 | THE METABOLIC SYNDROME X: Convergence of Insulin Resistance, Glucose Intolerance, Hypertension, Obesity, and Dyslipidemias-Searching for the Underlying Defects
Copyright © 1999 by the New York Academy of Sciences
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Annals of the New York Academy of Sciences 892:204-222 (1999)
© 1999 New York Academy of Sciences
Role of PC-1 in The Etiology of Insulin Resistance
IRA D. GOLDFINEa,d,
BETTY A. MADDUXa,
JACK F. YOUNGRENa,
VINCENZO TRISCHITTAb AND
LUCIA FRITTITTAc
aDepartment of Medicine, Division of Diabetes and Endocrine Research, Mount Zion Medical Center, University of California San Francisco, San Francisco, California 94143-1616, USA
bDivisione e Unita di Ricerca di Endocrinologia, Istituto Scientifico Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
cIstituto di Medicina Interna, Endocrinologia e Malattie Metaboliche, Universita di Catania, Ospedale Garibaldi, Catania, Italy
dAddress correspondence to Ira D. Goldfine, M.D., UCSF-Mt. Zion Diabetes & Endocrine Research, 2200 Post Street, Room C-415C, UCSF Box 1616, San Francisco, CA 94143-1616. Tel: (415) 885-7430; fax: (415) 885-7724; e-mail: idg{at}itsa.ucsf.edu
Defects in insulin receptor tyrosine kinase activity have been demonstrated in tissues from insulin resistant subjects, but mutations in the insulin receptor gene are rare. Therefore, other molecules that are capable of modulating the insulin receptor most likely play a major role in insulin resistance. In cultured fibroblasts from an insulin resistant patient with Type 2 diabetes, we first identified membrane glycoprotein PC-1 as an inhibitor of the insulin receptor tyrosine kinase activity. PC-1 is overexpressed in fibroblasts from other insulin resistant subjects, both with and without Type 2 diabetes. PC-1 is a large class II exoprotein whose function is unknown. Studies in muscle and fat of insulin resistant subjects, two primary tissues for insulin activation, reveal that elevated levels of PC-1 are inversely correlated with decreased insulin action both in vivo and in vitro. Transfection and expression of PC-1 in cultured cells demonstrate that overexpression of PC-1 produces impairments in insulin receptor tyrosine kinase activity, and the subsequent cellular responses to insulin. These studies indicate, therefore, that PC-1 is a major factor in the etiology of insulin resistance, and is a potential new therapeutic target for antidiabetic therapy.
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