Bioenergetic failure in diabetic peripheral neuropathy: from glucotoxicity to multidimensional metabolic imbalance.

Authors

Wang Tao, Yunfeng Yu, Xuerong Wu, Jiacheng He, Xiu Liu, Juan Huang, Fan Xiao, Rong Yu

Published in

Journal of neurology. Volume 273. Issue 7. Jun 24, 2026. Epub Jun 24, 2026.

Abstract

Diabetic peripheral neuropathy (DPN), particularly distal symmetric polyneuropathy, characterized by length‑dependent axonal damage, is a common chronic complication of type 2 diabetes mellitus. The pathogenesis of DPN is complicated, yet one thing is clear: long axons require a great deal of energy. When axonal transport is compromised by impaired energy metabolism, neuronal somata fall into an energy deficit that triggers neurodegeneration. While earlier work centered on hyperglycemia-induced cytotoxicity, recent studies have increasingly implicated dysregulation of glucose, lipid, and amino acid metabolism as key contributors to DPN. In this review, we integrate the anatomical organization of peripheral nerves, bioenergetic pathways, and axon-Schwann cell interactions to establish a framework for understanding how glucose, lipid, and amino acid dysregulation converge to induce bioenergetic failure in DPN. Based on these mechanisms, we further discuss novel strategies aimed at restoring metabolic homeostasis in neurons and Schwann cells. Importantly, correcting a single metabolic pathway is unlikely to halt or reverse DPN. Instead, restoring global energy homeostasis to rebalance axonal energy supply and demand may be essential for preserving peripheral nerve function.

PMID:
42342866
Bibliographic data and abstract were imported from PubMed on 25 Jun 2026.

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