Suppression of PC-1/ENPP-1 expression improves insulin sensitivity in vitro and in vivo.
Plasma cell membrane glycoprotein-1, or ectonucleotide pyrophosphatase/phosphodieterase (PC-1/ENPP1) has been shown to inhibit insulin signaling in cultured cells in vitro and in transgenic mice in vivo when overexpressed. Furthermore, both genetic polymorphism and increased expression of PC-1 have been reported to be associated with type 2 diabetes in humans. Thus it was proposed that PC-1 inhibition represents a potential strategy for the treatment of type 2 diabetes. However, it has not been proven that suppression of PC-1 expression or inhibition of its function will actually improve insulin sensitivity. We show in the current study that transient overexpression of PC-1 inhibits insulin-stimulated insulin receptor tyrosine phosphorylation in HEK293 cells, while knockdown of PC-1 with siRNA significantly increases insulin-stimulated Akt phosphorylation in HuH7 human hepatoma cells. Adenoviral vector expressing a short hairpin RNA against mouse PC-1 (PC-1shRNA) was utilized to efficiently knockdown PC-1 expression in the livers of db/db mice. In comparison with db/db mice treated with a control virus, db/db mice treated with the PC-1shRNA adenovirus had approximately 80% lower hepatic PC-1 mRNA levels, approximately 30% lower ambient fed plasma glucose, approximately 25% lower fasting plasma glucose, and significantly improved oral glucose tolerance. Taken together, these results demonstrate that suppression of PC-1 expression improves insulin sensitivity in vitro and in an animal model of diabetes, supporting the proposition that PC-1 inhibition is a potential therapeutic approach for the treatment of type 2 diabetes.
Zhou
Heather H
HH
Target Validation, Merck & Co., Inc., Rahway, NJ 07065, USA.
Chin
Chen-Ni
CN
Wu
Margaret
M
Ni
Weihua
W
Quan
Shuo
S
Liu
Franklin
F
Dallas-Yang
Qing
Q
Ellsworth
Kenneth
K
Ho
Thu
T
Zhang
Aiwu
A
Natasha
Tajneen
T
Li
Jing
J
Chapman
Kevin
K
Strohl
William
W
Li
Cai
C
Wang
I-Ming
IM
Berger
Joel
J
An
Zhiqiang
Z
Zhang
Bei B
BB
Jiang
Guoqiang
G
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation; D005215:Fasting; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008297:Male; D051379:Mice; D010727:Phosphoric Diester Hydrolases / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011755:Pyrophosphatases / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011972:Receptor, Insulin / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014443:Tyrosine; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases