Lowering plasma 1-deoxysphingolipids improves neuropathy in diabetic rats

Diabetes. 2015 Mar;64(3):1035-45. doi: 10.2337/db14-1325. Epub 2014 Oct 2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight / drug effects
  • Diabetic Neuropathies / blood*
  • Diabetic Neuropathies / drug therapy
  • Eating / drug effects
  • Electrophysiology
  • Hereditary Sensory and Autonomic Neuropathies / blood
  • Hereditary Sensory and Autonomic Neuropathies / drug therapy
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Serine / therapeutic use
  • Sphingosine / analogs & derivatives*
  • Sphingosine / blood


  • 1-deoxysphingosine
  • Serine
  • Sphingosine