Zhang Danyang, He Xiaoshi, Wang Yinbo, Wang Xiaoyu, Han Xiao, Liu Haodong, Xing Yan, Jiang Bo, Xiu Zhilong, Bao Yongming, Dong Yuesheng
MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian 116024, China.
Dianxi Research Institute, Dalian University of Technology, Baoshan 678000, China.
Int J Mol Sci. 2025 Feb 23;26(5):1923. doi: 10.3390/ijms26051923.
Diabetes constitutes a risk factor for cognitive impairment, whereas insulin resistance serves as the shared pathogenesis underlying both diabetes and cognitive decline. The use of metformin for treating cognitive impairment remains controversial. The present study found that hesperetin, a flavanone derived from citrus peel, enhanced metformin's 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 . Furthermore, this study demonstrated that hesperetin supplementation counteracted the upregulation of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), a pathological factor of Alzheimer's disease (AD) that was induced by metformin. Our findings reveal that hesperetin can be used in supplementary treatment for cognitive impairment associated with diabetes.
糖尿病是认知障碍的一个风险因素，而胰岛素抵抗是糖尿病和认知衰退共同的发病机制。使用二甲双胍治疗认知障碍仍存在争议。本研究发现，橙皮素（一种从柑橘皮中提取的黄烷酮）可增强二甲双胍降低血糖水平、改善胰岛素敏感性以及改善糖尿病大鼠认知障碍的功效。此外，它将二甲双胍的所需剂量降低至其常规剂量的三分之一。转录组分析和16S rRNA测序显示，胰岛素和环磷酸腺苷反应元件结合蛋白（CREB）/脑源性神经营养因子（BDNF）通路的激活得益于肠道微生物群的调节以及对短链脂肪酸（SCFA）产生菌（如……）的促进。此外，本研究表明，补充橙皮素可抵消由二甲双胍诱导的β-淀粉样前体蛋白裂解酶1（BACE1）的上调，BACE1是阿尔茨海默病（AD）的一个病理因素。我们的研究结果表明，橙皮素可用于糖尿病相关认知障碍的辅助治疗。
