O-GlcNAc modification is associated with insulin sensitivity in the whole blood of healthy young adult males

Background: Hemoglobin A1c (HbA1c) is the predominant diagnostic tool for diabetes diagnosis and progression. However, it has proven to be insensitive at pre-diabetic threshold values. O-linked-beta-N-acetylglucosamine (O-GlcNAc) modification has emerged as a sensitive biomarker. The purpose of this study was to explore the sensitivity of O-GlcNAc expression as a potential marker of early metabolic dysfunction in a young adult population. Healthy, young males (18-35 y) from the Assessing Inherited Metabolic syndrome Markers in the Young study (AIMMY), were divided into low (LH, 0.60) or high (HH, 1.61) homeostatic model assessment of insulin resistance (HOMA-IR) cohorts. Findings: The relationships between a panel of anthropometric, metabolic measures and whole blood global protein O-GlcNAc was examined. O-GlcNAc and O-GlcNAc transferase (OGT) levels were quantified by immunoblotting and compared to anthropometric measures: body mass index (BMI), percentage body fat, aerobic fitness, blood glucose, triglycerides, HDL, insulin, and HbA1c. HOMA-IR cohorts showed no differences in BMI, blood glucose or HbA1c, but differed in percent body fat, plasma triglycerides, and circulating insulin. Greater O-GlcNAc expression was observed in the whole blood of HH compared to LH. Moreover, a positive association between HOMA-IR and O-GlcNAc emerged, while no relationship was found between HbA1c and HOMA-IR. This effect was not related to OGT expression. Conclusions: Results indicate that O-GlcNAc has a greater sensitivity to metabolic status compared to HbA1c in this population. O-GlcNAc has the potential to serve as a screening tool for predicting future metabolic disturbances in a young healthy adult population free of any clinically relevant pathologies.