If key proteins laden with sugar are present in patients with diabetes, the findings may provide a target for developing new strategies to deal with this growing public health threat, says Hart. While diabetes can be fairly well controlled by diet and carefully monitoring one's blood sugar levels, finding a way to remove extra sugar tags may help treat or prevent diabetes someday, the researchers suggest.
"Textbooks frequently and incorrectly show glycosylation only happening to proteins on the cell surface," says Hart. "Complex sugars are added only to proteins outside the cell, but simple sugars are used all the time in the nucleus and cytoplasm to modify proteins. It's this glycosylation that happens inside the cell, involving simple sugars, that is the key in insulin resistance."
The "simple sugar" to which he refers is O-linked beta-N-acetylglucosamine, a complex name that condenses to a difficult acronym -- O-GlcNAc -- with an ugly pronunciation -- "oh-gluck-nack." But in many ways, O-GlcNAc is a beautiful and mysterious thing, says Hart.
"O-GlcNAc is a modifier on many proteins, but if you didn't know to look for it, you'd never find it," he says. "Instruments and the usual laboratory methods have a hard time measuring it, so we developed the techniques to detect it."
O-GlcNAc is added to proteins by one enzyme and removed from proteins by another. By selectively blocking that removal, the scientists hoped to load up proteins with sugar without adding extra sugar (the way other scientists have created insulin resistance). "We wanted to see the effect of glycosylation itself, so we used a molecular sledgehammer to increase the amount of sugar bound to proteins," says Hart, whose lab proved the ability of the blocker, a molecule called PUGNAc.
Not only did the blocker increase the amount of O-GlcNAc
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Contact: Joanna Downer
jdowner1@jhmi.edu
410-614-5105
Johns Hopkins Medical Institutions
15-Apr-2002