An integrated functional genomics screening program reveals a role for BMP-9 in glucose homeostasis |
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Authors: | Chen Cecil Grzegorzewski Krzysztof J Barash Steve Zhao Qinghai Schneider Helmut Wang Qi Singh Mallika Pukac Laurie Bell Adam C Duan Roxanne Coleman Tim Duttaroy Alokesh Cheng Susan Hirsch Jon Zhang Linyi Lazard Yanick Fischer Carrie Barber Melisa Carey Ma Zhi-Dong Zhang Ya-Qin Reavey Peter Zhong Lilin Teng Baiqin Sanyal Indra Ruben Steve M Blondel Olivier Birse Charles E |
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Affiliation: | Department of Lead Development and Characterization, Human Genome Sciences, Inc., 9800 Medical Center Dr., Rockville, MD 20850, USA. |
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Abstract: | ![]() 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, approximately 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. |
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