title: 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, 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.
authors.affiliation: Department of Lead Development and Characterization, Human Genome Sciences, Inc., 9800 Medical Center Dr., Rockville, MD 20850, USA.
authors.forename: Cecil
authors.initials: C
authors.lastname: Chen
authors.forename: Krzysztof J
authors.initials: KJ
authors.lastname: Grzegorzewski
authors.forename: Steve
authors.initials: S
authors.lastname: Barash
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Zhao
authors.forename: Helmut
authors.initials: H
authors.lastname: Schneider
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: Mallika
authors.initials: M
authors.lastname: Singh
authors.forename: Laurie
authors.initials: L
authors.lastname: Pukac
authors.forename: Adam C
authors.initials: AC
authors.lastname: Bell
authors.forename: Roxanne
authors.initials: R
authors.lastname: Duan
authors.forename: Tim
authors.initials: T
authors.lastname: Coleman
authors.forename: Alokesh
authors.initials: A
authors.lastname: Duttaroy
authors.forename: Susan
authors.initials: S
authors.lastname: Cheng
authors.forename: Jon
authors.initials: J
authors.lastname: Hirsch
authors.forename: Linyi
authors.initials: L
authors.lastname: Zhang
authors.forename: Yanick
authors.initials: Y
authors.lastname: Lazard
authors.forename: Carrie
authors.initials: C
authors.lastname: Fischer
authors.forename: Melisa Carey
authors.initials: MC
authors.lastname: Barber
authors.forename: Zhi-Dong
authors.initials: ZD
authors.lastname: Ma
authors.forename: Ya-Qin
authors.initials: YQ
authors.lastname: Zhang
authors.forename: Peter
authors.initials: P
authors.lastname: Reavey
authors.forename: Lilin
authors.initials: L
authors.lastname: Zhong
authors.forename: Baiqin
authors.initials: B
authors.lastname: Teng
authors.forename: Indra
authors.initials: I
authors.lastname: Sanyal
authors.forename: Steve M
authors.initials: SM
authors.lastname: Ruben
authors.forename: Olivier
authors.initials: O
authors.lastname: Blondel
authors.forename: Charles E
authors.initials: CE
authors.lastname: Birse
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism* / Q000627:therapeutic use; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D015195:Drug Design; D020869:Gene Expression Profiling / Q000379:methods*; D005947:Glucose / Q000378:metabolism; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D006801:Humans; D007668:Kidney / Q000737:chemistry / Q000196:embryology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012016:Reference Values; D016415:Sequence Alignment / Q000379:methods; D020539:Sequence Analysis, Protein / Q000379:methods; D018511:Systems Integration
chemical_list: D019485:Bone Morphogenetic Proteins; C525887:GDF2 protein, human; C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D011506:Proteins; D011994:Recombinant Proteins; D005947:Glucose