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The Role of Membrane Glycoprotein Plasma Cell Antigen 1/Ectonucleotide Pyrophosphatase Phosphodiesterase 1 in the Pathogenesis of Insulin Resistance and Related Abnormalities

Department of Medicine and Diabetes Center (I.D.G., B.A.M., J.F.Y.), University of California, San Francisco, California 94115; Division of Cardiovascular Medicine (G.R.), Stanford University School of Medicine, Stanford, California 94305; Diabetes Center (D.A.), Columbia University, New York, New York 10032; Department of Clinical Sciences (V.T.), Sapienza University, 00198 Rome, Italy; Research Unit of Diabetes and Endocrinology (V.T.), Scientific Institute Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; Casa Sollievo Della Sofferenza-Mendel Institute (V.T.), 00198 Rome, Italy; and Endocrinologia (R.V., L.F.), Ospedale Garibaldi, University of Catania, 95122 Catania, Italy

Correspondence: Address all correspondence and requests for reprints to: Ira D. Goldfine, University of California San Francisco, Department of Medicine, Box 1616 MZ, San Francisco, California 94143. 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 plasma cell antigen 1 (PC-1) [ectonucleotide pyrophosphatase phosphodiesterase 1] 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 -subunit that is located in residues 485–599. The connecting domain transmits insulin binding in the -subunit to activation of tyrosine kinase activation in the β-subunit. When PC-1 is overexpressed, it inhibits insulin-induced IR β-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 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.