The role of membrane glycoprotein plasma cell antigen 1/ectonucleotide pyrophosphatase phosphodiesterase 1 in the pathogenesis of insulin resistance and related abnormalities.

Abstract:

:Insulin resistance is a major feature of most patients with type 2 diabetes mellitus (T2D). A number of laboratories have observed that PC-1 (membrane [corrected] glycoprotein plasma cell antigen 1; also termed [corrected] ectonucleotide pyrophosphatase phosphodiesterase 1 or ENPP1) [corrected] is either overexpressed or overactive in muscle, adipose tissue, fibroblasts, and other tissues of insulin-resistant individuals, both nondiabetic and diabetic. Moreover, PC-1 (ENPP1) overexpression [corrected] in cultured cells in vitro and in transgenic mice in vivo, [corrected] impairs insulin stimulation of insulin receptor (IR) activation and downstream signaling. PC-1 binds to the connecting domain of the IR alpha-subunit that is located in residues 485-599. The connecting domain transmits insulin binding in the alpha-subunit to activation of tyrosine kinase activation in the beta-subunit. When PC-1 is overexpressed, it inhibits insulin [corrected]induced IR beta-subunit tyrosine kinase activity. In addition, a polymorphism of PC-1 (K121Q) in various ethnic populations is closely associated with insulin resistance, T2D, and cardio [corrected] and nephrovascular diseases. The product of this polymorphism has a 2- to 3-fold increased binding affinity for the IR and is more potent than the wild-type PC-1 protein (K121K) in inhibiting the IR. These data suggest therefore that PC-1 is a candidate protein that may play a role in human insulin resistance and T2D by its overexpression, its overactivity, or both.

journal_name

Endocr Rev

journal_title

Endocrine reviews

authors

Goldfine ID,Maddux BA,Youngren JF,Reaven G,Accili D,Trischitta V,Vigneri R,Frittitta L

doi

10.1210/er.2007-0004

subject

Has Abstract

pub_date

2008-02-01 00:00:00

pages

62-75

issue

1

eissn

0163-769X

issn

1945-7189

pii

er.2007-0004

journal_volume

29

pub_type

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