Inflammation has been implicated in the pathogenesis of diabetic peripheral neuropathy (DPN) as suggested in various cross-sectional studies. However, more convincing prospective studies in diabetes patients are scarce. Therefore, we aimed to evaluate whether proinflammatory cytokines could predict the incidence of DPN through a prospective study with a five-year follow-up. We followed up 315 patients with diabetes who did not have DPN, recruited from five community health centers in Shanghai in 2014, for an average of 5.06 years. Based on the integrity of blood samples, 106 patients were selected to obtain the proinflammatory cytokines. Plasma markers of proinflammatory cytokines at baseline included interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF), and intercellular adhesion molecule 1 (ICAM-1). Neuropathy was assessed by MSNI at baseline and during follow-up. Among the 106 chosen patients, 63 developed DPN after 5.06±1.14 years of follow-up. The baseline plasma levels of TNF-α, IL-6, and ICAM-1 were higher in the neuropathic group (p<0.05). In multivariate models, increased plasma levels of TNF-α (hazard ratio, HR: 8.74 [95% confidence interval, CI: 1.05–72.68]; p <0.05) and ICAM-1 (HR 23.74 [95% CI:1.47–383.81]; p<0.05) were both associated with incident DPN, after adjusting for known DPN risk factors. Increased plasma levels of proinflammatory factors, especially TNF-α and ICAM-1, predicted the incidence of DPN over 5 years in Chinese diabetes patients, but larger longitudinal studies are required for confirmation. National Natural Science Foundation of China, Shanghai Talent Development Fund Program, Shanghai Shenkang Hospital Developing Center Clinical Scientific and Technological Innovation Program, Shanghai Science and Technology Committee Program, Shanghai General Hospital Program of Chinese traditional and Western medicine combination and Shanghai Municipal Commission of Health and Family Planning Clinical Research Project.

Purpose: Type 2 diabetes mellitus (T2DM) with distal symmetric polyneuropathy (DSPN) is a disease involving the nervous system caused by metabolic disorder, while the metabolic spectrum and key metabolites remain poorly defined. Methods: Plasma samples of 30 healthy controls, 30 T2DM patients, and 60 DSPN patients were subjected to nontargeted metabolomics. Potential biomarkers of DSPN were screened based on univariate and multivariate statistical analyses, ROC curve analysis, and logistic regression. Finally, another 22 patients with T2DM who developed DSPN after follow-up were selected for validation of the new biomarker based on target metabolomics. Results: Compared with the control group and the T2DM group, 6 metabolites showed differences in the DSPN group (P < 0.05; FDR < 0.1; VIP > 1) and a rising step trend was observed. Among them, phenylacetylglutamine (PAG) and sorbitol displayed an excellent discriminatory ability and associated with disease severity. The verification results demonstrated that when T2DM progressed to DSPN, the phenylacetylglutamine content increased significantly (P = 0.004). Conclusion: The discovered and verified endogenous metabolite PAG may be a novel potential biomarker of DSPN and involved in the disease pathogenesis.

Objective: The 10 g Semmes–Weinstein monofilament evaluation (SWME) of 4 sites on each foot is recommended for distal symmetric polyneuropathy screening and diagnosis. A similar method has been proposed to diagnose ‘high-risk’ (for ulceration) feet, using 3 sites per foot. This study compared the effectiveness of SWME for testing 3, 4 and 10 sites per foot to identify patients with diabetic neuropathy. Methods: We included 3497 subjects in a SWME of 10 sites; records from the 10-site SWME were used for a SWME of 3 and 4 sites. Neuropathy symptom scores and neuropathy deficit scores were evaluated to identify patients with diabetic peripheral neuropathy. Results: The sensitivities of the 10 g SWME for 3, 4 and 10 sites were 17.8%, 19.0% and 22.4%, respectively. The Kappa coefficients for the SWME tests of 3, 4 and 10 sites were high (range: 0.78–0.93). Conclusions: There were no significant differences in the effectiveness of 3-, 4- and 10-site SWME testing for diabetic peripheral neuropathy screening. SWME testing of 3 sites on each foot may be sufficient to screen for diabetic neuropathy.