Lowering plasma 1-deoxysphingolipids improves neuropathy in diabetic rats

Alaa Othman, Roberto Bianchi, Irina Alecu, Yu Wei, Carla Porretta-Serapiglia, Raffaella Lombardi, Alessia Chiorazzi, Cristina Meregalli, Norberto Oggioni, Guido Cavaletti, Giuseppe Lauria, Arnold von Eckardstein, Thorsten Hornemann

Research output: Contribution to journalArticle

Abstract

1-Deoxysphingolipids (1-deoxySLs) are atypical neurotoxic sphingolipids that are formed by the serine-palmitoyltransferase (SPT). Pathologically elevated 1-deoxySL concentrations cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), an axonal neuropathy associated with several missense mutations in SPT. Oral L-serine supplementation suppressed the formation of 1-deoxySLs in patients with HSAN1 and preserved nerve function in an HSAN1 mouse model. Because 1-deoxySLs also are elevated in patients with type 2 diabetes mellitus, L-serine supplementation could also be a therapeutic option for diabetic neuropathy (DN). This was tested in diabetic STZ rats in a preventive and therapeutic treatment scheme. Diabetic rats showed significantly increased plasma 1-deoxySL concentrations, and L-serine supplementation lowered 1-deoxySL concentrations in both treatment schemes (P <0.0001). L-serine had no significant effect on hyperglycemia, body weight, or food intake. Mechanical sensitivity was significantly improved in the preventive (P <0.01) and therapeutic schemes (P <0.001). Nerve conduction velocity (NCV) significantly improved in only the preventive group (P <0.05). Overall NCV showed a highly significant (P = 5.2E-12) inverse correlation with plasma 1-deoxySL concentrations. In summary, our data support the hypothesis that 1-deoxySLs are involved in the pathology of DN and that an oral L-serine supplementation could be a novel therapeutic option for treating DN.

Original languageEnglish
Pages (from-to)1035-1045
Number of pages11
JournalDiabetes
Volume64
Issue number3
DOIs
Publication statusPublished - Mar 1 2015

ASJC Scopus subject areas

  • Medicine(all)

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    Othman, A., Bianchi, R., Alecu, I., Wei, Y., Porretta-Serapiglia, C., Lombardi, R., Chiorazzi, A., Meregalli, C., Oggioni, N., Cavaletti, G., Lauria, G., von Eckardstein, A., & Hornemann, T. (2015). Lowering plasma 1-deoxysphingolipids improves neuropathy in diabetic rats. Diabetes, 64(3), 1035-1045. https://doi.org/10.2337/db14-1325