Proinflammatory Cytokines Predict the Incidence of Diabetic Peripheral Neuropathy Over 5 Years in Chinese Type 2 Diabetes Patients: A Prospective Cohort Study

Aims: 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. Methods: 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. Results: Among the 106 randomly 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. Conclusions: 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. Funding Statement: The present study was supported by grants from the National Natural Science Foundation of China (81770807, to B Lu and 81800692, to LJ Ji), Shanghai Talent Development Fund Program (2018054, to B Lu), Shanghai Shenkang Hospital Developing Center Clinical Scientific and Technological Innovation Program (SHDC12016210, to B Lu), Shanghai Science and Technology Committee Program (17411961500, to S Zhang), Shanghai General Hospital Program of Chinese traditional and Western medicine combination (ZY(2018-2020)-FWTX-1002, to YM Li) and Shanghai Municipal Commission of Health and Family Planning Clinical Research Project (20184Y0318, to LJ Ji). Declaration of Interests: The authors declare that there is no conflict of interest. Ethics Approval Statement: The study was approved by the Human Investigation Ethics Committee of Huashan Hospital.