This Article Full Text Full Text (PDF) All Versions of this Article: 29/1/62    most recent Final Manuscript Author Manuscript Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goldfine, I. D. Articles by Frittitta, L. Search for Related Content PubMed PubMed Citation Articles by Goldfine, I. D. Articles by Frittitta, L.

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.

This article has been cited by other articles:

				R. Baratta, P. Rossetti, S. Prudente, F. Barbetti, D. Sudano, A. Nigro, M. G. Farina, F. Pellegrini, V. Trischitta, and L. Frittitta Role of the ENPP1 K121Q Polymorphism in Glucose Homeostasis Diabetes, December 1, 2008; 57(12): 3360 - 3364. [Abstract] [Full Text] [PDF]

				E. S. Stolerman, A. K. Manning, J. B. McAteer, J. Dupuis, C. S. Fox, L. A. Cupples, J. B. Meigs, and J. C. Florez Haplotype Structure of the ENPP1 Gene and Nominal Association of the K121Q Missense Single Nucleotide Polymorphism With Glycemic Traits in the Framingham Heart Study Diabetes, July 1, 2008; 57(7): 1971 - 1977. [Abstract] [Full Text] [PDF]