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This version published online on January 16, 2008
Endocrine Reviews, doi:10.1210/er.2007-0004
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Submitted on January 29, 2007
Accepted on November 8, 2007

The Role of Membrane Glycoprotein PC-1/ENPP1 in the Pathogenesis of Insulin Resistance and Related Abnormalities

Ira D. Goldfine*, Betty A. Maddux, Jack F. Youngren, Gerald Reaven, Domenico Accili, Vincenzo Trischitta, Riccardo Vigneri, and Lucia Frittitta

Department of Medicine and Diabetes Center, University of California, San Francisco, California; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, Diabetes Center, Columbia University, New York, New York, Department of Clinical Sciences, Sapienza University, Rome, Italy, Research Laboratory of Diabetes and Endocrinology, Scientific Institute Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy, CSS-Mendel Institute, Rome, Italy, Endocrinologia, Ospedale Garibaldi, University of Catania, Italy

* To whom correspondence should be addressed. E-mail: ira.goldfine{at}ucsf.edu.

Insulin resistance is a major feature of most patients with type 2 diabetes mellitus (T2D). A number of laboratories have observed that membrane glycoprotein PC-1 (ENNP1) is either overexpressed or overactive in muscle, adipose tissue, fibroblasts, and other tissues of insulin-resistant individuals, both nondiabetic and diabetic. Moreover, in cultured cells in vitro and in transgenic mice in vivo, PC-1 overexpression 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-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- and nephro-vascular 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 K 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 either its overexpression, overactivity, or both.




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