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To compare the differences \u00a0is aimed at serum metabolite levels between 81 DNP and 73 T2DM patients without neuropathy and found that the levels of branched\u2010chain amino acids (BCAA) are significantly lower in DNP patients than in T2DM patients. In high\u2010fat diet\/low\u2010dose streptozotocin (HFD\/STZ)\u2010induced T2DM and leptin receptor\u2010deficient 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\u2010free quantitative proteomic analysis of cultured cells, it is found that BCAA deficiency activated the expression of L\u2010type 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\u2010deficiency\u2010induced 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.<\/jats:p>","DOI":"10.1002\/advs.202402086","type":"journal-article","created":{"date-parts":[[2024,7,1]],"date-time":"2024-07-01T04:54:56Z","timestamp":1719809696000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Branched\u2010Chain Amino Acids Deficiency Promotes Diabetic Neuropathic Pain Through Upregulating LAT1 and Inhibiting Kv1.2 Channel"],"prefix":"10.1002","volume":"11","author":[{"given":"Ze\u2010Yu","family":"Zhou","sequence":"first","affiliation":[{"name":"State Key Laboratory of Genetic Engineering School of Life Sciences Fudan University  Shanghai 200438 China"},{"name":"Institute for Developmental and Regenerative Cardiovascular Medicine MOE\u2010Shanghai Key Laboratory of Children's Environmental Health Xinhua Hospital Shanghai Jiao Tong University School of Medicine  Shanghai 200092 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji\u2010Ying","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pain Medicine Shanghai Tenth People's Hospital Tongji University School of Medicine  Shanghai 200072 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi\u2010Xiao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy School of Basic Medical Sciences Zhengzhou University  Zhengzhou 450001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong\u2010Li","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Pain Medicine Shanghai Tenth People's Hospital Tongji University School of Medicine  Shanghai 200072 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya\u2010Nan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy School of 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