Candidate metabolite markers of peripheral neuropathy in Chinese patients with type 2 diabetes

Objectives: To analyze the serum and urine metabolites present in type 2 diabetes mellitus (T2DM) patients and T2DM patients with diabetic peripheral neuropathy (DPN) and to select differentially expressed biomarkers for early diagnosis of DPN. Methods: Serum and urine metabolites from 74 T2DM patients with peripheral neuropathy and 41 without peripheral neuropathy were analyzed using gas chromatograph system with time-of-flight mass spectrometer metabolomics to detect biomarkers of peripheral neuropathy in T2DM. Results: There were increased serum triglycerides, alanine aminotransferase, and decreased C-peptide, and total cholesterol levels in T2DM patients with DPN compared to those without peripheral neuropathy. Metabolomic analysis revealed visible differences in metabolic characteristics between two groups, and overall 53 serum differential metabolites and 56 urine differential metabolites were identified with variable influence on projection (VIP) > 1 and P < 0.05. To further analyze the correlation between the identified metabolites and DPN, four serum metabolites and six urine metabolites were selected with VIP > 2, and fold change (FC)> 1, including serum beta-alanine, caproic acid, beta-alanine/L-aspar tic acid, and L-arabinose/L-arabitol, and urine gluconic acid, erythritol, galactonic acid, guanidoacetic acid, cytidine, and aminoadipic acid. Furthermore, five serum biomarkers and six urine biomarkers were found to show significant changes (P < 0.05, VIP > 1, and FC > 1) respectively in patients with mild, moderate, and severe DPN. In addition, we found that glyoxylate and dicarboxylate metabolism was a differential metabolic pathway not only between T2DM and DPN, but also among different degrees of DPN. The differential metabolites such as beta-alanine and caproic acid are expected to be biomarkers for DPN patients, and the significant changes in glyoxylate and dicarboxylate metabolism may be related to the pathogenesis of DPN. Conclusion: There were serum and urine spectrum metabolomic differences in patients with DPN, which could serve as biomarkers for T2DM and DPN patients.