Leukocyte O-GlcNAcylation : a novel diagnostic tool for the earlier detection of type 2 diabetes mellitus?

[摘要] ENGLISH ABSTRACT: Context: There are serious deficiencies in the current tests and criteria available for the diagnosis of diabetes. A novel screening method for the earlier and more efficient detection of type 2 diabetes would be a significant clinical advance.Objective: The hexosamine biosynthetic pathway (HBP) usually acts as a fuel sensor and its activation leads to O-GlcNAcylation of target proteins in a glucose-responsive manner. O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) are responsible for O-GlcNAc addition and removal, respectively. As higher HBP flux is linked to insulin resistance/type 2 diabetes, we hypothesized that increased O-GlcNAcylation of leukocyte proteins can detect the onset of pre- and overt diabetes.Materials and methods: 74 participants from Bellville and Stellenbosch (Western Cape, South Africa) were recruited and characterized as normal, pre-diabetic or diabetic. Leukocytes (granulocytes and lymphocytes) isolated from study subjects were evaluated for O-GlcNAcylation, OGA and OGT expression by flow cytometry, immunofluorescence microscopy and Western blotting.Results: Leukocyte O-GlcNAcylation increased in both pre-diabetic and diabetic individuals, with leukocyte sub-population data showing the greatest sensitivity. OGA expression and O-GlcNAc/OGA ratios elevated in parallel with increasing glucose concentrations. OGT expression did not significantly change for any of the study subjects investigated.Conclusions: The initial and significant increases in leukocyte O-GlcNAcylation demonstrate great potential for the earlier detection of pre-diabetic and diabetic individuals. OGA expression and O-GlcNAc/OGA ratios may also have diagnostic value. Together our data show strong promise for eventual diagnostic utility and the more efficient detection of type 2 diabetes.

[发布机构] Stellenbosch University