Theola - I am sorry you are in so much pain. The following article about
glucosamine was posted on Dr Bernstein's diabetes forum. I don't know what
the original source of the article is.

"Scientists Close In On Trigger Of Insulin Resistance
Extra sugar can cause insulin resistance in cells. Now scientists have an
explanation.

In experiments with fat cells, Johns Hopkins scientists have discovered
direct evidence that a build-up of sugar on proteins triggers insulin
resistance, a key feature of most cases of diabetes.

The results underscore the importance of glycosylation - attachment of a
sugar to a protein -- as a way cells control proteins' activities, the
scientists report in the April 16 issue of the Proceedings of the National
Academy of Sciences. The scientists found that at least two proteins
involved in passing along insulin's message were unlikely to work properly
when coated in extra sugar.

Type 2 diabetes, the most common form in adults, occurs when muscle, fat and
other tissues stop responding to insulin's signals to mop up sugar from the
blood. The resulting high blood sugar, if uncontrolled, can lead to
blindness, amputation and death. Understanding sugar's precise influence on
insulin's activity may help improve treatment and prevention, scientists
hope.

"Cells don't respond to insulin itself. Instead, a whole cascade of events,
set in motion by insulin, eventually causes cells to take in sugar,"
explains Gerald Hart, Ph.D., professor and director of biological chemistry
in the school's Institute for Basic Biomedical Sciences. "We now have an
explanation of how sugar can affect these signals, and even a hypothesis for
how high blood sugar could cause tissue damage in diabetes -- by improperly
modifying proteins."

Hart's lab discovered 18 years ago that sugar is used routinely inside cells
to modify proteins, turning them on and off. The more commonly known
protein-controller, phosphate, actually binds to some of the same building
blocks of proteins as sugar does. If proteins have too many sugars on them,
they can't be controlled properly by the cell and are unlikely to work
correctly, suggests Hart.

"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. "

Jean