Sorry, I suspect individual energy store saturation trigger IR by downregulation.
I thought glycosylation - attachment of a sugar to a protein - cause IR as found by the John Hopkins study?
Perhaps, excess fat creates an environment where coversion of further sugar is not possible and thereby glycosylation and hence IR?
"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."
"We think we've come across a major mechanistic reason for insulin resistance," says Hart. "These cells developed insulin resistance simply because their proteins, and specific proteins in fact, had more than the normal number of sugar tags."
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 bound to proteins, but that increase caused the cells to stop responding to insulin, say co-first authors and postdoctoral fellows Lance Wells and Keith Vosseller.
Looking for proteins in the insulin-signaling pathway that were more glycosylated than normal, Vosseller and Wells found two: beta-catenin and insulin receptor substrate-1 (IRS-1). The crucial role these proteins play in passing along insulin's messages is likely to be adversely affected by the extra sugars they carry, the researchers say.
"Our experiments show that increasing O-GlcNAc on proteins is, by itself, a cause of insulin resistance, rather than an effect or a coincidence," says Vosseller.
In the body, sugar (glucose) is changed into glucosamine, which is changed into O-GlcNAc. Other scientists have shown that giving cells or animals excessive amounts of sugar or glucosamine, along with extra insulin, leads to insulin resistance. The new findings provide an explanation for others' experience with animal and laboratory models of insulin resistance.
There has been little study of glucosamine, a commonly used dietary supplement, in people. It is suggested that people taking glucosamine consult their doctors if they are concerned about the possibility of increasing their risk of developing diabetes.
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