1-Deoxysphingolipds (1-deoxySLs) are atypical neurotoxic sphingolipids which are formed by the serine-palmitoyltransferase (SPT). Pathologically elevated 1-deoxySL level cause hereditary sensory and autonomic neuropathy type 1 (HSAN1) an axonal neuropathy which is associated with several missense mutations in SPT. Oral L-serine supplementation suppressed 1-deoxySLs formation in HSAN1patients and preserved the nerve function in an HSAN1 mouse model. As 1-deoxySLs are also 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 levels and L-serine supplementation lowered 1-deoxySLs levels in both treatment schemes (p<0.0001). L-serine had no significant effect on hyperglycemia, body weight and food intake. Mechanical sensitivity was significantly improved in the preventive (p < 0.01) and therapeutic scheme (p < 0.001). NCV significantly improved in the preventive group only (p < 0.05). Overall NCV showed a highly significant (p = 5.2E-12) inverse correlation with plasma 1-deoxySL levels. 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.