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Increased Plasma Levels of Select Deoxy-ceramide and Ceramide Species are Associated with Increased Odds of Diabetic Neuropathy in Type 1 Diabetes: A Pilot Study

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Abstract

Plasma deoxy-sphingoid bases are elevated in type 2 diabetes patients and correlate with the stage of diabetic distal sensorimotor polyneuropathy; however, associations between deoxy-sphingolipids (DSL) and neuropathy in type 1 diabetes have not been examined. The primary aim of this exploratory pilot study was to assess the associations between multiple sphingolipid species including DSL and free amino acids and the presence of symptomatic neuropathy in a DCCT/EDIC type 1 diabetes subcohort. Using mass spectroscopy, plasma levels of DSL and free amino acids in DCCT/EDIC type 1 diabetes participants (n = 80), with and without symptoms of neuropathy, were investigated. Patient-determined neuropathy was based on 15-item self-administered questionnaire (Michigan Neuropathy Screening Instrument) developed to assess distal symmetrical peripheral neuropathy in diabetes. Patients who scored ≥4, or reported inability to sense their feet during walking or to distinguish hot from cold water while bathing were considered neuropathic. Plasma levels of ceramide, sphingomyelin, hexosyl- and lactosylceramide species, and amino acids were measured and analyzed relative to neuropathy status in the patient. Deoxy-C24-ceramide, C24- and C26-ceramide were higher in patients with neuropathy than those without neuropathy. Cysteine was higher in patients with neuropathy. No differences in other sphingolipids or amino acids were detected. The covariate-adjusted Odds Ratios of positive patient-reported neuropathy was associated with increased levels of deoxy-C24-, and deoxy-C24:1-ceramide; C22-, C24-, and C26-ceramide; and cysteine. Plasma deoxy-ceramide and ceramide species may have potential diagnostic and prognostic significance in diabetic neuropathy.

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Abbreviations

HSAN1:

Hereditary sensory and autonomic neuropathy type 1

DSL:

Deoxy-sphingolipids

SPT:

Serine palmitolytransferase

DCCT:

The Diabetes Control and Complications Trial

EDIC:

Epidemiology of Diabetes Interventions

AER:

Albumin excretion rate

MNSI:

Michigan Neuropathy Screening Instrument

HPLC-ESI-MS/MS:

High-performance liquid chromatography-tandem mass spectrometry

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Acknowledgments

The technical assistance of Ms. Charlyne Chassereau and Ms. Andrea Semler is acknowledged. The authors are grateful to the patients in the DCCT/EDIC for their long-term participation in this important trial.

Funding

Financial support for this work was provided by the NIDDK Diabetic Complications Consortium (DiaComp, www.diacomp.org), Grant DK076169 (RLK). This work was also supported by the National Institutes of Health Grant P01-HL55782 (MLV). Additional funding was obtained from the Department of Veterans Affairs Merit Review Program (MLV and RLK). The contents of this manuscript do not represent the views of the Department of Veterans Affairs or the United States Government. Sphingolipid analyses were supported in part by the Lipidomics Shared Resource, Hollings Cancer Center (P30 CA138313), and the Lipidomics Core in the SC Lipidomics and Pathobiology COBRE, Department Biochemistry (P20 RR017677), MUSC. The DCCT/EDIC is sponsored through research contracts from the National Institute of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney diseases (NIDDK) and the National Institutes of Health. Additional support was provided by the National Center for Research Resources through the GCRC program and by Genentech, Inc. through a cooperative research and development agreement with the NIDDK.

Author Contributions

SMH and RLK directed sample analyses and analyzed the data. SMH and RLK wrote the manuscript, and NLB conducted the statistical analyses of the data and wrote the relevant sections. JMELA contributed to data analysis and presentation. SDS, JSP and JB developed the methodology for the deoxy-sphingolipid analysis and generated the sphingolipid data using mass spectroscopy. MFL-V guided patient selection, contributed to the discussion and reviewed/edited the manuscript. SMH and RLK are the guarantors of this work and, as such, had full access to all the data in the study and took the responsibility for the integrity of the data and the accuracy of the data analysis.

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Authors and Affiliations

  1. Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, BSB 645, MSC 508, Charleston, SC, 29425, USA

    Samar M. Hammad & Jad M. El Abiad

  2. Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA

    Nathaniel L. Baker

  3. Division of Hematology/Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA

    Stefanka D. Spassieva

  4. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA

    Jason S. Pierce, Barbara Rembiesa & Jacek Bielawski

  5. Research Service, Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, SC, USA

    Maria F. Lopes-Virella & Richard L. Klein

  6. Division of Endocrinology, Metabolism, and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA

    Richard L. Klein

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  1. Samar M. Hammad
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  2. Nathaniel L. Baker
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  7. Jacek Bielawski
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DCCT/EDIC Group of Investigators

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Correspondence to Samar M. Hammad.

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The authors declare that they have no conflict of interest.

Ethical Approval

The Institutional Review Board (IRB) at the Medical University of South Carolina (MUSC) and all participating DCCT/EDIC centers approved the sample collection procedures. Written informed consent was obtained from all participants.

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Hammad, S.M., Baker, N.L., El Abiad, J.M. et al. Increased Plasma Levels of Select Deoxy-ceramide and Ceramide Species are Associated with Increased Odds of Diabetic Neuropathy in Type 1 Diabetes: A Pilot Study. Neuromol Med 19, 46–56 (2017). https://doi.org/10.1007/s12017-016-8423-9

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  • DOI: https://doi.org/10.1007/s12017-016-8423-9

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