2. Academic Validation
  3. Branched-Chain Amino Acids Deficiency Promotes Diabetic Neuropathic Pain Through Upregulating LAT1 and Inhibiting Kv1.2 Channel

Branched-Chain Amino Acids Deficiency Promotes Diabetic Neuropathic Pain Through Upregulating LAT1 and Inhibiting Kv1.2 Channel

  • Adv Sci (Weinh). 2024 Jul 1:e2402086. doi: 10.1002/advs.202402086.
Ze-Yu Zhou 1 2,  Ji-Ying Wang 3,  Zhi-Xiao Li 4,  Hong-Li Zheng 3,  Ya-Nan Zhou 4,  Li-Na Huang 5,  Li-Juan Wang 5,  Xiao-Wei Ding 2,  Xin Sun 2,  Ke Cai 2,  Rui Zhao 2,  Yan Shi 2,  Alex F Chen 2,  Zhi-Qiang Pan 6,  Jing Cao 4,  Fu-Qing Lin 3,  Jian-Yuan Zhao 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China.
  • 2 Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
  • 3 Department of Pain Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
  • 4 Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
  • 5 Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 20080, China.
  • 6 Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China.
PMID: 38946582 DOI: 10.1002/advs.202402086
Abstract

Diabetic neuropathic pain (DNP), one of the most common complications of diabetes, is characterized by bilateral symmetrical distal limb pain and substantial morbidity. To compare the differences is aimed at serum metabolite levels between 81 DNP and 73 T2DM patients without neuropathy and found that the levels of branched-chain Amino acids (BCAA) are significantly lower in DNP patients than in T2DM patients. In high-fat diet/low-dose streptozotocin (HFD/STZ)-induced T2DM and Leptin receptor-deficient diabetic (db/db) mouse models, it is verified that BCAA deficiency aggravated, whereas BCAA supplementation alleviated DNP symptoms. Mechanistically, using a combination of RNA Sequencing of mouse dorsal root ganglion (DRG) tissues and label-free quantitative proteomic analysis of cultured cells, it is found that BCAA deficiency activated the expression of L-type amino acid transporter 1 (LAT1) through ATF4, which is reversed by BCAA supplementation. Abnormally upregulated LAT1 reduced Kv1.2 localization to the cell membrane, and inhibited Kv1.2 channels, thereby increasing neuronal excitability and causing neuropathy. Furthermore, intraperitoneal injection of the LAT1 inhibitor, BCH, alleviated DNP symptoms in mice, confirming that BCAA-deficiency-induced LAT1 activation contributes to the onset of DNP. These findings provide fresh insights into the metabolic differences between DNP and T2DM, and the development of approaches for the management of DNP.

Keywords

Kv1.2; L‐type amino acid transporter 1; branched‐chain amino acids; diabetic neuropathic pain.

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Inhibitors & Agonists
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-108540
    99.13%, LAT1抑制剂
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