Findings presented at session of the American Diabetes
Association
PHOENIX, Ariz. - June 15, 2009 - Translational Genomics Research
Institute (TGen) scientists have identified five genetic biomarkers
that could help lead to improved treatments, with fewer
side-effects, for patients with diabetes.
TGen Senior Investigator Dr. Johanna DiStefano presented the
findings in New Orleans on June 6, 2009, at the 69th Scientific
Sessions of the American Diabetes Association.
"We identified genetic variants that may predict how well someone
will respond to the common anti-diabetes drug, Actos," said Dr.
DiStefano, Director of TGen's Diabetes, Cardiovascular &
Metabolic Diseases Division. "The implications of these findings
include determining which patients will best respond to the drug
for the prevention or treatment of diabetes. In addition, this work
lays the foundation for personalized medicine for patients with
this disease."
Personalized medicine involves the rapid application of laboratory
discoveries to therapies, depending on the individual genetic
make-up of each patient.
A TGen-led team, working with scientists from the University of
Southern California's Keck School of Medicine, investigated why as
many as 30-40 percent of diabetes patients treated with
thiazolidinediones (TZDs), such as Actos, fail to respond to the
drug with the expected improvement in insulin sensitivity.
TZDs are a class of insulin-sensitizing drugs used to treat type 2
diabetes mellitus (T2DM). TZDs are agonists for the nuclear
receptor peroxisome proliferator-activated receptor-g (PPARG).
Although the exact mechanism by which TZDs act is not yet known,
data indicate that TZDs improve insulin sensitivity by direct and
indirect effects on adipose tissue and muscle. TZD therapy can
significantly lower diabetes incidence in at-risk subjects,
suggesting this treatment may be an effective means to prevent the
disease.
Previously, TGen and Keck investigators found that genetic
variations in the PPARG gene were associated with TZD metabolism
and the biological effects of TZD, and thereby contribute to the
therapeutic response associated with TZD. However, these variants
did not fully account for the non-response rate, suggesting that
other variants may contribute to TZD response.
To identify other variants that predict response to TZDs, TGen
researchers performed a genome-wide analysis of 115,352 single
nucleotide polymorphisms, or SNPs (a DNA sequence variation within
the more than 3 billion base pairs in the human genome). In
addition, the scientists also systematically screened 28 key genes
involved in TZD metabolism or PPARG-stimulated pathways.
Of the markers examined, DiStefano and her team identified five
critical markers that may predict response to TZD mono-therapy.
These markers include variants in a key drug metabolizing gene
called cytochrome P450 3A4 and a PPARG-coactivator known as
PPARGC1B. Other markers were located in genes associated with PPARG
function and include the protein kinase MAP2K6, a potassium
inwardly-rectifying channel called KCNJ16, and the farnesoid X
receptor (NR1H4).
Together, these markers predicted both response to Actos therapy
and improvement in insulin sensitivity in the patients taking the
drug.
Dr. DiStefano said the next steps in this research will be to
characterize the functional effects of the polymorphisms and assess
the effect of these variants in other patients.
"This work may help treat the right people with the right drug,
design better drugs that will effectively improve insulin
sensitivity for more people, and possibly safeguard against adverse
side reactions seen with some members of this drug class," she
said. Importantly, these findings will enable us to dissect the
pharmacogenetics of TZD response, which will expand our
understanding of the genetic determinants of insulin resistance and
its treatment, provide critical baseline information for the
development and implementation of genetic screening into the
therapeutic decision making process, and lay the foundation for
"individualized medicine" for patients with T2D.
Other TGen scientists involved in the study were: Investigator Dr.
David W. Craig and Research Associate Kimberly A. Yeatts.
Researchers from USC were: Drs. Anny H. Xiang, Thomas A. Buchanan
and Richard M. Watanabe, and graduate student Mohamad T.
Hassanein.
About TGen
The Translational Genomics Research Institute (TGen) is a Phoenix,
Arizona-based non-profit organization dedicated to conducting
groundbreaking research with life changing results. Research at
TGen is focused on helping patients with diseases such as cancer,
neurological disorders and diabetes. TGen is on the cutting edge of
translational research where investigators are able to unravel the
genetic components of common and complex diseases. Working with
collaborators in the scientific and medical communities, TGen
believes it can make a substantial contribution to the efficiency
and effectiveness of the translational process. TGen is affiliated
with the Van Andel Research Institute in Grand Rapids, Michigan.
For more information, visit: www.tgen.org.
Press Contact:
Steve Yozwiak
TGen Senior Science Writer
602-343-8704
[email protected]
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