Penn Researchers Describe Paradox Underlying the Effectiveness
of Anti-Diabetes Drugs
PA) - If obesity is the leading cause of type II diabetes,
then why do thiazolidinediones (TZDs), the only available
drugs that treats this form of diabetes, actually cause
more weight gain? Today, in the online version of Nature
Medicine, researchers at the University of Pennsylvania
School of Medicine address the fundamental workings
of TZDs (also known as glitazones or under brand names
such as Actos® and Avandia®), and provide a
potential new target for further study.
Their research describes how TZDs trigger the creation
of glycerol kinase, an enzyme that causes fat cells
to store fatty acids faster than it produces them.
"It is what researchers call a 'futile' cycle.
Just as fat cells release their larder of fatty acids,
glycerol kinase causes the fat cells to put them back
in storage," said Mitchell A. Lazar, MD, PhD,
Chief of the Division of Endocrinology, Diabetes, and
Metabolism and Director of the Penn Diabetes Center.
"The glycerol kinase is packing the pantry faster
than fat cells can pull the cans off of the shelves.
The net influx of fatty acids into fat tissue contributes
to reduced fatty acids in the bloodstream that, in turn,
leads to increased sensitivity to insulin."
Type II, or adult-onset diabetes, occurs as cells lose
the ability to respond to insulin, a hormone which allows
cells to absorb sugar for fuel. The disease affects
millions, and has become an epidemic in the industrialized
world. According to Lazar, two big mysteries remain
concerning type II diabetes: how cells become insulin
resistant and how TZDs cause them to lose resistance
to insulin. By studying how the drug works, the researchers
have uncovered a fundamental clue that may allow the
development of better therapies.
"Right now, our findings suggest that weight gain
is an inherent part of how TZDs function and diabetics
should bear in mind the role of a healthy diet in combination
with drug therapy," said Lazar. "TZDs actually
lower insulin requirements in diabetics, and this is
likely to be beneficial in terms of the risk of hypertension
and heart disease associated with diabetes."
Despite their beneficial qualities, it seems that TZDs
have little respect for medical textbooks. "According
to conventional medical knowledge, fat cells do not
produce glycerol kinase for precisely the reason that
helps TZDs to be effective," said Lazar.
Fatty acids are stored in fat cells as triglycerides
(TGs). When the body senses that it needs fuel, such
as what happens when diabetic cells cannot absorb blood
sugar, fat cells breakdown TGs to produce glycerol,
which travels to the liver to make the sugar glucose,
and fatty acids, which muscles use an emergency fuel
TZDs, however, reverse this process as it happens. When
the drug binds to a receptor in fat cells called PPARgamma,
TZD causes the cells to uncharacteristically produce
glycerol kinases. These enzymes then recombine glycerol
and fatty acids into TGs. They also open the cell's
door to trap passing fatty acids, which lowers the amount
of fatty acids in the bloodstream.
In addition, researchers have found that TZDs may also
alter the chemical signals produced by fat cells, which
may prove beneficial in producing the next generation
of anti-diabetes drugs.
"We have come to understand that fat cells are
more than just storage bins for excess fats," said
Lazar. "They produce hormones and actively regulate
how our bodies process and use fats. Future drug discovery
may depend on the role of fat itself."
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