蜂胶是一种传统的自然药物，具有抗氧化、抗炎、免疫调节、抗肿瘤、治疗和预防胃肠炎、抗微生物和寄生虫、葡萄糖调节及抗糖尿病等多种活性，被认为是一种具有很少副作用的抗糖尿病候选药物，但蜂胶对于2型糖尿病（T2DM）的作用机制尚未完全阐明。本研究旨在研究蜂胶乙醇提取物（EEP）对于调节T2DM小鼠血糖的作用机制。我们采用高脂饮食和腹腔注射链脲佐菌素（STZ）诱导的T2DM动物模型，研究蜂胶对于T2DM的潜在机制。实验分为正常组（HC）、模型组（T2DM）、EEP组和二甲双胍组（MET）四组。通过1H-NMR比较血清代谢产物的差异，测定生化指标和细胞因子，并通过16S rDNA扩增子测序研究粪便中肠道菌群的多样性。结果表明，在EEP和MET治疗后，小鼠的体重下降趋势得到缓解，空腹血糖、胰岛素分泌水平、胰岛素抵抗指数、C肽水平和口服葡萄糖耐受度水平下降，而胰岛素敏感性指数升高，因此EEP有效缓解了T2DM和胰岛素抵抗的发生。与T2DM组相比，EEP和MET组中的促炎细胞因子白细胞介素-1β（IL-1β）、白细胞介素6（IL-6）和肿瘤坏死因子-α（TNF-α）的浓度显著降低，而抗炎细胞因子白细胞介素-10（IL-10）的浓度显著增加。代谢组学的结果表明，EEP和MET调节了小鼠的碳水化合物代谢，恢复了小鼠的氨基酸和脂类代谢。对小鼠粪便菌群的相关性分析显示，在T2DM组中发现了可致病的细菌如双螺旋菌、Eubacterium ventriosum群和Desulfovibrio，而有益菌Lactobacillus的丰度显著降低。相比之下，EEP组中存在丰富的Parabacteroides、Akkermansia、Leuconostoc和Alloprevotella，而MET组则出现了能调节能量代谢和胰岛素敏感性的Parasutterella属的增多。结果表明，EEP和MET降低了T2DM小鼠的空腹血糖，并缓解了胰岛素抵抗，改善了小鼠的炎症反应，调节了小鼠的代谢，并影响了肠道微生物群的稳态。然而，EEP的总体治疗效果优于MET。 版权所有 © 2023 by Elsevier B.V.

Propolis is a traditional natural medicine with various activities such as antioxidant and anti-inflammatory, immunomodulatory, anti-tumour, gastroenteritis treatment and prevention, anti-microbial and parasitic, as well as glucose regulation and anti-diabetes, and is expected to be an anti-diabetic candidate with few side effects, but the mechanism of action of propolis on type 2 diabetes mellitus (T2DM) has not been fully elucidated.The purpose of this study was to investigate the mechanism of the effect of ethanol extract of propolis (EEP) on the regulation of blood glucose in T2DM mice.We studied the possible mechanism of EEP on T2DM using an animal model of T2DM induced by a combination of a high-fat diet and intraperitoneal injection of streptozotocin (STZ). The experiment was divided into four groups, namely, the normal group (HC), model group (T2DM), EEP and metformin group (MET). Biochemical indexes and cytokines were measured, and the differences of metabolites in the serum were compared by 1H-NMR. In addition, the diversity of intestinal flora in feces was studied by 16S rDNA amplicon sequencing.The results showed that following treatment with EEP and MET, the weight-loss trend of mice was alleviated, and the fasting blood glucose, insulin secretion level, insulin resistance index, C peptide level and oral glucose tolerance level decreased, whereas the insulin sensitivity index increased, thereby EEP effectively alleviated the occurrence of T2DM and insulin resistance. Compared with the T2DM group, the concentrations of pro-inflammatory cytokines interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) decreased significantly in EEP and MET groups, whereas the concentrations of anti-inflammatory cytokine interleukin-10 (IL-10) increased significantly. Metabolomics results revealed that EEP and MET regulate carbohydrate metabolism and restore amino acid and lipid metabolism. Correlation analysis of intestinal flora in mouse feces showed that compared with the HC group, harmful bacteria such as Bilophila, Eubacterium_ventriosum_group, Mucispirillum and Desulfovibrio were found in the T2DM group, whereas the abundance of beneficial bacteria such as Lactobacillus was significantly reduced. Parabacteroides, Akkermansia, Leuconostoc, and Alloprevotella were abundantly present in the EEP group; however, the MET group showed an increase in the genus Parasutterella, which could regulate energy metabolism and insulin sensitivity.The results showed that EEP and MET reduce fasting blood glucose in T2DM mice, followed by alleviating insulin resistance, improving the inflammatory reaction of mice, regulating the metabolism of mice, and affecting the steady state of gut microbiota. However, the overall therapeutic effect of EEP is better than that of MET.Copyright © 2023. Published by Elsevier B.V.