title: Increased hepatic levels of the insulin receptor inhibitor, PC-1/NPP1, induce insulin resistance and glucose intolerance.
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.
authors.affiliation: Department of Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Hengjiang
authors.initials: H
authors.lastname: Dong
authors.forename: Betty A
authors.initials: BA
authors.lastname: Maddux
authors.forename: Jennifer
authors.initials: J
authors.lastname: Altomonte
authors.forename: Marcia
authors.initials: M
authors.lastname: Meseck
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
authors.forename: Robert
authors.initials: R
authors.lastname: Terkeltaub
authors.forename: Kristen
authors.initials: K
authors.lastname: Johnson
authors.forename: Jack F
authors.initials: JF
authors.lastname: Youngren
authors.forename: Ira D
authors.initials: ID
authors.lastname: Goldfine
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003001:Cloning, Molecular; D005822:Genetic Vectors; D018149:Glucose Intolerance / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D007328:Insulin; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases