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

• Published in: Journal of diabetes and its complications 2021-04, Vol.35 (4), p.107852-107852, Article 107852
• Main Authors: Fridman, V., Zarini, S., Sillau, S., Harrison, K., Bergman, B.C., Feldman, E.L., Reusch, J.E.B., Callaghan, B.C.
• Format: Article
• Language: English
• Subjects: Age; Amino acids; Blood pressure; Body mass index; Diabetes; Diabetes Mellitus, Type 2 - complications; Diabetic Neuropathies - complications; Diabetic neuropathy; Gastrointestinal surgery; Humans; Mass spectrometry; Metabolic syndrome; Metabolomics; Mutation; Neuropathy; Obesity; Obesity - complications; Plasma; Questionnaires; Serine; Sphingolipids; Suicides & suicide attempts; Tandem Mass Spectrometry; Type 2 diabetes
• ISSN: 1056-8727; 1873-460X
• DOI: 10.1016/j.jdiacomp.2021.107852

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 observed a step wise increase in 1-deoxydihydroceramides across these four groups (spearman correlation coefficient 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 μL for total 1-deoxydihydroceramides p = 0.005). No significant differences in 1-deoxydihydroceramides were observed between the ob/T2D and ob/T2D/DN groups. l-alanine was higher and l-serine lower in ob/T2D/DN versus LC groups (326.2 vs. 248.0 μM, p = 0.0086 and 70.2 vs. 89.8 μM, p = 0.0110), consistent with a potential contribution of these changes to the observed 1-deoxysphingolipids profiles. 1-deoxydihydroceramides correlated 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. •Plasma deoxydihydroceramides correlate with diabetic neuropathy severity.•Advanced mass spectrometry methods reveal elevated deoxydihydroceramides in diabetes.•Low plasma serine associated with elevations in deoxydihydroceramides in diabetes.