Solving the Riddle of the Sphinx May Provide New Insights Into Diabetes and Polyneuropathy

The biological mechanisms of diabetic polyneuropathy (DPN) are diverse, but only limited clinical benefits are found in therapeutic approaches beyond glucose control where major impact on polyneuropathy development is demonstrated (1). In this issue of Diabetes, a new hope emerges with an article by Hornemann and colleagues (2) that reports that L-serine dietary supplementation showed a remarkably favorable effect on neuropathy in a diabetic streptozotocin (STZ) rat model. Not only was the neurotoxic sphingolipid byproduct, 1-deoxysphingolipid (1-deoxySL), reduced in plasma by serine supplementation but also sensory nerve function was improved by measures of 1) mechanical sensitivity, 2) nerve conductions, 3) percentage of large diameter fibers/axons, and 4) neuronal NA/K-ATPase activity. The serine-enriched diet did not affect body weight, hyperglycemia, hypertriglyceridemia, or food intake in STZ rats, directly supporting the causal relation of the deoxysphingolipids in the pathogenesis of DPN. The complex and enigmatic nature of sphingolipids are similar to the sphinx, a mythological creature for which sphingolipids are named. This heterogeneous group of sphingolipids is unique compared to the more abundant phospholipids because their hydrophobic tails are attached to a serine rather than a glycerol molecule. They are ubiquitously expressed in eukaryotic cells and essential in signal transduction, cell metabolism, and channel localization in neural tissues (3). Sphinganine is an abundant sphingolipid intermediate that is formed with the nonessential amino acid serine serving as the substrate. In contrast, toxic 1-deoxySLs are formed when alanine or glycine is used as the substrate under atypical conditions (Fig. 1). The concentrations of 1-deoxySL subclasses have a significant impact on neural cell differentiation and survival. Elevated levels of 1-deoxySLs can lead to cell stress, a process coupled to carbohydrate metabolic pathways such as glycolysis. This has previously been shown in diabetes (4). The increased concentration of deoxysphingoid bases is also found in the LDL and VLDL fractions of plasma and serves as a useful toxic biomarker (5). The enthusiasm for investigating the neurotoxic effect of deoxysphingolipids comes from an unlikely source, a rare inherited metabolic disorder named hereditary sensory and autonomic neuropathy (HSAN1). This disorder established the neurotoxic effects of deoxysphingolipids through explicit genetic and biochemical studies and provided hope for a rational therapy (6). Both diabetes and HSAN1 have similar components of progressive lengthdependent sensory greater than motor polyneuropathy from an axonopathy, including with complications of skin ulcers and infections. Mutations in the genes encoding enzymes catalyzing the de novo sphingolipid synthesis pathway, serine palmitoyltransferase, long chain 1 and 2 (SPTLC), are found causal for HSAN1 and result in elevated ceramide levels and increased neuronal apoptosis (7,8). More important, mutant SPTLCs result in a change of substrate preference, away from canonical substrate L-serine to alanine and glycine, with resultant accumulation of the two atypical deoxysphingoid bases 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine, which are cytotoxic (Fig. 1). After these deoxysphingoid bases are acylated into deoxysphingolipids, they can no longer be further metabolized to complex sphingolipids or degraded by the canonical degradation pathway. In the plasma of HSAN1 patients, deoxysphingoid levels are found at pathological levels of 10–40 nmol/L. In addition, L-serine supplementation in SPTLC mutant rodents led to modestly improved nerve conductions that correlate with reduced deoxysphingolipid concentrations (9). Trials in HSAN1 patients are under way to investigate the effect of L-serine supplementation on neuropathy, and the preliminary results in humans