New Enzymatic Blood Test Could Detect Prediabetes

A pilot study reports that O-linked beta-N-acetylglucosamine (O-GlcNAc), an easy-to-detect enzyme in erythrocytes is up to two to three times higher in people with diabetes and pre-diabetes than in those with no disease.

Researchers at Johns Hopkins University (JHU; Baltimore, MD, USA) studied blood samples from volunteers with no diabetes (36 samples), prediabetes (13 samples), and diabetes (53 samples), according to traditional tests that require patient fasting. Erythrocyte proteins were then extracted from the samples, and the hemoglobins were depleted. Then, global O-GlcNAcylation (O-GlcNAc) of the proteins was confirmed by Western blotting using an O-GlcNAc-specific antibody. Relative O-GlcNAc transferase (OGT) and O-GlcNAcase--an enzyme that removes O-GlcNAc in red blood cells--protein amounts were similarly determined. The relative expression of O-GlcNAcase was then compared with the measured level of A1C.

The results showed that erythrocyte proteins are highly O-GlcNAcylated, and O-GlcNAcase expression is significantly increased in erythrocytes from both individuals with prediabetes and diabetes, compared with normal control subjects. However, unlike O-GlcNAcase, protein levels of OGT did not show significant changes. The researchers therefore suggest that the upregulation of O-GlcNAcase might be an adaptive response to hyperglycemia-induced increases in O-GlcNAcylation, which are likely deleterious to erythrocyte functions. The study was published in the July 2010 issue of Diabetes.

"This is an example of how basic research is directly affecting a serious disease,” said Gerald Hart, Ph.D., director of biological chemistry at the JHU School of Medicine. "The question was whether the elevation happened in the earliest stages of diabetes and therefore might have value as a diagnostic tool. Only a much larger clinical trial will determine if, by measuring O-GlcNAcase, we can accurately diagnose prediabetes.”

O-GlcNAc plays an important role in the development of insulin resistance and glucose toxicity, since it modifies many of the cell's proteins to control their functions in response to nutrients (such as glucose and lipids) and stress. O-GlcNAcylation is regulated by OGT, which attaches O-GlcNAc to serine and/or threonine residues of proteins, and by O-GlcNAcase, which removes O-GlcNAc. When the extent of O-GlcNAc attached to proteins becomes too high, as occurs in diabetes, it is harmful to the cell.

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