An integrated functional genomics screening program reveals a role for BMP-9 in glucose homeostasis
An integrated functional genomics screening program reveals a role for BMP-9 in glucose homeostasis
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DOI：
10.1038/nbt795
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发表时间：
2003-03-01
影响因子：
46.9
通讯作者：
Birse, CE
中科院分区：
文献类型：
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作者：
Chen, C;Grzegorzewski, KJ;Birse, CE
实施协调的功能基因组学程序以鉴定在糖尿病治疗中具有治疗应用的分泌多肽。使用生物信息学算法的组合，从代表> 1，000个cDNA文库的不同表达序列标签（EST）数据库预测分泌因子。随后，在基于细胞的高通量测定中筛选了8，000种人类蛋白质，该测定旨在监测已知主要参与2型糖尿病生理学的关键生理转变。骨形态发生蛋白-9（BMP-9）在两个独立的测定中给出了阳性反应：减少肝细胞中磷酸烯醇式丙酮酸羧激酶（PEPCK）的表达和激活分化肌管中的Akt激酶。纯化的重组BMP-9有效地抑制肝脏葡萄糖的产生并激活脂代谢关键酶的表达。在自由喂养的糖尿病小鼠中，单次皮下注射BMP-9将血糖降低至接近正常水平，治疗后30小时观察到最大降低。BMP-9代表第一个显示调节血糖浓度的肝脏因子。使用生物信息学和高通量功能分析的组合，我们已经确定了一个可以用于治疗糖尿病的因素。
A coordinated functional genomics program was implemented to identify secreted polypeptides with therapeutic applications in the treatment of diabetes. Secreted factors were predicted from a diverse expressed-sequence tags (EST) database, representing >1,000 cDNA libraries, using a combination of bioinformatic algorithms. Subsequently, 8,000 human proteins were screened in high-throughput cell-based assays designed to monitor key physiological transitions known to be centrally involved in the physiology of type 2 diabetes. Bone morphogenetic protein-9 (BMP-9) gave a positive response in two independent assays: reducing phosphoenolpyruvate carboxykinase (PEPCK) expression in hepatocytes and activating Akt kinase in differentiated myotubes. Purified recombinant BMP-9 potently inhibited hepatic glucose production and activated expression of key enzymes of lipid metabolism. In freely fed diabetic mice, a single subcutaneous injection of BMP-9 reduced glycemia to near-normal levels, with maximal reduction observed 30 hours after treatment. BMP-9 represents the first hepatic factor shown to regulate blood glucose concentration. Using a combination of bioinformatic and high-throughput functional analyses, we have identified a factor that may be exploited for the treatment of diabetes.