An integrated functional genomics screening program reveals a role for BMP-9 in glucose homeostasis.
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.
Chen
Cecil
C
Department of Lead Development and Characterization, Human Genome Sciences, Inc., 9800 Medical Center Dr., Rockville, MD 20850, USA.
Grzegorzewski
Krzysztof J
KJ
Barash
Steve
S
Zhao
Qinghai
Q
Schneider
Helmut
H
Wang
Qi
Q
Singh
Mallika
M
Pukac
Laurie
L
Bell
Adam C
AC
Duan
Roxanne
R
Coleman
Tim
T
Duttaroy
Alokesh
A
Cheng
Susan
S
Hirsch
Jon
J
Zhang
Linyi
L
Lazard
Yanick
Y
Fischer
Carrie
C
Barber
Melisa Carey
MC
Ma
Zhi-Dong
ZD
Zhang
Ya-Qin
YQ
Reavey
Peter
P
Zhong
Lilin
L
Teng
Baiqin
B
Sanyal
Indra
I
Ruben
Steve M
SM
Blondel
Olivier
O
Birse
Charles E
CE
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
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