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- Title
An integrated functional genomics screening program reveals a role for BMP-9 in glucose homeostasis.
- 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
- 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 expressedsequence 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.
- Subjects
BONE morphogenetic proteins; GENOMICS; PEPTIDE hormones; TREATMENT of diabetes; THERAPEUTICS
- Publication
Nature Biotechnology, 2003, Vol 21, Issue 3, p294
- ISSN
1087-0156
- Publication type
Article
- DOI
10.1038/nbt795