Hesperetin-Enhanced Metformin to Alleviate Cognitive Impairment via Gut–Brain Axis in Type 2 Diabetes Rats

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 <i>Romboutsia</i>. 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.