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Impact of type‐2 diabetes on the hexosamine biosynthesis pathway and protein O‐glycosylation
Author(s) -
Fülöp Norbert,
Wang Peipei,
Marchase Richard B,
Chatham John C
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a297-b
Subject(s) - glycosylation , type 2 diabetes , chemistry , biosynthesis , biochemistry , diabetes mellitus , biology , endocrinology , gene
O‐linked attachment of N‐acetyl‐glucosamine ( O ‐GlcNAc) onto Ser/Thr residues plays an important role in the development of insulin resistance and diabetic complications. The goal of this study was to determine the effect of the development of Type‐2 diabetes on O ‐GlcNAc levels in the heart. Hearts were isolated from 6‐wk and 22‐wk old obese Zucker diabetic fatty rats and age‐matched lean littermates. UDP‐GlcNAc, a precursor of O ‐GlcNAc was assessed by HPLC and protein O ‐GlcNAc and O ‐GlcNAc transferase (OGT) levels were assessed by immunoblot analysis. 6‐wk old obese animals were hyperinsulinemic but normoglycemic; whereas by 22‐wk of age the obese group was hyperglycemic. There were no differences in UDP‐GlcNAc or O ‐GlcNAc levels between 6‐wk old obese and lean groups; however, at 22 weeks, both UDP‐GlcNAc and O ‐GlcNAc levels were significantly increased in the obese diabetic group compared to controls. OGT expression was unaffected between lean and obese groups at any age; however, there was a significant decrease in OGT expression and O ‐GlcNAc levels between 6 and 22 weeks in both control and the obese groups. These data suggest that the increase in O ‐GlcNAc levels in the 22‐wk old obese diabetic group relative to lean controls was due to increased hexosamine biosynthesis flux rather than changes in OGT expression. In contrast the decrease in O ‐GlcNAc levels with age within both lean and obese groups appeared to be due to reduced OGT expression. Thus, cardiac O ‐GlcNAc levels appear to be modulated in opposing directions by age and diabetes. This work was supported by NIH grants HL076165, HL67464, HL077100.