Leptin deficiency leads to nerve degeneration and impairs axon remyelination by inducing Schwann cell apoptosis and demyelination in type 2 diabetic peripheral neuropathy in rats

Yuan-Shuo Hsueh; Szu-Han Chen; Wan-Ling Tseng; Sheng-Che Lin; De-Quan Chen; Chih-Chung Huang; Yuan-Yu Hsueh

doi:10.1016/j.neuint.2024.105908

Leptin deficiency leads to nerve degeneration and impairs axon remyelination by inducing Schwann cell apoptosis and demyelination in type 2 diabetic peripheral neuropathy in rats

Neurochem Int. 2024 Nov 26:182:105908. doi: 10.1016/j.neuint.2024.105908. Online ahead of print.

Authors

Yuan-Shuo Hsueh¹, Szu-Han Chen², Wan-Ling Tseng², Sheng-Che Lin³, De-Quan Chen⁴, Chih-Chung Huang⁴, Yuan-Yu Hsueh⁵

Affiliations

¹ Department of Physiology, School of Post Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
² Division of Plastic and Reconstructive Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
³ Division of Plastic Surgery, Department of Surgery, An-Nan Hospital, China Medical University, Tainan, 709, Taiwan.
⁴ Department of Biomedical Engineering, National Cheng Kung University, Tainan, 701, Taiwan.
⁵ Division of Plastic and Reconstructive Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan; Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan. Electronic address: yyhsueh@mail.ncku.edu.tw.

PMID: 39608454
DOI: 10.1016/j.neuint.2024.105908

Abstract

Diabetic peripheral neuropathy, characterized by symptoms such as paresthesia, neuropathic pain, and potential lower limb amputation, poses significant clinical management challenges. Recent studies suggest that chronic hyperglycemia-induced Schwann cells (SCs) apoptosis contributes to neurodegeneration and impaired nerve regeneration, but the detailed mechanisms are still unknown. Our study investigated a mixed-sex type 2 diabetes mellitus (T2DM) rat model using leptin knockout (KO) to simulate obesity and diabetes-related conditions. Through extensive assessments, including mechanical allodynia, electrophysiology, and microcirculation analyses, along with myelin degradation studies in KO versus wild-type rats, we focused on apoptosis, autophagy, and SCs dedifferentiation in the sciatic nerve and examined nerve regeneration in KO rats. KO rats exhibited notable reductions in mechanical withdrawal force, prolonged latency, decreased compound muscle action potential (CMAP) amplitude, reduced microcirculation, myelin sheath damage, and increases in apoptosis, autophagy, and SCs dedifferentiation. Moreover, leptin KO was found to impair peripheral nerve regeneration postinjury, as indicated by reduced muscle weight, lower CMAP amplitude, extended latency, and decreased remyelination and SCs density. These findings underscore the effectiveness of the T2DM rat model in clarifying the impact of leptin KO on SCs apoptosis, dedifferentiation, and demyelination, providing valuable insights into new therapeutic avenues for treating T2DM-induced peripheral neuropathy.

Keywords: Apoptosis; Dedifferentiation; Demyelination; Diabetic peripheral neuropathy; Leptin knockout; Schwann cell.