocorticoid-induced cataract in chick lens.Exp Eye Res. 1999; 68: 229-236
- Ceramide accumulation during oxidant renal tubular injury: mechanisms and potential consequences.J Am Soc Nephrol. 1998; 9: 1670-1680
- Role of neutral sphingomyelinases in aging and inflammation.Subcell Biochem. 2008; 49: 469-486
- Increase in sphingolipid catabolic enzyme activity during aging.Acta Pharmacol Sin. 2009; 30: 1454-1461
- Dysregulations in circulating sphingolipids associate with disease activity indices in female patients with systemic lupus erythematous: a cross-sectional study.Lupus. 2017; 26: 1023-1033
- Very long chain fatty acids: elongation, physiology and related disorders.J Biochem. 2012; 152: 387-395
- The role of fatty acid elongation in epidermal structure and function.Dermatoendocrinol. 2011; 3: 65-69
- Accumulation of long-chain glycosphingolipids during aging is prevented by caloric restriction.PLoS One. 2011; 6: e20411
Article info
Publication history
Published online: April 03, 2019
Accepted:
March 26,
2019
Received:
October 25,
2018
Identification
Copyright
© 2019 Published by Elsevier Inc. on behalf of National Lipid Association.
