'Surprising'
Mechanism For Thiazolidinedione-Related Weight Gain Uncovered
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?
Thiazolidinediones
stimulate the uptake of fatty acids by adipocytes and the production
of triglycerides, leading to weight gain.
That,
according to a multicenter team of researchers reports in an advance
online publication of Nature Medicine for September 23rd. Rresearchers 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 source.
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."
Nature
Med 2002 University
Of Pennsylvania Medical Center
================================
Special
News Bulletin
Pyridoxamine
Protects Against Diabetic Retinopathy
Study
shows efficacy of pyridoxamine in preventing aspects of diabetic
retinopathy
See
item 15
