Animal Models Offer Newborn Opportunity to Permanently
Rescue Insulin-making Cells and Possibly Even Protect
Against Future Onset
(Philadelphia, PA) - A
common condition that leads to low birthweight babies
may predispose the infants to obesity and diabetes later
in life by denying cells in the pancreas access to the
chemical signals they need to mature, according to researchers
at the University of Pennsylvania School of Medicine.
Moreover, the condition, which they have successfully
modeled in rodents, may be reversed soon after birth
by the administration of hormones that stimulate the
maturation of the pancreatic beta cells, which produce
insulin. Their findings suggest a way of preventing
diabetes in people at-risk for the disease by boosting
the creation of beta cells soon after birth.
According to Rebecca A. Simmons, MD, assistant
professor in Penn's Department of Pediatrics, "the condition,
called intrauterine growth retardation (IUGR), is generally
caused by the inability of a developing fetus to receive
adequate nutrition and can effect as many as one in
10 newborns." Diminished fetal growth is due to a number
of different processes such as high blood pressure and
intrauterine infections. Epidemiological studies have
also shown that there is a strong link between IUGR
and the development of obesity and diabetes in adulthood.
The Penn researchers believe the link may be due to
the decreased formation of blood vessels in the pancreas.
"Our findings show that the blood vessels themselves
- not just a signal carried in the blood - appear to
provide a signal for pancreatic islets to mature normally
in the fetus," said Doris A. Stoffers, MD, PhD,
assistant professor in Penn's Division of Endocrinology,
Diabetes, and Metabolism. "The defect in the blood vessels
may be involved in the later loss of beta cells within
islets, which leads to diabetes."
Stoffers, Simmons and colleagues reported their findings
in the March 2003 issue of the journal Diabetes,
which they and have expanded upon today at a poster
session at the annual meeting of the Endocrine Society
being held in Philadelphia.
The researchers also found that exendin-4, an analog
of a pancreatic hormone, normalizes beta-cells, the
cells within the pancreatic islets that produce insulin.
"Soon after birth, there is a normal period in which
the endocrine function of the pancreas is still being
remodeled through periods of increased cell growth and
differentiation, as the newborn's body is putting the
finishing touches on the endocrine system," said Stoffers.
"It is a critical period that, in our IUGR rodents,
can be dramatically rescued by exendin-4, which prevents
the progressive reduction of insulin-producing beta-cells."
In addition to a life-long normalization of sugar tolerance,
the researchers observed that the animal models maintained
a healthy number of beta-cells as well as a normal body
weight. Their studies suggest that exendin-4 stimulates
beta cells by influencing PDX, a protein that mediates
how the pancreas responds to sugar by triggering the
production of insulin. PDX is also thought to have a
role in islet regeneration in adults. Therefore, the
researchers believe that exendin-4 and related substances
show promise in the treatment of diabetes not only because
the restorative effects of exendin-4 on beta-cells,
but also because of its potential to regulate PDX and
thereby expand the amount of beta-cells overall.
"It seems that there is a window of opportunity to
prevent the development of human adult-onset diabetes
by treating newborns," said Stoffers and Simmons. "If
this research translates into humans, then we can envision
a way to prevent the development of adult onset diabetes--
by increasing the amount of beta-cells that children
will carry with them into adulthood."
Other contributors to this research include Biva M.
Desai and Michael Crutchlow of Penn and Diva D. DeLeon,
of Penn and The Children's Hospital Of Philadelphia.
The ongoing research of Drs. Stoffers and Simmons is
supported by grants made by the National Institutes
of Health, the American Diabetes Association, and the
Pennsylvania Diabetes Center.
Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $7.8 billion enterprise.
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