O-GlcNAc modification on IRS-1 and Akt2 by PUGNAc inhibits their phosphorylation and induces insulin resistance in rat primary adipocytes (original) (raw)

Experimental & Molecular Medicine volume 37, pages 220–229 (2005)Cite this article

Abstract

It has been known that _O_-linked β-_N_-acetylglucosamine (_O_-GlcNAc) modification of proteins plays an important role in transcription, translation, nuclear transport and signal transduction. The increased flux of glucose through the hexosamine biosynthetic pathway (HBP) and increased _O_-GlcNAc modification of protein have been suggested as one of the causes in the development of insulin resistance. However, it is not clear at the molecular level, how _O_-GlcNAc protein modification results in substantial impairment of insulin signaling. To clarify the association of _O_-GlcNAc protein modification and insulin resistance in rat primary adipocytes, we treated the adipocytes with _O_-(2-acetamido-2deoxy-_D_-glucopyranosylidene)amino-_N_-phenylcarbamate (PUGNAc), a potent inhibitor of _O_-GlcNAcase that catalyzes removal of _O_-GlcNAc from proteins. Prolonged treatment of PUGNAc (100 µM for 12 h) increased _O_-GlcNAc modification on proteins in adipocytes. PUGNAc also drastically decreased insulin-stimulated 2-deoxyglucose (2DG) uptake and GLUT4 translocation in adipocytes, indicating that PUGNAc developed impaired glucose utilization and insulin resistance in adipocytes. Interestingly, the _O_-GlcNAc modification of IRS-1 and Akt2 was increased by PUGNAc, accompanied by a partial reduction of insulin-stimulated phosphorylations of IRS-1 and Akt2. The PUGNAc treatment has no effect on the expression level of GLUT4, whereas _O_-GlcNAc modification of GLUT4 was increased. These results suggest that the increase of _O_-GlcNAc modification on insulin signal pathway intermediates, such as IRS-1 and Akt2, reduces the insulin-stimulated phosphorylation of IRS-1 and Akt2, subsequently leading to insulin resistance in rat primary adipocytes.

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  1. Department of Biochemistry, College of Medicine, Dongguk University, Gyeongju, 780-714, Korea
    Seung Yoon Park

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  1. Seung Yoon Park
  2. Jiwon Ryu
  3. Wan Lee

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Park, S., Ryu, J. & Lee, W. _O_-GlcNAc modification on IRS-1 and Akt2 by PUGNAc inhibits their phosphorylation and induces insulin resistance in rat primary adipocytes.Exp Mol Med 37, 220–229 (2005). https://doi.org/10.1038/emm.2005.30

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