title: Suppression of PC-1/ENPP-1 expression improves insulin sensitivity in vitro and in vivo.
abstract: 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.
authors: Target Validation, Merck & Co., Inc., Rahway, NJ 07065, USA.
authors: Heather H
authors: HH
authors: Zhou
authors: Chen-Ni
authors: CN
authors: Chin
authors: Margaret
authors: M
authors: Wu
authors: Weihua
authors: W
authors: Ni
authors: Shuo
authors: S
authors: Quan
authors: Franklin
authors: F
authors: Liu
authors: Qing
authors: Q
authors: Dallas-Yang
authors: Kenneth
authors: K
authors: Ellsworth
authors: Thu
authors: T
authors: Ho
authors: Aiwu
authors: A
authors: Zhang
authors: Tajneen
authors: T
authors: Natasha
authors: Jing
authors: J
authors: Li
authors: Kevin
authors: K
authors: Chapman
authors: William
authors: W
authors: Strohl
authors: Cai
authors: C
authors: Li
authors: I-Ming
authors: IM
authors: Wang
authors: Joel
authors: J
authors: Berger
authors: Zhiqiang
authors: Z
authors: An
authors: Bei B
authors: BB
authors: Zhang
authors: Guoqiang
authors: G
authors: Jiang
mesh_terms: 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
chemical_list: 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