Nature Biotechnology
21, 294 - 301 (2003)
Published online: 24 February 2003; | doi:10.1038/nbt795
An integrated functional genomics screening program reveals a role for
BMP-9 in glucose homeostasisCecil Chen1, Krzysztof J. Grzegorzewski2, Steve Barash3, Qinghai Zhao1, Helmut Schneider1, Qi Wang2, Mallika Singh1, Laurie Pukac1, Adam C. Bell4, Roxanne Duan4, Tim Coleman4, Alokesh Duttaroy2, Susan Cheng1, Jon Hirsch2, Linyi Zhang2, Yanick Lazard1, Carrie Fischer4, Melisa Carey Barber4, Zhi-Dong Ma5, Ya-Qin Zhang5, Peter Reavey4, Lilin Zhong1, Baiqin Teng4, Indra Sanyal1, Steve M. Ruben4, Olivier Blondel4
& Charles E. Birse41
Department of Lead Development and
Characterization, Human Genome Sciences, Inc., 9800 Medical Center Dr.,
Rockville, MD 20850, USA. 2
Department of Preclinical Development, Human
Genome Sciences, Inc., 9800 Medical Center Dr., Rockville,
MD 20850, USA. 3
Department of Information Technology, Human Genome
Sciences, Inc., 9800 Medical Center Dr., Rockville,
MD 20850, USA. 4
Department of Preclinical Discovery, Human Genome
Sciences, Inc., 9800 Medical Center Dr., Rockville,
MD 20850, USA. 5
Department of Antibody Development, Human Genome
Sciences, Inc., 9800 Medical Center Dr., Rockville,
MD 20850, USA.
Correspondence should be addressed to Charles E. Birse charlie_birse@hgsi.comA 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.
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