Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin. receptor expression
Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin. receptor expression
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DOI：
10.1016/j.metabol.2008.08.013
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发表时间：
2009-01-01
影响因子：
9.8
通讯作者：
Jiang, Jian-Dong
中科院分区：
文献类型：
--
作者：
Kong, Wei-Jia;Zhang, Hao;Jiang, Jian-Dong
据报道，天然产物小檗碱（BBR）具有降血糖和胰岛素增敏活性；然而，其机制尚不清楚。本研究旨在探讨BBR抗胰岛素抵抗的分子机制。在这里，我们确定胰岛素受体（InsR）作为BBR增加胰岛素敏感性的靶点。在培养的人肝细胞中，BBR以剂量和时间依赖的方式增加InsR信使RNA （mRNA）和蛋白的表达。小檗碱也增加了L6大鼠骨骼肌细胞中InsR的表达。小檗碱增强的InsR表达仅在胰岛素存在时改善细胞葡萄糖消耗。用小干扰RNA沉默InsR基因或阻断磷酸肌醇-3激酶可减少这种作用。小檗碱通过蛋白激酶C （PKC）依赖性启动子激活诱导InsR基因表达。PKC抑制可消除bbr引起的InsR启动子激活和InsR mRNA转录。在动物模型中，用BBR治疗2型糖尿病大鼠可降低空腹血糖和空腹血清胰岛素，增加胰岛素敏感性，升高肝脏中InsR mRNA和PKC活性。此外，BBR降低了KK-Ay 2型糖尿病小鼠的血糖，但对胰岛素缺乏的NOD/LtJ 1型糖尿病小鼠没有作用。我们的研究结果表明，BBR是治疗2型糖尿病和代谢综合征胰岛素抵抗的独特天然药物。(C) 2009爱思唯尔公司版权所有。
Natural product berberine (BBR) has been reported to have hypoglycemic and insulin-sensitizing activities; however, its mechanism remains unclear. This study was designed to investigate the molecular mechanism of BBR against insulin resistance. Here, we identify insulin receptor (InsR) as a target of BBR to increase insulin sensitivity. In cultured human liver cells, BBR increased InsR messenger RNA (mRNA) and protein expression in a dose- and time-dependent manner. Berberine increased InsR expression in the L6 rat skeletal muscle cells as well. Berberine-enhanced InsR expression improved cellular glucose Consumption only in the presence of insulin. Silencing InsR gene with small interfering RNA or blocking the phosphoinositol-3-kinase diminished this effect. Berberine induced InsR gene expression through a protein kinase C (PKC)-dependent activation of its promoter. Inhibition of PKC abolished BBR-caused InsR promoter activation and InsR mRNA transcription. In animal models, treatment of type 2 diabetes mellitus rats with BBR lowered fasting blood glucose and fasting serum insulin, increased insulin sensitivity, and elevated InsR mRNA as well as PKC activity in the liver. In addition, BBR lowered blood glucose in KK-Ay type 2 but not in NOD/LtJ type 1 diabetes mellitus mice that were insulin deficient. Our results suggest that BBR is a unique natural medicine against insulin resistance in type 2 diabetes mellitus and metabolic syndrome. (C) 2009 Elsevier Inc. All rights reserved.