Abstract
Hyperglycemia intensifies flux through the hexosamine biosynthetic pathway (HBP), increasing O‐GlcNAcylation of target proteins (a post‐translational modification). The HBP acts as a “fuel sensor” and regulates O‐GlcNAcylation, subject to intracellular glucose availability. This reversible modification is controlled by two enzymes, O‐GlcNAc transferase (OGT), that attaches O‐GlcNAc to protein residues and O‐GlcNAcase (OGA), responsible for O‐GlcNAc removal. Since O‐GlcNAc protein sites are found in leukocytes, we hypothesized increased OGlcNAcylation of leukocyte proteins in the pre‐diabetic milieu. Participants fitting normal, pre‐diabetic or diabetic criteria were recruited through the Bellville South Study (Tygerberg, South Africa). Leukocytes were isolated and the degree of O‐GlcNAcylation, OGT and OGA protein levels evaluated by flow cytometry, Western blotting and fluorescence microscopy. We found significant increases in O‐GlcNAcylation and OGlcNAc/OGA ratios in pre‐diabetic and diabetic subjects (fasting blood glucose, A1C) vs. normal individuals. The O‐GlcNAc/OGA ratio also showed significant differences between pre‐diabetic and diabetic volunteers, representing a sensitive marker for prediabetes. No significant changes were observed for OGT levels. Our data show great promise for a novel diagnostic tool for the earlier detection and management of type 2 diabetes.
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