Skip to main content
Top
Published in:

03-01-2024 | Type 2 Diabetes | Original Article

Urinary sphingolipids in adolescents and young adults with youth-onset diabetes

Authors: Edward J. Nehus, Nicole M. Sheanon, Wujuan Zhang, Santica M. Marcovina, Kenneth D. R. Setchell, Mark M. Mitsnefes

Published in: Pediatric Nephrology | Issue 6/2024

Login to get access

Abstract

Background

This study evaluated urinary sphingolipids as a marker of diabetic kidney disease (DKD) in adolescents and young adults with youth-onset type 1 and type 2 diabetes.

Methods

A comprehensive panel of urinary sphingolipids, including sphingomyelin (SM), glucosylceramide (GC), ceramide (Cer), and lactosylceramide (LC) species, was performed in patients with youth-onset diabetes from the SEARCH for Diabetes in Youth cohort. Sphingolipid levels, normalized to urine creatinine, were compared in 57 adolescents and young adults with type 1 diabetes, 59 with type 2 diabetes, and 44 healthy controls. The association of sphingolipids with albumin-to-creatinine (ACR) ratio and estimated glomerular filtration rate (eGFR) was evaluated.

Results

The median age (interquartile range [IQR]) of participants was 23.1 years (20.9, 24.9) and the median duration of diabetes was 9.3 (8.5, 10.2) years. Urinary sphingolipid concentrations in patients with and without DKD (ACR ≥ 30 mg/g) were significantly elevated compared to healthy controls. There were no significant differences in sphingolipid levels between participants with type 1 and type 2 diabetes. In multivariable analysis, many sphingolipid species were positively correlated with ACR. Most significant associations were evident for the following species: C18 SM, C24:1 SM, C24:1 GC, and C24:1 Cer (all p < 0.001). Sphingolipid levels were not associated with eGFR. However, several interaction terms (diabetes type*sphingolipid) were significant, indicating diabetes type may modify the association of sphingolipids with eGFR.

Conclusion

Urinary sphingolipids are elevated in adolescents and young adults with youth-onset diabetes and correlate with ACR. Urinary sphingolipids may therefore represent an early biomarker of DKD.

Graphical abstract

Appendix
Available only for authorised users
Literature
1.
go back to reference Saran R, Robinson B, Abbott KC et al (2019) US Renal Data System 2018 Annual Data Report: Epidemiology of Kidney Disease in the United States. Am J Kidney Dis 73:A7–A8CrossRefPubMedPubMedCentral Saran R, Robinson B, Abbott KC et al (2019) US Renal Data System 2018 Annual Data Report: Epidemiology of Kidney Disease in the United States. Am J Kidney Dis 73:A7–A8CrossRefPubMedPubMedCentral
2.
go back to reference Macisaac RJ, Jerums G (2011) Diabetic kidney disease with and without albuminuria. Curr Opin Nephrol Hypertens 20:246–257CrossRefPubMed Macisaac RJ, Jerums G (2011) Diabetic kidney disease with and without albuminuria. Curr Opin Nephrol Hypertens 20:246–257CrossRefPubMed
3.
go back to reference Caramori ML, Fioretto P, Mauer M (2003) Low glomerular filtration rate in normoalbuminuric type 1 diabetic patients: an indicator of more advanced glomerular lesions. Diabetes 52:1036–1040CrossRefPubMed Caramori ML, Fioretto P, Mauer M (2003) Low glomerular filtration rate in normoalbuminuric type 1 diabetic patients: an indicator of more advanced glomerular lesions. Diabetes 52:1036–1040CrossRefPubMed
4.
go back to reference Dwyer JP, Parving HH, Hunsicker LG, Ravid M, Remuzzi G, Lewis J (2012) Renal dysfunction in the presence of normoalbuminuria in type 2 diabetes: Results from the demand study. Cardiorenal Med 2:1–10CrossRefPubMed Dwyer JP, Parving HH, Hunsicker LG, Ravid M, Remuzzi G, Lewis J (2012) Renal dysfunction in the presence of normoalbuminuria in type 2 diabetes: Results from the demand study. Cardiorenal Med 2:1–10CrossRefPubMed
5.
go back to reference MacIsaac RJ, Tsalamandris C, Panagiotopoulos S, Smith TJ, McNeil KJ, Jerums G (2004) Nonalbuminuric renal insufficiency in type 2 diabetes. Diabetes Care 27:195–200CrossRefPubMed MacIsaac RJ, Tsalamandris C, Panagiotopoulos S, Smith TJ, McNeil KJ, Jerums G (2004) Nonalbuminuric renal insufficiency in type 2 diabetes. Diabetes Care 27:195–200CrossRefPubMed
7.
go back to reference Sas KM, Nair V, Byan J et al (2015) Targeted lipidomic and transcriptomic analysis identifies dysregulated renal ceramide metabolism in a mouse model of diabetic kidney disease. J Proteomics Bioinform Suppl 14:002 Sas KM, Nair V, Byan J et al (2015) Targeted lipidomic and transcriptomic analysis identifies dysregulated renal ceramide metabolism in a mouse model of diabetic kidney disease. J Proteomics Bioinform Suppl 14:002
8.
go back to reference Liu G, Han F, Yang Y et al (2011) Evaluatin of sphingolipid metabolism in renal cortex of rats with streptoztocin-induced diabetes and the effects of rapamycin. Nephrol Dial Transplant 26:1493–1502CrossRefPubMed Liu G, Han F, Yang Y et al (2011) Evaluatin of sphingolipid metabolism in renal cortex of rats with streptoztocin-induced diabetes and the effects of rapamycin. Nephrol Dial Transplant 26:1493–1502CrossRefPubMed
9.
go back to reference Zador IZ, Deshmukh GD, Kunkel R, Johnson K, Radin NS, Shayman JA (1993) A role for glycosphingolipid accumulation in the renal hypertrophy of streptozotocin-induced diabetes mellitus. J Clin Invest 91:797–803CrossRefPubMedPubMedCentral Zador IZ, Deshmukh GD, Kunkel R, Johnson K, Radin NS, Shayman JA (1993) A role for glycosphingolipid accumulation in the renal hypertrophy of streptozotocin-induced diabetes mellitus. J Clin Invest 91:797–803CrossRefPubMedPubMedCentral
10.
go back to reference Subathra M, Korrapati M, Howell LA et al (2015) Kidney glycosphingolipids are elevated early in diabetic nephropathy and mediate hypertrophy of mesangial cells. Am J Physiol Renal Physiol 309:F204–F215CrossRefPubMedPubMedCentral Subathra M, Korrapati M, Howell LA et al (2015) Kidney glycosphingolipids are elevated early in diabetic nephropathy and mediate hypertrophy of mesangial cells. Am J Physiol Renal Physiol 309:F204–F215CrossRefPubMedPubMedCentral
11.
go back to reference Bijl N, Sokolovic M, Vrins C et al (2009) Modulation of glycosphingolipid metabolism significantly improves hepatic insulin sensitivity and reverses hepatic steatosis in mice. Hepatology 50:1431–1441CrossRefPubMed Bijl N, Sokolovic M, Vrins C et al (2009) Modulation of glycosphingolipid metabolism significantly improves hepatic insulin sensitivity and reverses hepatic steatosis in mice. Hepatology 50:1431–1441CrossRefPubMed
12.
go back to reference Boon J, Hoy AJ, Stark R et al (2013) Ceramides contained in LDL are elevated in type 2 diabetes and promote inflammation and skeletal muscle insulin resistance. Diabetes 62:401–410CrossRefPubMedPubMedCentral Boon J, Hoy AJ, Stark R et al (2013) Ceramides contained in LDL are elevated in type 2 diabetes and promote inflammation and skeletal muscle insulin resistance. Diabetes 62:401–410CrossRefPubMedPubMedCentral
13.
go back to reference Griess K, Rieck M, Muller N et al (2023) Sphingolipid subtypes differentially control proinsulin processing and systemic glucose homeostasis. Nat Cell Biol 25:20–29CrossRefPubMed Griess K, Rieck M, Muller N et al (2023) Sphingolipid subtypes differentially control proinsulin processing and systemic glucose homeostasis. Nat Cell Biol 25:20–29CrossRefPubMed
14.
go back to reference Aburasayn H, Al Batran R, Ussher JR (2016) Targeting ceramide metabolism in obesity. Am J Physiol Endocrinol Metab 311:E423-435CrossRefPubMed Aburasayn H, Al Batran R, Ussher JR (2016) Targeting ceramide metabolism in obesity. Am J Physiol Endocrinol Metab 311:E423-435CrossRefPubMed
15.
go back to reference SEARCH Study Group (2004) SEARCH for Diabetes in Youth: a multicenter study of the prevalence, incidence and classification of diabetes mellitus in youth. Control Clin Trials 25:458–471CrossRef SEARCH Study Group (2004) SEARCH for Diabetes in Youth: a multicenter study of the prevalence, incidence and classification of diabetes mellitus in youth. Control Clin Trials 25:458–471CrossRef
16.
go back to reference Hamman RF, Bell RA, Dabelea D et al (2014) The SEARCH for Diabetes in Youth study: rationale, findings, and future directions. Diabetes Care 37:3336–3344CrossRefPubMedPubMedCentral Hamman RF, Bell RA, Dabelea D et al (2014) The SEARCH for Diabetes in Youth study: rationale, findings, and future directions. Diabetes Care 37:3336–3344CrossRefPubMedPubMedCentral
17.
go back to reference Pierce CB, Munoz A, Ng DK, Warady BA, Furth SL, Schwartz GJ (2021) Age- and sex-dependent clinical equations to estimate glomerular filtration rates in children and young adults with chronic kidney disease. Kidney Int 99:948–956CrossRefPubMed Pierce CB, Munoz A, Ng DK, Warady BA, Furth SL, Schwartz GJ (2021) Age- and sex-dependent clinical equations to estimate glomerular filtration rates in children and young adults with chronic kidney disease. Kidney Int 99:948–956CrossRefPubMed
18.
go back to reference Davis S, Nehus E, Inge T, Zhang W, Setchell K, Mitsnefes M (2018) Effect of bariatric surgery on urinary sphingolipids in adolescents with severe obesity. Surg Obes Relat Dis 14:446–451CrossRefPubMed Davis S, Nehus E, Inge T, Zhang W, Setchell K, Mitsnefes M (2018) Effect of bariatric surgery on urinary sphingolipids in adolescents with severe obesity. Surg Obes Relat Dis 14:446–451CrossRefPubMed
20.
go back to reference Li G, Kidd J, Gehr T, Li P (2021) Podocyte sphingolipid signaling in nephrotic syndrome. Cell Phsiol Biochem 55(Suppl 4):13–34 Li G, Kidd J, Gehr T, Li P (2021) Podocyte sphingolipid signaling in nephrotic syndrome. Cell Phsiol Biochem 55(Suppl 4):13–34
21.
go back to reference Roszczyc-Owsiejczuk K, Zabielski P (2021) Sphingolipids as a culprit of mitochondrial dysfunction in insulin resistance and type 2 diabetes. Front Endcrionol 12:635175CrossRef Roszczyc-Owsiejczuk K, Zabielski P (2021) Sphingolipids as a culprit of mitochondrial dysfunction in insulin resistance and type 2 diabetes. Front Endcrionol 12:635175CrossRef
22.
go back to reference Hammand S, Lopes-Virella M (2023) Circulating sphingolipids in insulin resistance, diabetes, and associated complications. Int J Mol Sci 24:14015CrossRef Hammand S, Lopes-Virella M (2023) Circulating sphingolipids in insulin resistance, diabetes, and associated complications. Int J Mol Sci 24:14015CrossRef
23.
go back to reference Lui J, Ghosh S, Kovalik J et al (2016) Profiling of plasma metabolites suggests altered mitochondrial fuel usage and remodeling of sphingolipid metabolism in individuals with type 2 diabetes and kidney disease. Kidney Int Rep 2:470–480 Lui J, Ghosh S, Kovalik J et al (2016) Profiling of plasma metabolites suggests altered mitochondrial fuel usage and remodeling of sphingolipid metabolism in individuals with type 2 diabetes and kidney disease. Kidney Int Rep 2:470–480
24.
go back to reference Barlovic D, Harjustsalo V, Sandhom N, Forsblom C; FinnDiane Study Group (2020) Sphingomyelin and progression of renal and coronary heart disease in individuals with type 1 diabetes. Diabetologia 63:1847–1856CrossRef Barlovic D, Harjustsalo V, Sandhom N, Forsblom C; FinnDiane Study Group (2020) Sphingomyelin and progression of renal and coronary heart disease in individuals with type 1 diabetes. Diabetologia 63:1847–1856CrossRef
25.
go back to reference Makinen V, Tynkkynen T, Soininen P et al (2012) Sphingomyelin is associated with kidney disease in type 1 diabetes (The FinnDiane Study). Metabolomics 8:369–375CrossRefPubMed Makinen V, Tynkkynen T, Soininen P et al (2012) Sphingomyelin is associated with kidney disease in type 1 diabetes (The FinnDiane Study). Metabolomics 8:369–375CrossRefPubMed
26.
go back to reference Morita Y, Kuran M, Sakai E et al (2020) Analysis of urinary sphingolipids usiing liquid chromatography-tandem mass spectrometyr in diabetic nephropathy. J Diabetes Invest 11:441–449CrossRef Morita Y, Kuran M, Sakai E et al (2020) Analysis of urinary sphingolipids usiing liquid chromatography-tandem mass spectrometyr in diabetic nephropathy. J Diabetes Invest 11:441–449CrossRef
28.
go back to reference Russo SB, Ross JS, Cowart LA (2013) Spingolipids in obesity, type 2 diabetes, and metabolic disease. Handb Exp Pharmacol 216:373–401 Russo SB, Ross JS, Cowart LA (2013) Spingolipids in obesity, type 2 diabetes, and metabolic disease. Handb Exp Pharmacol 216:373–401
29.
go back to reference Stathem M, Marimuthu S, O’Neal J et al (2015) Glucose availability and glycolytic metabolism dictate glycosphingolipid levels. J Cell Biochem 116:67–80CrossRefPubMedPubMedCentral Stathem M, Marimuthu S, O’Neal J et al (2015) Glucose availability and glycolytic metabolism dictate glycosphingolipid levels. J Cell Biochem 116:67–80CrossRefPubMedPubMedCentral
31.
go back to reference Tonneijck L, Muskiet MH, Smits MM et al (2017) Glomerular Hyperfiltration in Diabetes: Mechanisms, Clinical Significance, and Treatment. J Am Soc Nephrol 28:1023–1039CrossRefPubMedPubMedCentral Tonneijck L, Muskiet MH, Smits MM et al (2017) Glomerular Hyperfiltration in Diabetes: Mechanisms, Clinical Significance, and Treatment. J Am Soc Nephrol 28:1023–1039CrossRefPubMedPubMedCentral
32.
34.
go back to reference Retnakaran R, Cull CA, Thorne KI, Adler AI, Holman RR, Group US (2006) Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes Study 74. Diabetes 55:1832–1839CrossRefPubMed Retnakaran R, Cull CA, Thorne KI, Adler AI, Holman RR, Group US (2006) Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes Study 74. Diabetes 55:1832–1839CrossRefPubMed
35.
go back to reference Yu MK, Lyles CR, Bent-Shaw LA, Young BA, Authors P (2012) Risk factor, age and sex differences in chronic kidney disease prevalence in a diabetic cohort: the pathways study. Am J Nephrol 36:245–251CrossRefPubMed Yu MK, Lyles CR, Bent-Shaw LA, Young BA, Authors P (2012) Risk factor, age and sex differences in chronic kidney disease prevalence in a diabetic cohort: the pathways study. Am J Nephrol 36:245–251CrossRefPubMed
36.
go back to reference Bjornstad P, Cherney DZ (2018) Renal hyperfiltration in adolescents with type 2 diabetes: physiology, sex differences, and implications for diabetic kidney disease. Curr Diab Rep 18:22CrossRefPubMedPubMedCentral Bjornstad P, Cherney DZ (2018) Renal hyperfiltration in adolescents with type 2 diabetes: physiology, sex differences, and implications for diabetic kidney disease. Curr Diab Rep 18:22CrossRefPubMedPubMedCentral
37.
go back to reference Bjornstad P, Nehus E, El Ghormli L et al (2018) Insulin sensitivity and diabetic kidney disease in children and adolescents with type 2 diabetes: An observational Analysis of data from the today clinical trial. Am J Kidney Dis 71:65–74CrossRefPubMed Bjornstad P, Nehus E, El Ghormli L et al (2018) Insulin sensitivity and diabetic kidney disease in children and adolescents with type 2 diabetes: An observational Analysis of data from the today clinical trial. Am J Kidney Dis 71:65–74CrossRefPubMed
38.
go back to reference Lovshin JA, Skrtic M, Bjornstad P et al (2018) Hyperfiltration, urinary albumin excretion, and ambulatory blood pressure in adolescents with Type 1 diabetes mellitus. Am J Physiol Renal Physiol 314:F667–F674CrossRefPubMed Lovshin JA, Skrtic M, Bjornstad P et al (2018) Hyperfiltration, urinary albumin excretion, and ambulatory blood pressure in adolescents with Type 1 diabetes mellitus. Am J Physiol Renal Physiol 314:F667–F674CrossRefPubMed
39.
go back to reference Silverstein J, Klingensmith G, Copeland K et al (2005) Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association. Diabetes Care 28:186–212CrossRefPubMed Silverstein J, Klingensmith G, Copeland K et al (2005) Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association. Diabetes Care 28:186–212CrossRefPubMed
40.
go back to reference Tagami S, Inokuchi Ji J, Kabayama K et al (2002) Ganglioside GM3 participates in the pathological conditions of insulin resistance. J Biol Chem 277:3085–3092CrossRefPubMed Tagami S, Inokuchi Ji J, Kabayama K et al (2002) Ganglioside GM3 participates in the pathological conditions of insulin resistance. J Biol Chem 277:3085–3092CrossRefPubMed
41.
go back to reference Yamashita T, Hashiramoto A, Haluzik M et al (2003) Enhanced insulin sensitivity in mice lacking ganglioside GM3. Proc Natl Acad Sci U S A 100:3445–3449CrossRefPubMedPubMedCentral Yamashita T, Hashiramoto A, Haluzik M et al (2003) Enhanced insulin sensitivity in mice lacking ganglioside GM3. Proc Natl Acad Sci U S A 100:3445–3449CrossRefPubMedPubMedCentral
Metadata
Title
Urinary sphingolipids in adolescents and young adults with youth-onset diabetes
Authors
Edward J. Nehus
Nicole M. Sheanon
Wujuan Zhang
Santica M. Marcovina
Kenneth D. R. Setchell
Mark M. Mitsnefes
Publication date
03-01-2024
Publisher
Springer Berlin Heidelberg
Published in
Pediatric Nephrology / Issue 6/2024
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI
https://doi.org/10.1007/s00467-023-06257-6

Keynote webinar | Spotlight on adolescent vaping

Growing numbers of young people are using e-cigarettes, despite warnings of respiratory effects and addiction. How can doctors tackle the epidemic, and what health effects should you prepare to manage in your clinics?

Prof. Ann McNeill
Dr. Debbie Robson
Benji Horwell
Developed by: Springer Medicine
Watch now