Berberine Attenuates Hyperglycemia by Inhibiting the Hepatic Glucagon Pathway in Diabetic Mice
Berberine Attenuates Hyperglycemia by Inhibiting the Hepatic Glucagon Pathway in Diabetic Mice
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小檗碱通过抑制糖尿病小鼠的肝胰高血糖素途径减轻高血糖
DOI：
10.1155/2020/6210526
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发表时间：
2020-01
影响因子：
--
通讯作者：
Jiang Bijie
中科院分区：
文献类型：
--
作者：
Zhong Ying;Jin Jing;Liu Peiyu;Song Yu;Zhang Hui;Sheng Liang;Zhou Huifang;Jiang Bijie
胰高血糖素失调导致肝葡萄糖输出功能亢进，这是2型糖尿病持续高血糖的主要原因。小檗碱（Zhang等人，2010）已被用作降血糖剂，但BBR抑制肝细胞生成的机制仍不完全清楚。在这项研究中，我们用BBR治疗糖尿病小鼠，检测血糖水平，然后进行胰岛素、葡萄糖乳酸盐和胰高血糖素耐受试验。ELISA法检测肝细胞内cAMP水平，RT-qPCR法检测肝细胞内促凋亡基因，Western blot法检测促凋亡基因表达调控因子CREB的磷酸化水平。BBR可降低ob/ob和STZ诱导的糖尿病小鼠的血糖水平，改善胰岛素和葡萄糖耐量，并抑制乳酸和胰高血糖素诱导的肝脏新生。重要的是，BBR减弱了胰高血糖素诱导的葡萄糖产生和肝细胞中的促凋亡基因表达，可能是通过减少cAMP，导致CREB磷酸化。通过利用cAMP类似物腺苷酸环化酶（AC）激活cAMP合成酶和cAMP降解酶磷酸二酯酶（PDE）的抑制剂，我们发现BBR加速细胞内cAMP降解。BBR通过激活PDE降低细胞内cAMP水平，从而阻断下游CREB的激活，并最终下调致炎基因以抑制肝葡萄糖产生。
Dysregulated glucagon drives hyperfunction in hepatic glucose output, which is the main cause of persistent hyperglycemia in type 2 diabetes. Berberine (Zhang et al., 2010) has been used as a hypoglycemic agent, yet the mechanism by which BBR inhibits hepatic gluconeogenesis remains incompletely understood. In this study, we treated diabetic mice with BBR, tested blood glucose levels, and then performed insulin, glucose lactate, and glucagon tolerance tests. Intracellular cAMP levels in hepatocytes were determined by ELISA, hepatic gluconeogenetic genes were assayed by RT-qPCR, and the phosphorylation of CREB, which is the transcriptional factor controlling the expression of gluconeogenetic genes, was detected by western blot. BBR reduced blood glucose levels, improved insulin and glucose tolerance, and suppressed lactate- and glucagon-induced hepatic gluconeogenesis in ob/ob and STZ-induced diabetic mice. Importantly, BBR blunted glucagon-induced glucose production and gluconeogenic gene expression in hepatocytes, presumably through reducing cAMP, which resulted in the phosphorylation of CREB. By utilizing a cAMP analogue, adenylate cyclase (AC), to activate cAMP synthetase, and an inhibitor of the cAMP degradative enzyme, phosphodiesterase (PDE), we revealed that BBR accelerates intracellular cAMP degradation. BBR reduces the intracellular cAMP level by activating PDE, thus blocking activation of downstream CREB and eventually downregulating gluconeogenic genes to restrain hepatic glucose production.
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影响因子：
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作者：
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作者：
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DOI：
10.1017/cbo9781139207249.009
发表时间：
2012
期刊：
--
影响因子：
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作者：
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通讯作者：
W. Marsden
影响因子：
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作者：
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影响因子：
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作者：
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