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Diabetes 54:367-372, 2005
© 2005 by the American Diabetes Association, Inc.

Increased Hepatic Levels of the Insulin Receptor Inhibitor, PC-1/NPP1, Induce Insulin Resistance and Glucose Intolerance

Hengjiang Dong1, Betty A. Maddux2, Jennifer Altomonte1, Marcia Meseck1, Domenico Accili3, Robert Terkeltaub4, Kristen Johnson4, Jack F. Youngren2, and Ira D. Goldfine2

1 Department of Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, New York
2 Department of Medicine and Diabetes Center, University of California San Francisco, San Francisco, California
3 Russ Berrie Pavilion, Columbia University, New York, New York
4 Veterans Administration Medical Center, University of California San Diego, San Diego, California

The ectoenzyme, plasma cell membrane glycoprotein-1 (PC-1), is an insulin receptor (IR) inhibitor that is elevated in cells and tissues of insulin-resistant humans. However, the effects of PC-1 overexpression on insulin action have not been studied in animal models. To produce mice with overexpression of PC-1 in liver, a key glucose regulatory organ in this species, we injected them with a PC-1 adenovirus vector that expresses human PC-1. Compared with controls, these mice had two- to threefold elevations of PC-1 content in liver but no changes in other tissues such as skeletal muscle. In liver of PC-1 animals, insulin-stimulated IR tyrosine kinase and Akt/protein kinase B activation were both decreased. In this tissue, the IR-dependent nuclear factor Foxo1 was increased along with two key gluconeogenic enzymes, glucose-6-phosphatase and phosphenolpyruvate carboxykinase. The PC-1 animals had 30–40 mg/dl higher glucose levels and twofold higher insulin levels. During glucose tolerance tests, these animals had peak glucose levels that were >100 mg/dl higher than those of controls. These in vivo data support the concept, therefore, that PC-1 plays a role in insulin resistance and suggest that animals with overexpression of human PC-1 in liver may be interesting models to investigate this pathological process.

Address correspondence and reprint requests to Ira D. Goldfine, University of California San Francisco, Department of Medicine, Box 1616, MZ, San Francisco, CA 94143-1616. E-mail: idg43{at}itsa.ucsf.edu

Abbreviations: ELISA, enzyme-linked immunosorbent assay; IR, insulin receptor; NPP, nucleotide pyrophosphatase-phosphodiesterase; PC-1, plasma cell membrane glycoprotein-1; PNTP, thymididne-5'-monophosphate-p-nitrophenyl ester; Pck1, phosphenolpyruvate carboxykinase; PKB, protein kinase B; G6pc, glucose-6-phosphatase


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