L-serine supplementation suppresses the formaiton of neurotoxic deoxysphingolipids and improves neuropathy in a type 1 diabetic rat model

1-Deoxyceramides (deoxyCer) are atypical ceramides which are formed by the enzyme serine-palmitoyltransferase (SPT) due to a promiscuous use of L-alanine over its canonical substrate L-serine. DeoxyCer are neurotoxic and induce neurite retraction in cultured primary neurons. Pathologically increased deoxyCer levels cause HSAN1, an inherited axonal neuropathy which is associated with several missense mutations in SPT. Also patients with type 2 diabetes (T2DM) have significantly elevated deoxyCer plasma levels suggesting that these lipids are also involved in the pathology of the diabetic sensory neuropathy (DSN). The formation of deoxyCer is markedly suppressed by an oral L-serine supplementation as demonstrated in HSAN1 patients and a transgenic HSAN1 mouse model. Serine supplemented HSAN1 mice were protected and did not develop neuropathic symptoms.

We were therefore interested whether a serine supplementation is equally effective in preventing DSN. This was tested in a streptozotocin (STZ) induced diabetic rat model applying a preventive and therapeutic treatment scheme. STZ rats developed a severe hyperglycaemia and had significantly increased plasma 1-deoxySL levels. Serine supplementation lowered 1-deoxyCer levels in both treatment schemes (p < 0.0001) but had no influence on hyperglycemia, body weight or food intake. After 18 weeks mechanical sensitivity, NCV and neuronal Na⁺,K⁺-ATPase activity were significantly better in the serine treated vs. non treated animals.

In summary our data support the hypothesis that 1-deoxySLs are involved in the pathology of DSN and that the lowering of these lipids by a simple and inexpensive serine supplementation could be a novel therapeutic option for the treatment of DSN.