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An integrated functional genomics screening program reveals a role for BMP-9 in glucose homeostasis

Nature Biotechnology volume 21, pages 294–301 (2003)Cite this article

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, ∼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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Figure 1: Selection of secreted proteins.
Figure 2: Overview of diabetic screening.
Figure 3: High-throughput screening reveals previously unknown activities for BMP-9 in gluconeogenesis and Akt signaling.
Figure 4: BMP-9 regulates hepatic gluconeogenesis and lipid metabolism in vitro.
Figure 5: BMP-9 is a hypoglycemic agent in diabetic mice.
Figure 6: BMP-9 mediates insulin release and improves glucose tolerance.

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Acknowledgements

We thank Viktor Roschke, Partha Chowdhury, Michael Bloom, and Kathy McCormick for technical assistance, and Paul Moore for a critical review of the manuscript.

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Authors and Affiliations

  1. Department of Lead Development and Characterization, Human Genome Sciences, Inc., 9800 Medical Center Dr., Rockville, 20850, MD, USA

    Cecil Chen, Qinghai Zhao, Helmut Schneider, Mallika Singh, Laurie Pukac, Susan Cheng, Yanick Lazard, Lilin Zhong & Indra Sanyal

  2. Department of Preclinical Development, Human Genome Sciences, Inc., 9800 Medical Center Dr., Rockville, 20850, MD, USA

    Krzysztof J. Grzegorzewski, Qi Wang, Alokesh Duttaroy, Jon Hirsch & Linyi Zhang

  3. Department of Information Technology, Human Genome Sciences, Inc., 9800 Medical Center Dr., Rockville, 20850, MD, USA

    Steve Barash

  4. Department of Preclinical Discovery, Human Genome Sciences, Inc., 9800 Medical Center Dr., Rockville, 20850, MD, USA

    Adam C. Bell, Roxanne Duan, Tim Coleman, Carrie Fischer, Melisa Carey Barber, Peter Reavey, Baiqin Teng, Steve M. Ruben, Olivier Blondel & Charles E. Birse

  5. Department of Antibody Development, Human Genome Sciences, Inc., 9800 Medical Center Dr., Rockville, 20850, MD, USA

    Zhi-Dong Ma & Ya-Qin Zhang

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Chen, C., Grzegorzewski, K., Barash, S. et al. An integrated functional genomics screening program reveals a role for BMP-9 in glucose homeostasis. Nat Biotechnol 21, 294–301 (2003). https://doi.org/10.1038/nbt795

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