Geng Feng-Hao, Li Guo-Hua, Zhang Xing, Zhang Peng, Dong Ming-Qing, Zhao Zhi-Jing, Zhang Yuan, Dong Ling, Gao Feng
School of Aerospace Medicine, The Fourth Military Medical University, Xi'an, China.
Department of Orthopedic Surgery, Urumqi General Hospital, Urumqi, China.
Br J Pharmacol. 2016 May;173(10):1569-79. doi: 10.1111/bph.13466. Epub 2016 Apr 5.
Berberine, a small molecule derived from Coptidis rhizome, has been found to be potent at lowering blood glucose and regulating lipid metabolism. Recent clinical studies have shown that berberine reduces blood pressure and increases systemic insulin sensitivity in patients with metabolic syndrome; however, the underlying mechanism is still unclear. Here, we investigated the mechanism by which berberine improves vascular insulin sensitivity in diabetic rats.
Diabetes was induced in male Sprague–Dawley rats by feeding a high-fat diet and administration of a low dose of streptozotocin. These diabetic rats were treated with berberine (200 mg·kg(−1)·day(−1), gavage) for 4 weeks. Vascular dilation was determined in isolated mesenteric artery rings. Effects of berberine on insulin signalling were also studied in human artery endothelial cells cultured in high glucose (25 mmol·L(−1)) and palmitate (500 μmol·L(−1)).
Berberine treatment for 4 weeks significantly restored the impaired ACh- and insulin-induced vasodilatation of mesenteric arteries from diabetic rats. In isolated mesenteric artery rings, berberine (2.5–10 μmol·L(−1)) elicited dose-dependent vasodilatation and significantly enhanced insulin-induced vasodilatation. Mechanistically, berberine up-regulated phosphorylation of the insulin receptor and its downstream signalling molecules AMPK, Akt and eNOS, and increased cell viability and autophagy in cultured endothelial cells. Moreover, down-regulating insulin receptors with specific siRNA significantly attenuated berberine-induced phosphorylation of AMPK.
Berberine improves diabetic vascular insulin sensitivity and mesenteric vasodilatation by up-regulating insulin receptor-mediated signalling in diabetic rats. These findings suggest berberine has potential as a preventive or adjunctive treatment of diabetic vascular complications.
This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23.
黄连素是一种从黄连根茎中提取的小分子物质，已被发现具有降低血糖和调节脂质代谢的作用。近期临床研究表明，黄连素可降低代谢综合征患者的血压并提高全身胰岛素敏感性；然而，其潜在机制仍不清楚。在此，我们研究了黄连素改善糖尿病大鼠血管胰岛素敏感性的机制。
通过喂食高脂饮食并给予低剂量链脲佐菌素诱导雄性Sprague-Dawley大鼠患糖尿病。这些糖尿病大鼠用黄连素（200mg·kg⁻¹·天⁻¹，灌胃）治疗4周。在分离的肠系膜动脉环中测定血管舒张情况。还在高糖（25mmol·L⁻¹）和棕榈酸（500μmol·L⁻¹）培养的人动脉内皮细胞中研究了黄连素对胰岛素信号传导的影响。
黄连素治疗4周显著恢复了糖尿病大鼠肠系膜动脉受损的乙酰胆碱和胰岛素诱导的血管舒张。在分离的肠系膜动脉环中，黄连素（2.5 - 10μmol·L⁻¹）引起剂量依赖性血管舒张，并显著增强胰岛素诱导的血管舒张。机制上，黄连素上调胰岛素受体及其下游信号分子AMPK、Akt和eNOS的磷酸化，并增加培养内皮细胞的细胞活力和自噬。此外，用特异性siRNA下调胰岛素受体可显著减弱黄连素诱导的AMPK磷酸化。
黄连素通过上调糖尿病大鼠胰岛素受体介导的信号传导来改善糖尿病血管胰岛素敏感性和肠系膜血管舒张。这些发现表明黄连素具有作为糖尿病血管并发症预防或辅助治疗的潜力。
本文是心血管药物发现中的中国创新主题部分的一部分。要查看本部分的其他文章，请访问http://dx.doi.org/10.1111/bph.2015.172.issue-23。
