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

Nat Biotechnol. 2003 Mar;21(3):294-301. doi: 10.1038/nbt795. Epub 2003 Feb 24.


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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / chemistry
  • Bone Morphogenetic Proteins / genetics*
  • Bone Morphogenetic Proteins / metabolism*
  • Bone Morphogenetic Proteins / therapeutic use
  • Cells, Cultured
  • Diabetes Mellitus / drug therapy
  • Diabetes Mellitus / genetics*
  • Diabetes Mellitus / metabolism*
  • Drug Design
  • Gene Expression Profiling / methods*
  • Glucose / metabolism
  • Growth Differentiation Factor 2
  • Growth Differentiation Factors
  • Humans
  • Kidney / chemistry
  • Kidney / embryology
  • Kidney / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Proteins / chemistry
  • Proteins / genetics
  • Proteins / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Reference Values
  • Sequence Alignment / methods
  • Sequence Analysis, Protein / methods
  • Systems Integration


  • Bone Morphogenetic Proteins
  • GDF2 protein, human
  • Gdf2 protein, mouse
  • Growth Differentiation Factor 2
  • Growth Differentiation Factors
  • Proteins
  • Recombinant Proteins
  • Glucose