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.
Many nuclear and cytoplasmic proteins are O-glycosylated on serine or threonine residues with the monosaccharide beta-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.
Akimoto
Yoshihiro
Y
Department of Anatomy, Kyorin University School of Medicine, Mitaka, Tokyo, Japan. yakimoto@kyorin-u.ac.jp
Hart
Gerald W
GW
Wells
Lance
L
Vosseller
Keith
K
Yamamoto
Koji
K
Munetomo
Eiji
E
Ohara-Imaizumi
Mica
M
Nishiwaki
Chiyono
C
Nagamatsu
Shinya
S
Hirano
Hiroshi
H
Kawakami
Hayato
H
D000117:Acetylglucosamine / Q000032:analysis / Q000378:metabolism*; D000818:Animals; D003920:Diabetes Mellitus / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000032:analysis / Q000378:metabolism*; D007328:Insulin / Q000032:analysis / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D010179:Pancreas / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D015534:Trans-Activators / Q000032:analysis / Q000378:metabolism*
D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D017351:N-Acetylglucosaminyltransferases; C063057:UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase; D005947:Glucose; D000117:Acetylglucosamine