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Research Suggests How Steroids Cause Diabetes and Hypertension; Liver
Plays Critical Role

St. Louis, July 17, 2003 — Steroids called glucocorticoids are
critical for treating diseases such as asthma, arthritis and pain
syndromes, but they also can trigger diabetes and hypertension.
Research at Washington University School of Medicine in St. Louis now
shows why these commonly used drugs have such dangerous side effects.

The team found that a protein called peroxisome proliferator-activated
receptor-alpha (PPAR-alpha) is critical in this process and that the
liver plays a key role. The findings help explain the high incidence
of diabetes and hypertension in obese individuals, a group that
normally produces significantly more glucocorticoids than people of
average weight.

"Glucocorticoids are very effective for treating many diseases," says
first author Carlos Bernal-Mizrachi, M.D., instructor of medicine. "If
we can understand the mechanisms by which these drugs cause side
effects like diabetes and hypertension, we may be able to intervene
and prevent these disorders in people who are taking steroids and in
people who are obese."

The study appears online and in the August issue of the journal Nature
Medicine. Bernal-Mizrachi led the study, in collaboration with Clay F.
*****kovich, M.D., professor of medicine and of cell biology and
physiology and director of the Division of Endocrinology, Metabolism
and Lipid Research, and Daniel P. Kelly, M.D., professor of medicine,
of molecular biology and pharmacology and of pediatrics and director
of the Center for Cardiovascular research.

Hypertension (persistent high blood pressure) and diabetes (chronic
insulin deficiency) both are related to insulin-resistance, in which
the body does not properly respond to insulin.

PPAR-alpha is found in the liver, kidney, muscles, blood vessels and
other organs. Since it is activated by fatty acids and since
glucocorticoids alter fatty acid processing, Bernal-Mizrachi and his
colleagues hypothesized that the two may act together to produce the
disease-causing side effects. They therefore compared mice lacking
PPAR-alpha and LDLR (the receptor for low density lipoprotein, also
known as "bad cholesterol") with mice lacking only LDLR.

The team found that when given the glucocorticoid dexamethasone, mice
lacking only LDLR had increased levels of insulin, fasting glucose and
leptin, all signs of diabetes. The animals also became less
hypoglycemic when given insulin, suggesting that they were developing
insulin resistance, the precursor to diabetes. Mice lacking both LDLR
and PPAR-alpha showed no signs of diabetes.

Surprisingly, dexamethasone also increased blood pressure in mice that
had PPAR-alpha but not LDLR; it did not have an affect on blood
pressure in mice lacking both PPAR-alpha and LDLR.

"Somehow, animals missing PPAR-alpha were protected from developing
diabetes and hypertension," *****kovich says.

The team then replaced PPAR-alpha in the liver in mice lacking both
PPAR-alpha and LDLR. The animals developed the same symptoms of
diabetes and hypertension (high blood pressure) when chronically
treated with dexamethasone as mice with normal levels of PPAR-alpha
throughout the body.

The team also examined human liver cells in a petri dish. When
PPAR-alpha was activated and steroids were added, expression of genes
related to glucose production tripled.

"The scientific community hasn't fully appreciated the potentially
important role of the liver in these conditions," *****kovich says.
"These results strongly suggest that the liver is the key to
controlling blood pressure and glucose, and our preliminary evidence
with human liver cells strongly suggests that the results in mice are
relevant to human disease."

Next, *****kovich, Bernal-Mizrachi and their colleagues plan to
investigate the role of PPAR-alpha in healthy humans.

"We believe that diabetes, hypertension and many other disorders of
western civilization are related to metabolism of fatty acids, not
just glucose metabolism," *****kovich says. "These results support
that theory, because PPAR-alpha is activated by fatty acids and
appears to be important in the development of these problems.
Hopefully, studying this process in humans will lead to ways of
preventing these potentially adverse effects of steroids and help us
understand why people who get overweight have many of the symptoms of
excess production of glucocorticoids."

###

Bernal-Mizrachi C, Weng S, Feng C, Finck BN, Knutsen RH, Leone TC,
Coleman T, Mecham RP, Kelly DP, *****kovich CF. Dexamethasone
induction of hypertension and diabetes is PPAR-alpha dependent in LDL
receptor-null mice. Nature Medicine, August, 2003.

Funding from the National Institutes of Health, the Clinical Nutrition
Research Unit and the Diabetes Research and Training Center supported
this research.

The full-time and volunteer faculty of Washington University School of
Medicine are the physicians and surgeons of Barnes-Jewish and St.
Louis Children's hospitals. The School of Medicine is one of the
leading medical research, teaching and patient-care institutions in
the nation. Through its affiliations with Barnes-Jewish and St. Louis
Children's hospitals, the School of Medicine is linked to BJC
HealthCare

http://mednews.wustl.edu/medadmin/PAnews.nsf/0/7F52FFDD989B671786256D6600761F9B