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

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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Correspondence to Charles E. Birse.

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The authors declare no competing financial interests.

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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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