| January 17,
2001
PENN RESEARCHERS DISCOVER FAT
CELL HORMONE THAT PROMOTES TYPE 2 DIABETES
A newly discovered hormone
produced by fat cells may provide a long-sought explanation
for how obesity triggers insulin resistance and type
2 diabetes, a University of Pennsylvania School of Medicine
team reports in the January 18 issue of Nature. The
discovery of the hormone, called resistin (resistance
to insulin), is also helping researchers understand
how a new class of antidiabetic drugs promotes insulin
sensitivity in people with type 2 diabetes. Insulin
resistance, a disorder in which target tissues -- muscle,
fat, and liver cells -- fail to use insulin effectively,
accompanies and usually precedes type 2 diabetes. Eighty
percent of people with type 2 diabetes are overweight,
but the mechanism by which obesity sets the stage for
insulin resistance and diabetes has long puzzled scientists.
A research team led by Dr. Mitchell Lazar, director
of the Penn Diabetes Center at the University of Pennsylvania
School of Medicine, discovered resistin while studying
thiazolidinediones (TZDs), a group of insulin-sensitizing
drugs that include the oral diabetes medications pioglitazone
(Actos(tm)) and rosiglitazone (Avandia(tm)). The researchers
knew that the TZDs activate a nuclear receptor in fat
cells called PPARgamma, which belongs to a family of
receptors that regulate gene expression in response
to hormones, vitamins, and some drugs. The researchers
discovered resistin by screening fat cells for a gene
that was inhibited by TZDs.
"It seemed likely that the TZDs were acting on PPARgamma
to regulate a gene," says Dr. Lazar. "We reasoned that
this gene might encode a previously undiscovered fat
cell hormone that impaired the actions of insulin on
peripheral tissues. If the gene were overactive in obesity,
it could explain the association between diabetes and
obesity. And, if TZDs reduced the expression of this
gene, we'd have an explanation for some of the benefit
of the TZDs in diabetes."
Resistin circulates in the blood of normal mice, falling
after a fast and rising after feeding, and it dramatically
rises in mouse models with genetic as well as diet-induced
obesity. When the researchers administered resistin
to normal mice, the animals developed impaired insulin
action and glucose.
Penn Researchers Discover Fat Cell Hormone That Promote
Type 2 Diabetes ...page 2 intolerance, precursors to
type 2 diabetes. Treatment with the TZD rosiglitazone,
however, decreased blood levels of resistin. Alternatively,
administration of an agent that blocked resistin's effects
in mice with diet-induced obesity improved both insulin
action and blood glucose.
"I don't think it's an exaggeration to say this is
a blockbuster paper with potentially major clinical
impact," said Dr. Allen Spiegel, director of the National
Institute of Diabetes and Digestive and Kidney Diseases,
the part of the National Institutes of Health that funded
the research. "In one fell swoop, Lazar and colleagues
have discovered a novel hormone secreted by fat cells,
possibly explained how TZDs act as antidiabetic agents,
and provided a key link between obesity and type 2 diabetes."
Not only do blood levels of resistin in mice correlate
with insulin resistance and diabetes, Lazar's work suggests
that increased resistin levels are one of the causes
of type 2 diabetes.
"If this observation also turns out to be true in humans,
measuring resistin levels could help diagnose people
at risk for type 2 diabetes. If resistin is really causing
insulin resistance, then lowering levels of the hormone
or blocking its action could constitute a new treatment
for type 2 diabetes," says Dr. Lazar.
About 16 million people in the United States have diabetes,
the most common cause of blindness, kidney failure,
and amputations in adults. Type 2, which accounts for
about 90 percent of diabetes in the United States, is
most common in people who are overweight, inactive,
over age 40, and have a family history of diabetes.
The disease is also more common in minorities: African
Americans, Hispanic/Latino Americans, American Indians,
and some Asian Americans and Pacific Islanders are at
particularly high risk for this form of diabetes. With
the onset of insulin resistance, the pancreas compensates
by producing more insulin, but gradually its capacity
to secrete insulin in response to meals falters, and
the timing of insulin secretion becomes abnormal. After
diabetes develops, pancreatic production of insulin
continues to decline. Many people can control their
blood glucose by following a careful diet and exercise
program, losing excess weight, and taking oral medication.
However, the longer a person has type 2 diabetes, the
more likely he or she will need insulin injections,
either alone or combined with oral drugs.
About 10 percent, or 1.6 million of people with diabetes,
have type 1, formerly known as juvenile onset diabetes
or insulin-dependent diabetes. This form of diabetes,
which usually occurs in children and adults under age
30, develops when the body's immune system attacks the
insulin-producing cells of the pancreas. This research
was funded by the NIDDK under grant 5R01DK49780-06.
Claire Steppan was supported by an unrestricted postdoctoral
grant from Pfizer, Inc. Ronadip Banerjee, is a MD/PhD
trainee in the NIH-sponsored Medical Scientist Training
Program. Elizabeth Brown, was supported by a medical
student research fellowship from the American Diabetes
Association.
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