Elevation of the post-translational modification of proteins by O-linked N-acetylglucosamine leads to deterioration of the glucose-stimulated insulin secretion in the pancreas of diabetic Goto-Kakizaki rats

Yoshihiro Akimoto, Gerald Warren Hart, Lance Wells, Keith Vosseller, Koji Yamamoto, Eiji Munetomo, Mica Ohara-Imaizumi, Chiyono Nishiwaki, Shinya Nagamatsu, Hiroshi Hirano, Hayato Kawakami

Research output: Contribution to journalArticle

Abstract

Many nuclear and cytoplasmic proteins are O-glycosylated on serine or threonine residues with the monosaccharide β-N-acetylglucosamine, which is then termed O-linked N -acetylglucosamine (O-GlcNAc). It has been shown that abnormal O-GlcNAc modification (O-GlcNAcylation) of proteins is one of the causes of insulin resistance and diabetic complications. In this study, in order to examine the relationship between O-GlcNAcylation of proteins and glucose-stimulated insulin secretion in noninsulin-dependent type (type 2) diabetes, we investigated the level of O-GlcNAcylation of proteins, especially that of PDX-1, and the expression of O-GlcNAc transferase in Goto-Kakizaki (GK) rats, which are an animal model of type-2 diabetes. By immunoblot and immunohistochemical analyses, the expression of O-GlcNAc transferase protein and O-GlcNAc-modified proteins in whole pancreas and islets of Langerhans of 15-week-old diabetic GK rats and nondiabetic Wistar rats was examined. The expression of O-GlcNAc transferase at the protein level and O-GlcNAc transferase activity were increased significantly in the diabetic pancreas and islets. The diabetic pancreas and islets also showed an increase in total cellular O-GlcNAc-modified proteins. O-GlcNAcylation of PDX-1 was also increased. In the diabetic GK rats, significant increases in the immunoreactivities of both O-GlcNAc and O-GlcNAc transferase were observed. PUGNAc, an inhibitor of O -GlcNAcase, induced an elevation of O -GlcNAc level and a decrease of glucose-stimulated insulin secretion in isolated islets. These results indicate that elevation of the O-GlcNAcylation of proteins leads to deterioration of insulin secretion in the pancreas of diabetic GK rats, further providing evidence for the role of O-GlcNAc in the insulin secretion.

Original languageEnglish (US)
Pages (from-to)127-140
Number of pages14
JournalGlycobiology
Volume17
Issue number2
DOIs
StatePublished - Feb 1 2007

ASJC Scopus subject areas

  • Biochemistry

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    Akimoto, Y., Hart, G. W., Wells, L., Vosseller, K., Yamamoto, K., Munetomo, E., Ohara-Imaizumi, M., Nishiwaki, C., Nagamatsu, S., Hirano, H., & Kawakami, H. (2007). Elevation of the post-translational modification of proteins by O-linked N-acetylglucosamine leads to deterioration of the glucose-stimulated insulin secretion in the pancreas of diabetic Goto-Kakizaki rats. Glycobiology, 17(2), 127-140. https://doi.org/10.1093/glycob/cwl067