Association of Plasma Deoxysphingolipids with Neuropathy in the DCCT/EDIC Cohort
Neuropathy is the most common chronic complication of diabetes mellitus. Clinically, diabetic neuropathy presents similarly to the neuropathy of patients with hereditary sensory and autonomic neuropathy type 1 (HSAN1). HSAN1 patients exhibit elevated plasma levels of a newly identified sphingolipid class, deoxy¬sphingolipids (DSL). Plasma levels of DSL also are elevated in Type 2 diabetes patients and in patients exhibiting symptoms of the Metabolic Syndrome but no studies reporting DSL levels in Type 1 diabetes patients or in patients with diabetic neuropathy have been reported. Although DSL were shown to have pronounced neurotoxic effects, studies suggest that oral supplementation with L-serine reduces plasma DSL concentration and raise the prospect of a treatment option to modulate plasma DSL levels. The overarching hypothesis guiding our research program is that the changes in sphingolipidomic profile in plasma from Type 1 diabetes patients are associated with the development of diabetes complications. We will investigate the hypothesis that plasma levels of DSL in Type 1 diabetes patients exhibiting clinically confirmed and documented diabetic neuropathy are elevated compared to those of Type 1 diabetes patients without neuropathy. Additionally, we hypothesize that the distribution and concentration of free amino acids necessary for the generation of DSL are altered in Type 1 diabetes patients exhibiting diabetic neuropathy. To evaluate these hypotheses, the studies proposed in Specific Aim 1 will determine the plasma concentrations of DSL, ceramide and sphingomyelin species, and the glucosyl- and galactosylceramide species in banked plasma samples obtained during EDIC Year 9 from 40 Type 1 diabetic patients who exhibit clinically confirmed and documented diabetic neuropathy and from 40 matched Type 1 diabetes patients who did not develop diabetic nephropathy. In Specific Aim 2, we will determine the concentrations of free amino acids in the same banked plasma samples which will be analyzed in Specific Aim 1. These studies will determine for the first time in Type 1 diabetes patients, the plasma concentrations of DSL, a newly identified, neurotoxic class of sphingolipids and, additionally, determine their association with diabetic neuropathy.

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