Scientists
Close In On Trigger Of Insulin Resistance; Extra Sugar and
Glucosamine Can Cause Insulin Resistance In Cells
Johns
Hopkins scientists have discovered direct evidence that a build-up
of sugar on proteins triggers insulin resistance.
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.
Johns
Hopkins Medical Institutions
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on reservations are equipped with hazardous waste disposal boxes
mounted in rest rooms for safe disposal of insulin syringes and
lancets used in testing blood.
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