Prolonged Incubation in PUGNAc Results in Increased Protein O-Linked Glycosylation and Insulin Resistance in Rat Skeletal Muscle
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- Edward B. Arias
- From the Department of Kinesiology, University of Wisconsin-Madison, Madison, Wisconsin
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- Junghoon Kim
- From the Department of Kinesiology, University of Wisconsin-Madison, Madison, Wisconsin
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- Gregory D. Cartee
- From the Department of Kinesiology, University of Wisconsin-Madison, Madison, Wisconsin
抄録
<jats:p>Increased flux through the hexosamine biosynthetic pathway and increased O-linked glycosylation (N-acetylglucosamine [O-GlcNAc]) of proteins have been implicated in insulin resistance. Previous research in 3T3-L1 adipocytes indicated that insulin-stimulated glucose uptake and phosphorylation of Akt were reduced after incubation with O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc; 100 μmol/l), an inhibitor of the O-GlcNAcase that catalyzes removal of O-GlcNAc from proteins. Therefore, in this study, we tested the effects of PUGNAc on skeletal muscle. Incubation of rat epitrochlearis muscles for 19 h with 100 μmol/l PUGNAc resulted in a marked increase in O-GlcNAcylation of multiple proteins. Incubation with PUGNAc reduced glucose transport with a physiologic insulin concentration without affecting glucose transport without insulin or with supraphysiologic insulin. PUGNAc did not significantly alter insulin-stimulated phosphorylation of Akt (serine and threonine) or its substrates glycogen synthase kinase (GSK)3α and GSK3β. Insulin stimulated a dose-dependent (12.0 > 0.6 > 0 nmol/l) increase in the phosphorylation of a 160-kDa protein detected using an antibody against an Akt substrate phosphomotif. PUGNAc treatment did not alter phosphorylation of this protein. These results indicate that PUGNAc is an effective inhibitor of O-GlcNAcase in skeletal muscle and suggest that O-GlcNAc modification of proteins can induce insulin resistance in skeletal muscle independent of attenuated phosphorylation of Akt, GSK3α, GSK3β, and a 160-kDa protein with an Akt phosphomotif.</jats:p>
収録刊行物
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- Diabetes
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Diabetes 53 (4), 921-930, 2004-04-01
American Diabetes Association
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詳細情報 詳細情報について
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- CRID
- 1362544420567411456
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- NII論文ID
- 30026272179
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- ISSN
- 1939327X
- 00121797
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- データソース種別
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