We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Prolonged incubation in PUGNAc results in increased protein O-Linked glycosylation and insulin resistance in rat skeletal muscle.
- Authors
Arias, Edward B.; Kim, Junghoon; Cartee, Gregory D.
- Abstract
Increased flux through the hexosamine biosynthetic pathway and increased O-linked glycosylation (Nacetylglucosamine [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 OGlcNAcase 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.
- Subjects
HEXOSAMINES; AMINO sugars; INSULIN; HYPOGLYCEMIC agents; DIABETES complications; INSULIN resistance
- Publication
Diabetes, 2004, Vol 53, Issue 4, p921
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/diabetes.53.4.921