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 …