Impact of Type 2 diabetes and aging on cardiomyocyte function and O-linked N-acetylglucosamine levels in the heart

Increased levels of O- linked attachment of N- acetylglucosamine ( OGlcNAc) on nucleocytoplasmic proteins are implicated in the development of diabetic cardiomyopathy and are regulated by O- GlcNAc transferase ( OGT) expression and its substrate UDP- GlcNAc. Therefore, the goal of this study was to determine whether the development of diabetes in the Zucker diabetic fatty ( ZDF) rat, a model of Type 2 diabetes, results in defects in cardiomyocyte mechanical function and, if so, whether this is associated with increased levels of O- GlcNAc and increased OGT expression. Six- week- old ZDF rats were hyperinsulinemic but normoglycemic, and there were no differences in cardiomyocyte mechanical function, UDP- GlcNAc, O- GlcNAc, or OGT compared with age- matched lean control rats. Cardiomyocytes isolated from 22- wk- old hyperglycemic ZDF rats exhibited significantly impaired relaxation, compared with both age- matched lean control and 6- wk- old ZDF groups. There was also a significant increase in O- GlcNAc levels in high- molecular- mass proteins in the 22- wk- old ZDF group compared with age- matched lean control and 6- wk- old ZDF groups; this was associated with increased UDPGlcNAc levels but not increased OGT expression. Surprisingly, there was a significant decrease in overall O- GlcNAc levels between 6 and 22 wk of age in lean, ZDF, and Sprague- Dawley rats that was associated with decreased OGT expression. These results support the notion that an increase in O- GlcNAc on specific proteins may contribute to impaired cardiomyocyte function in diabetes. However, this study also indicates that in the heart the level of O- GlcNAc on proteins appears to be differentially regulated by age and diabetes.