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
- 1Department of Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, New York
- 2Department of Medicine and Diabetes Center, University of California San Francisco, San Francisco, California
- 3Russ Berrie Pavilion, Columbia University, New York, New York
- 4Veterans Administration Medical Center, University of California San Diego, San Diego, California
- 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
Abstract
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.
- 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
Footnotes
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- Accepted November 4, 2004.
- Received September 3, 2004.
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