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The use of metformin for treating cognitive impairment remains controversial. The present study found that hesperetin, a flavanone derived from citrus peel, enhanced metformin\u2019s efficacy in reducing blood sugar levels, improving insulin sensitivity, and ameliorating cognitive impairment in diabetic rats. Additionally, it reduced the required dosage of metformin to one-third of its conventional dose. Transcriptome analysis and 16S rRNA sequencing revealed that the activation of insulin and cyclic-adenosine monophosphate response element binding protein (CREB)\/brain-derived neurotrophic factor (BDNF) pathways benefited from the regulation of gut microbiota and the promotion of short-chain fatty acid (SCFA) producers such as Romboutsia. Furthermore, this study demonstrated that hesperetin supplementation counteracted the upregulation of \u03b2-site amyloid precursor protein cleaving enzyme 1 (BACE1), a pathological factor of Alzheimer\u2019s disease (AD) that was induced by metformin. Our findings reveal that hesperetin can be used in supplementary treatment for cognitive impairment associated with diabetes.<\/jats:p>","DOI":"10.3390\/ijms26051923","type":"journal-article","created":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T06:47:17Z","timestamp":1740379637000},"page":"1923","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Hesperetin-Enhanced Metformin to Alleviate Cognitive Impairment via Gut\u2013Brain Axis in Type 2 Diabetes Rats"],"prefix":"10.3390","volume":"26","author":[{"given":"Danyang","family":"Zhang","sequence":"first","affiliation":[{"name":"MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian 116024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoshi","family":"He","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian 116024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinbo","family":"Wang","sequence":"additional","affiliation":[{"name":"Dianxi Research Institute, Dalian University of Technology, Baoshan 678000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Wang","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian 116024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Han","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian 116024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haodong","family":"Liu","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian 116024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9659-3079","authenticated-orcid":false,"given":"Yan","family":"Xing","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian 116024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Jiang","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian 116024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhilong","family":"Xiu","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian 116024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0866-8630","authenticated-orcid":false,"given":"Yongming","family":"Bao","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian 116024, China"},{"name":"School of Ocean Science and Technology, Dalian University of Technology, Panjin 124221, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5010-6426","authenticated-orcid":false,"given":"Yuesheng","family":"Dong","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian 116024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,23]]},"reference":[{"key":"ref_1","unstructured":"GBD 2021 Diabetes Collaborators (2023). 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