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Glycobiology Advance Access published online on November 9, 2006
Glycobiology, doi:10.1093/glycob/cwl067
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

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 Akimoto1,§, Gerald W. Hart2, Lance Wells2, Keith Vosseller2, Koji Yamamoto3, Eiji Munetomo3, Mica Ohara-Imaizumi4, Chiyono Nishiwaki4, Shinya Nagamatsu4, Hiroshi Hirano1 and Hayato Kawakami1

1 Departments of Anatomy, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan
2 Department of Biological Chemistry, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205, USA
3 Medicinal Research Laboratories, Taisho Pharmaceutical Co., LTD., Saitama 331-9530, Japan
4 Departments of Biochemistry, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan

§ To whom correspondence should be addressed: Department of Anatomy, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan. Phone: +81-422-47-5511 Fax: +81-422-44-0866 E-mail address: yakimoto{at}kyorin-u.ac.jp

Received on April 26, 2006; revised on November 2, 2006; accepted on November 3, 2006

Many nuclear and cytoplasmic proteins are O-glycosylated on serine or threonine residue with the monosaccharide ß-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 non-insulin-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.

Key words: diabetic Goto-Kakizaki rat / hexosamine biosynthetic pathway / pancreas / PDX-1 / O-GlcNAc / diabetes


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