Prospective Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Jun 15, 2025; 16(6): 105592
Published online Jun 15, 2025. doi: 10.4239/wjd.v16.i6.105592
Identification and validation of serum amino acids as diagnostic biomarkers for diabetic peripheral neuropathy
Wei-Sheng Xu, Huan Xing, Qing-Qing Wang, Hui Qi, Jian-Tao He, Tong Jin, Yan-Peng Kan, Shi-Yu Sun, Ji-Ying Wang, Fu-Qing Lin
Wei-Sheng Xu, Hui Qi, Jian-Tao He, Tong Jin, Yan-Peng Kan, Shi-Yu Sun, Ji-Ying Wang, Fu-Qing Lin, Department of Pain Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
Huan Xing, Qing-Qing Wang, Department of Anesthesiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
Co-first authors: Wei-Sheng Xu and Huan Xing.
Co-corresponding authors: Ji-Ying Wang and Fu-Qing Lin.
Author contributions: Xu WS, Wang JY and Lin FQ conceptualized and designed the research; Wang QQ, Xing H, Qi H, He JT, Jin T and Kan YP screened patients and acquired clinical data; Xu WS, Xing H and Wang QQ collected blood specimen and performed laboratory analysis; Xu WS, Wang JY, Xing H and Lin FQ performed Data analysis; Xu WS, Wang JY and Xing H wrote the paper. Sun SY applied for and obtained the funds for this research project. All the authors have read and approved the final manuscript. Xu WS proposed, designed and conducted serum amino acids analysis, performed data analysis and prepared the first draft of the manuscript. Xing H was responsible for patient screening, enrollment, collection of clinical data and blood specimens. The two authors have made crucial and indispensable contributions towards the completion of the project and thus qualified as the co-first authors of the paper. Wang JY and Lin FQ have played important and indispensable roles in the experimental design, data interpretation and manuscript preparation as the co-corresponding authors.
Supported by the Youth Fund for Specialized Clinical Research of the Health Commission, No. 20214Y0149.
Institutional review board statement: The study was reviewed and approved by the Shanghai Tenth People’s Hospital Institutional Review Board, Approval No. SHYS-IEC-5.0/22K151/PO1.
Clinical trial registration statement: This study is registered at https://www.chictr.org.cn. The registration identification number is ChiCTR2400088659.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: The authors report no conflicts of interest in this work.
CONSORT 2010 statement: The authors have read the CONSORT 2010 statement, and the manuscript was prepared and revised according to the CONSORT 2010 statement.
Data sharing statement: The datasets included in this study are available from the first author at Xuweisheng203@163.com upon request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Fu-Qing Lin, Chief Physician, Department of Pain Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No. 301 Yanchang Middle Road, Jingan District, Shanghai 200072, China. fuqinglin@tongji.edu.cn
Received: January 30, 2025
Revised: March 27, 2025
Accepted: May 14, 2025
Published online: June 15, 2025
Processing time: 136 Days and 2.9 Hours
Abstract
BACKGROUND

Diabetic peripheral neuropathy (DPN) is the most prevalent complication of type 2 diabetes mellitus (T2DM). Due to a lack of specific biomarkers, the early diagnosis of this disorder is limited.

AIM

To identify and validate serum amino acids that could discriminate T2DM patients with DPN from those without DPN.

METHODS

T2DM patients with DPN, T2DM patients without DPN, and healthy controls were recruited for this study. The participants comprised two nonoverlapping cohorts: A training cohort (DPN = 84 participants, T2DM = 82 participants, normal = 50 participants) and a validation cohort (DPN = 112 participants, T2DM = 93 participants, normal = 58 participants). A prediction model of the ability of serum amino acids to distinguish DPN from T2DM was established using a logistic regression model, and area under the curve (AUC) analysis was used to evaluate the diagnostic ability of the model. In addition, the serum amino acid levels of 13 DPN patients were also detected before treatment and after 3 months of treatment.

RESULTS

A clinical detection method for the diagnosis of DPN based on a biomarker panel of three serum amino acids and diabetes duration was developed. The diagnostic model demonstrated AUC values of 0.805 (95%CI: 0.739-0.871) and 0.810 (95%CI: 0.750-0.870) in the training and verification cohorts, respectively. In the identification of T2DM patients and normal controls, the AUC values were 0.891 (95%CI: 0.836-0.945) and 0.883 (95%CI: 0.832-0.934) in the training and validation cohorts, respectively. Arginine and tyrosine levels were increased after treatment, whereas aspartic acid levels were decreased after treatment.

CONCLUSION

This study successfully identified and validated the metabolomic significance of arginine, tyrosine, and glutamic acid as potential biomarkers for diagnosing DPN. These findings are particularly valuable, as they establish a foundational step toward developing the first routine laboratory test for DPN. Moreover, the diagnostic model that was constructed in this study effectively distinguishes DPN patients from those with T2DM without neuropathy, thereby potentially facilitating early diagnosis and intervention.

Keywords: Diabetic peripheral neuropathy; Type 2 diabetes mellitus; Arginine; Tyrosine; Glutamic acid

Core Tip: This study involves the most extensive identification of serum amino acids as biomarkers for the detection of diabetic peripheral neuropathy (DPN), including the use of both training and validation cohorts. This is the first study demonstrating that a signature consisting of 3 serum amino acids (arginine, tyrosine, and glutamic acid) and diabetes duration can successfully distinguish DPN from type 2 diabetes mellitus with acceptable accuracy. Thirteen DPN patients received treatment in our department, and their clinical symptoms were relieved; moreover, their serum arginine and tyrosine levels were significantly increased, which may reflect the reliability of our model. These findings may provide potential therapeutic targets for the diagnosis and treatment of DPN.