Preventive carnosine supplementation attenuates painful diabetic neuropathy via restoring mitochondrial function and suppressing inflammasome activation

doi:10.4239/wjd.123730

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World Journal of Diabetes

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1948-9358

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Diabetes. Oct 15, 2026; 17(10): 123730
Published online Oct 15, 2026. doi: 10.4239/wjd.123730

Preventive carnosine supplementation attenuates painful diabetic neuropathy via restoring mitochondrial function and suppressing inflammasome activation

Zhuo-Ying Yu, Jing Yang, Ye Jiang, Yong-Zheng Han, Min Wei, Jia-Yin Shou, Shi-Xiong Shen, Yan-Han Lyu, Xin-Sheng Li, Qian Chen, Xin-Ru Zhao, Guo-Gang Xing, Da-Qing Ma, Min Li

Zhuo-Ying Yu, Jing Yang, Ye Jiang, Yong-Zheng Han, Min Wei, Jia-Yin Shou, Shi-Xiong Shen, Yan-Han Lyu, Xin-Sheng Li, Xin-Ru Zhao, Min Li, Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China

Qian Chen, Department of Anesthesiology, Zhejiang University School of Medicine Children’s Hospital, Hangzhou 310052, Zhejiang Province, China

Guo-Gang Xing, Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Neuroscience Research Institute, Peking University, Beijing 100191, China

Da-Qing Ma, Department of Surgery and Cancer, Imperial College London, London SW10 9NH, United Kingdom

Co-first authors: Zhuo-Ying Yu and Jing Yang.

Co-corresponding authors: Da-Qing Ma and Min Li.

Author contributions: Yu ZY and Yang J jointly completed major experiments, data analysis and manuscript drafting, they contributed equally to this article, they are the co-first authors of this manuscript; Yu ZY, Yang J, Jiang Y, Han YZ, Wei M, Shou JY, Shen SX, Lyu YH, and Li XS performed the investigation; Yu ZY, Yang J, Han YZ, Shou JY, and Zhao XR curated and analyzed the data; Yu ZY drafted the original manuscript; Yu ZY, Yang J, Chen Q, Xing GG, Ma DQ, and Li M revised the manuscript; Yu ZY, Ma DQ, and Li M conceived the study and acquired funding; Ma DQ and Li M supervised the whole research project, interpreted research findings, repeatedly revised the manuscript and approved the final version, they contributed equally to this article, they are the co-corresponding authors of this manuscript; and all authors have read and approved the final manuscript.

AI contribution statement: No artificial intelligence tools were utilized during the drafting, revision, data analysis or manuscript preparation process.

Supported by the National Natural Science Foundation of China, No. 82001329 and 82071411; the Beijing Municipal Natural Science Foundation, No. 7204325; the Key Research Foundation of Peking University Third Hospital, No. BYSYZD2019036; and the Special Fund of the National Clinical Key Specialty Construction Program, China (2025).

Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Peking University Third Hospital, approval No. 2022-111-01.

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Data sharing statement: Technical appendix, statistical code, and datasets are available from the corresponding author at liminanesth@bjmu.edu.cn upon reasonable request.

Corresponding author: Min Li, MD, Chief Physician, Deputy Director, Professor, Department of Anesthesiology, Peking University Third Hospital, No. 49 North Garden Road, Haidian District, Beijing 100191, China. liminanesth@bjmu.edu.cn

Received: June 2, 2026
Revised: July 8, 2026
Accepted: September 4, 2026
Published online: October 15, 2026
Processing time: 122 Days and 23.4 Hours

Abstract

BACKGROUND

Painful diabetic neuropathy (PDN) is a common and debilitating complication of diabetes mellitus characterized by chronic pain resulting from peripheral nerve damage. Although PDN substantially impairs quality of life, its underlying mechanisms remain incompletely understood.

AIM

To investigate whether preventive carnosine supplementation attenuates PDN-related abnormalities and is associated with alterations in mitochondrial homeostasis and inflammasome-related signaling.

METHODS

This study used untargeted metabolomics to analyze dorsal root ganglia (DRG) from rat model of type 2 diabetic neuropathy. Transmission electron microscopy, JC-1 staining, whole-cell patch-clamp recordings, motor and sensory nerve conduction velocity measurements, and molecular analyses were used to evaluate mitochondrial function, neuronal excitability, peripheral nerve function, and inflammasome-related signaling in vivo. Complementary mechanistic studies were performed in high-glucose-stimulated PC12 cells with dynamin-related protein 1 (Drp1) knockdown or overexpression.

RESULTS

In the DRG of rats with PDN, mitochondrial ultrastructural abnormalities, altered expression of fission/fusion-related proteins, and reduced mitochondrial membrane potential were identified. Untargeted metabolomic analysis identified 147 upregulated and 211 downregulated metabolites, among which carnosine was significantly reduced. Preventive carnosine supplementation attenuated mechanical allodynia, thermal hyperalgesia, neuronal hyperexcitability, and peripheral nerve conduction deficits while improving mitochondrial abnormalities. In DRG tissues, carnosine treatment was associated with reduced Drp1 expression and NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation. In high-glucose-stimulated PC12 cells, carnosine similarly ameliorated mitochondrial dysfunction and suppressed Drp1-related mitochondrial fission and NLRP3 inflammasome signaling.

CONCLUSION

Preventive carnosine supplementation attenuated PDN-related behavioral, electrophysiological, and mitochondrial abnormalities, and was associated with PDN and was associated with reduced Drp1- and NLRP3-related signaling in the DRG. These findings support further preclinical evaluation of carnosine as a potential early-intervention strategy for PDN.

Keywords: Painful diabetic neuropathy; Mitochondrial fission; Dynamin-related protein 1; NOD-like receptor pyrin domain-containing protein 3 inflammasome; Carnosine

Core Tip: Painful diabetic neuropathy (PDN) is characterized by impaired mitochondrial function and reduced carnosine levels in the dorsal root ganglia. Untargeted metabolomic analysis identified carnosine deficiency as a metabolic alteration associated with PDN. Preventive carnosine supplementation alleviated behavioral, electrophysiological, and mitochondrial abnormalities in diabetic rats and was associated with reduced dynamin-related protein 1-related mitochondrial fission and NOD-like receptor pyrin domain-containing protein 3 inflammasome activation in dorsal root ganglia. These findings were further supported by complementary in vitro experiments, collectively supporting further preclinical and translational evaluation of carnosine as a potential early-intervention strategy for PDN.