Altered plasma serine and 1-deoxydihydroceramide profiles are associated with diabetic neuropathy in type 2 diabetes and obesity

Recent studies suggest that the accumulation of atypical, 1-deoxysphingolipids that lack the C1 hydroxyl group may be associated with diabetic neuropathy (DN). We hypothesized that specific plasma 1-deoxysphingolipids associate with DN severity, and that alterations in plasma serine and alanine associate with 1-deoxysphingolipid elevation in patients with type 2 diabetes (T2D). We examined individual 1-deoxysphingolipid species using LC/ MS/MS in plasma samples from 75 individuals including lean controls (LC, n = 19), those with obesity (n = 19), obesity with T2D without DN (ob/T2D, n = 18), and obesity with T2D with DN (Ob/T2D/DN, n = 19). We ob-served a step wise increase in 1-deoxydihydroceramides across these four groups (spearman correlation coeffi-cient r = 0.41, p = 0.0002). Mean total concentrations of 1-deoxydihydroceramides, and most individual 1-deoxydihydroceramide species, were higher in ob/T2D/DN versus LC group (8.939 vs. 5.195 pmol/100 mu L for total 1-deoxydihydroceramides p = 0.005). No significant differences in 1-deoxydihydroceramides were ob-served between the ob/T2D and ob/T2D/DN groups. L-alanine was higher and L-serine lower in ob/T2D/DN ver-sus LC groups (326.2 vs. 248.0 mu M, p = 0.0086 and 70.2 vs. 89.8 mu M, p = 0.0110), consistent with a potential contribution of these changes to the observed 1-deoxysphingolipids profiles. 1-deoxydihydroceramides corre-lated inversely with leg intraepidermal nerve fiber density (CC-0.40, p = 0.003). These findings indicate that 1-deoxydihydroceramides may be important biomarkers and/or mediators of DN. (C) 2021 Elsevier Inc. All rights reserved.

Automated summary

Recent studies suggest that atypical 1-deoxysphingolipids lacking the C1 hydroxyl group may be associated with diabetic neuropathy. Specific plasma 1-deoxysphingolipids may be linked to the severity of DN, while alterations in plasma serine and alanine could relate to the elevation of 1-deoxysphingolipids in patients with type 2 diabetes.