Increased hepatic levels of the insulin receptor inhibitor, PC-1/NPP1, induce insulin resistance and glucose intolerance.
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.
Dong
Hengjiang
H
Department of Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, New York, USA.
Maddux
Betty A
BA
Altomonte
Jennifer
J
Meseck
Marcia
M
Accili
Domenico
D
Terkeltaub
Robert
R
Johnson
Kristen
K
Youngren
Jack F
JF
Goldfine
Ira D
ID
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
D001786:Blood Glucose; D007328:Insulin; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases