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in the United States have been diagnosed with diabetes and another 6.2 million people are unaware they have the disease, according to the American Diabetes Association. It is estimated that 5-10 percent of Americans diagnosed with diabetes have type 1 diabetes (previously referred to as juvenile diabetes).
Since the early 1990s, as the waistlines of Americans continue to grow, there has been a sharp increase in those diagnosed with the disease, specifi cally type 2 diabetes mellitus, formerly known as adult onset diabetes. Diabetes is quickly becoming more prevalent in our culture, among younger and younger populations as well.
Sadly, this dramatic increase in diabetes has earned its ranking as the fi fth-leading cause of death in the U.S. The cost of diabetes to the American people is staggering, exceeding $132 billion per year.
Because of the rapid increase in Americans diagnosed with diabetes, combined with the continued problem of obesity in the U.S., researchers in the School of Allied Health have formed an interdisciplinary team to unlock the secrets of diabetes. These researchers study diabetes for a variety of reasons, and though their motivations and expertise vary, they share a common goal – reducing the devastating effects of the disease.
22
24The Islet of Promise
28Aiding the Diabetic Heart
31Send in the Nanoparticles!
32Protein May Be a Key
34An Exercise
in Pain Relief23
24
According to the Juvenile Diabe-
tes Research Foundation, islet
transplantation has emerged
as the most promising option
for achieving restoration of normal blood
sugar in people with type 1 diabetes. In
type 1 diabetes, the lack of insulin is due to
an autoimmune process in which the body’s
immune system destroys the beta cells in the
islets of Langerhans.
Lisa Stehno-Bittel, PhD, PT, associate
professor and chair of the Department of
Physical Therapy and Rehabilitation Science,
is working on pancreatic islet transplanta-
tion—the transplantation of cells from a
donor pancreas to a person with type 1 diabe-
tes. Once implanted, the new islets begin to
make and release insulin. The goal of islet
transplantation is to prevent people with type
1 diabetes from having to administer daily
injections of insulin.
Stehno-Bittel first became interested
in diabetes research when she was earning
her PhD at the University of Missouri. Her
mentor’s 2-year-old son was diagnosed with
type 1 diabetes mellitus. Determined to
learn more about this disease that invaded
his family, her mentor suddenly changed the
focus of his lab from cardiovascular research
to diabetes research. Stehno-Bittel made
the switch with him and has devoted her
career to the study of diabetes. Since then,
OPTIMISM BUBBLES UNDER THE SURFACE of a rat islet
(left). In this cluster of cells, green represents cells dying via
apoptosis, orange indicates death by necrosis and living cells do not pick up the dye. Current research
in the school is uncovering mysteries buried deep in the cells
of diabetes patients.25
Unlocking the Secrets of D
iabetes
Stehno-Bittel has earned
an international reputation
for her research on improv-
ing treatment options for
people with diabetes and
on the effects of exercise
on diabetes.
“Unfortunately, the
small number of avail-
able donor organs limits the
number of islet transplants
that can be performed.
Worse, the current proto-
cols require islets from one
to three donor pancreata per
recipient. Research aimed
at increasing islet yield,
viability or functional activ-
ity would make a valuable
contribution toward the
clinical treatment of type
1 diabetes,” Stehno-Bittel
explained.
In one project, funded
by the Emilie Rosebud
Diabetes Research Foun-
dat ion, Stehno -Bit te l
discovered that the islets
typically used in transplants
were not healthy—possibly
underlying the need for
multiple transplants. Her
work with rats showed that
small islets consumed more
oxygen than large islets,
indicative of good mito-
chondrial function. They
secreted more insulin in
vitro than large islets. And,
most important, the trans-
plants resulted in improved
outcomes as compared
with transplantation of
the same volume of large
islets. Without a human
islet transplant site in
Kansas City, Stehno-Bittel
explained, they had to hope
that other transplant sites
around the world would
read about the work at KU
and adopt their transplant
procedures, based on the
KU fi ndings. Within a year
of Stehno-Bittel’s publica-
tion, a transplant site in
Switzerland reported using
Stehno-Bittel’s approach to
islet transplants in humans
and showed
i m p r o v e d
outcomes.
“It’s rare
that a basic
s c i e n t i s t
w o r k i n g
wi th ra t s
can make an
impact in clinical practice in
a short period of time. We
have done that in less than
a year, and we are thrilled,”
Stehno-Bittel said.
Now the group is
looking for innovative
ways to capitalize on these
observations to continue
improving t ransplant
success rates. With funding
from the Juvenile Diabe-
tes Research Foundation,
Stehno-Bittel and her
colleagues are currently
testing gel patches of the
Lisa Stehno-Bittel, PhD
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diabetes is the5thleading cause of death in the U.S.
insulin-producing beta cells to be
used for transplantation and exam-
ining ways to genetically modify
the beta cells from large islets so
that they will produce more insulin
like the small ones.
Stehno-Bittel is also engaged in
ongoing studies that examine the
effects of exercise on diabetes.
“We have looked at the changes
in the risk of cardiovascular disease
if you exercise or do not exercise,”
she said. “In rats we’ve seen that a
certain protein goes up with diabe-
tes that puts the heart at risk. We
can bring the protein levels back
down with exercise, and the risk of
diabetes goes down.”
Now her team is translating
what they have learned from their
animal research into an interven-
tion study using humans. They
have set up an exercise program in
their clinic as a community service
and are beginning to collect data
for research.
Stehno-Bittel’s research in rat
exercise tests has gained interna-
tional attention and scientists from
around the world seek her advice
and assistance. Right now, the
team is helping researchers from
the University of Houston with
a three-year research project that
evaluates the effects of exercise on
rats with Parkinson’s disease.
Dr. Stehno-Bittel’s research has recently led to exciting international developments.
After listening to her presentation at an American Diabetes Association conference, a research group in Switzerland was able to implement Stehno-Bittel’s ideas about the superiority of smaller islet cells in transplantations from her rat studies to transform their work in human studies.
Patrick Kugelmeier, PhD, a researcher at Universitats Spital in Zurich, Switzerland, spoke highly of Stehno-Bittel’s work:
“... your data was a big motivation for us to summarize our collected data and analyse our remaining data, so fi nally we could submit our work.”
Findings by Kugelmeier’s team were published in the March 2007 issue of Diabetes, the scientifi c journal of the American Diabetes Association that focuses on original research.
Copyright © 2007 American Diabetes AssociationFrom Diabetes, Vol. 56, 2007. Reprinted with permission from the American Diabetes Association.
27
Unlocking the Secrets of D
iabetes
4,110americans are newly diagnosedwith diabetes every day
OOf the 20.8 million adults and children
in the United States who currently
suffer from diabetes, two-thirds
will die from heart disease or stroke,
according to the American Diabetes
Association. Yet most diabetics do not
recognize heart disease as a complication
of diabetes.
With training in both biochemistry
and protein chemistry, Irina Smirnova,
PhD, wanted to dig deeper to learn more
about the molecular mechanism underly-
ing exercise’s positive effect on the heart
in diabetics.
Smirnova is an assistant professor in
the Department of Physical Therapy and
Rehabilitation Science. She has focused
much of her research on the cellular sign-
aling involved in pathological cardiac
processes associated with diabetes and
how physical training can protect the
damaged heart.
Currently, she is engaged in a four-year
study funded by the American Heart Asso-
ciation that is testing the effect of a drug
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23 Billiondollars are spent annually on direct care for diabetes
Irina Smirnova, PhD
29
designed to inhibit Protein
Kinase C, a molecule that
induces stiffening of the
heart muscles in people
with diabetes causing the
heart to pump blood less
effi ciently and eventually to
fail. The goal of the study
is to see if the drug can
replace exercise to improve
the heart so that those
who are physically unable
to exercise, due to other
complications of diabetes,
can receive the same health
benefi ts.
In Smirnova’s animal
study, rats with type 1
diabetes are divided into
three groups. One group
receives neither the drug
nor exercise. A second
group exercises only. The
third group receives the
drug but does not exercise.
“So far the data show
the drug helps the animals
be more tolerant of an
exercise stress test, and
their general appearance is
better,” Smirnova reported.
“They are doing better than
the plain diabetic rats, but
not as well as the exercised
diabetic rats – but they are
close, which is what we
had hoped.”
Now that Smirnova has
one piece of the puzzle in
place, she is ready to move
on to another. In the next
phase of her study, she will
use Magnetic Resonance
Imaging (MRI) technol-
ogy to evaluate the cardiac
performance of the three
groups of rats during the
entire course of the disease.
“We would like to have
data showing when you can
implement exercise and at
what phase of the disease
is exercise most effi cient. Is
it better to exercise at the
beginning of the disease
or later? We are trying to
determine when the inter-
A SERIOUS THREAT to patients withdiabetes is heart fi brosis – undermining the organ’s ability to pump blood as scar tissue overtakes healthy muscle cells. Above, the heart tissue of a diabetic rat (A) is signifi cantly improved with exercise (B), as evidenced by the reduction in scar tissue (blue areas). Image (C) is the control sample.
A B C
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7 percent of the u.s. population has diabetes (20.8 million people)
In a study funded by the Juvenile Diabetes Research Foundation, Irina Smirnova is investigating how to promote wound healing in diabetic patients. Wound healing is critical to managing diabetes because of the rate of amputations as a complication from the disease. National Institute of Diabetes and Digestive and Kidney Diseases statistics show that more than 60 percent of non-traumatic, lower-limb amputations occur among people with diabetes.
Smirnova’s research team will be filling Magnetic Resonance Imaging-traceable nanoparticles – tiny, chemically produced receptacles – with molecules that they hope will help promote blood vessel development.
“We pack the nanoparticles with vascular endothelial growth factor and inject them into rats’ blood, and they spread throughout the body,” she explained. “The nanoparticles are formulated so that they are attracted to the wound site, and when they reach the site, they release the medication.” This medication (growth factor) theoretically should enhance blood vessel formation to the wound, thus speeding the time of recovery.
Smirnova’s team just finished testing the nanoparticles and will now begin to introduce them in rats to see if they form new blood vessels and increase blood supply to the wound site, which is expected to promote healing.
vention would be most
benefi cial,” she explained.
To collect the MRI data,
Smirnova is collaborating
with Mehmet Bilgen, PhD,
director of high-fi eld MRI at
the Hoglund Brain Imaging
Center at The University
of Kansas Medical Center.
In another study of
the diabetic heart, Smir-
nova is trying to shed
light on the underlying
causes of diabetic cardiac
muscle disease or cardio-
myopathy. Her National
Institutes of Health-funded
study hypothesizes that
diabetes causes increased
acetylation, a type of chem-
ical modifi cation, of cardiac
proteins, which may result
in altered protein func-
tion. During the two-year
study, she hopes to iden-
tify the acetylated proteins
and localize the acetyla-
tion sites, then explore the
mechanism for increasing
protein acetylation in the
diabetic heart. Her goal is
to fi nd out how this modi-
fication affects cardiac
proteins’ function in the
diabetic heart pathology.
Irina Smirnova, PhD
31
Unlocking the Secrets of D
iabetes
hu, assistant professor in the Depart-
ment of Clinical Laboratory Sciences,
identifi ed three novel proteins, one
of which he thinks may be helpful in
preventing diabetes and obesity: Ncb5or.
With a grant from the National Institute of
Diabetes and Digestive and Kidney Diseases, he is
collaborating with other researchers on an animal
model that is shedding light on Ncb5or’s role in
helping protect people from diabetes.
Zhu has genetically engineered a breed of mice
that does not have the Ncb5or protein so he can
determine what effect the absence of this protein has
on the animals.
“We are seeing that the animals become diabetic
very early,” he reported. “When they are six weeks
old, the male mice will develop diabetes. For
humans, that would be about the same timing as
type 1 diabetes.”
Depending upon their genetic background, some,
but not all, of the mutated female mice also devel-
oped diabetes early in life.
He hopes the information his team gleans about
lypogenesis – the development of fat tissues – will
one day aid in fi ghting obesity.
In addition, Zhu has observed that the mutated
mice are more sensitive to oxidative stress and more
prone to experience it than are mice that have the
normal Ncb5or protein. One goal of his research is
mmmmmm
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Z
to lower the oxidative stress inside
the mouse cells in anticipation that it
will prevent or slow down the onset
of diabetes in the animals.
“We do not know the exact link
between oxidative stress and the onset
of diabetes,” Zhu stated. “But because
our mutant animals are showing both
symptoms, we can study how they
are related in these animals.”
To learn as much as he can about
the role of Ncb5or, Zhu is collaborat-
ing with other KU School of Allied
Health researchers who bring with
them a broad range of expertise.
Susan Carlson, PhD, professor in the
Department of Dietetics and Nutri-
tion, has spent her career studying
the impact of docosahexaenoic acid
(DHA) supplementation in infants
and new mothers. Carlson is working
with Zhu to analyze the fatty acid
profi les of the mutated mice to deter-
mine how plasma and tissue levels
of fatty acids have changed in the
mutant animals. Karen Kuphal is
monitoring the metabolic state of the
mutant mice, Irina Smirnova, PhD,
is looking at the pathological changes
in their hearts, and Stehno-Bittel is
planning to study how exercise affects
the health of these mice.
“We are trying to take advantage
of this knowledge for the benefi t of
human beings,” Zhu said. “Diabe-
tes, especially in developed countries
like the United States, is so dominant
now, it’s becoming more problematic.
By targeting Ncb5or protein and its
related players, we can potentially
help control some forms of diabetes
and obesity.”
Dr. Hao Zhu (right) with assistant Kevin Grantham
33
Unlocking the Secrets of D
iabetes
246Million
children and adultsworldwide are estimated to have diabetes in 2007
Karen Kuphal, PhD, along with
her research colleagues,
believes in the restorative
power of exercise. Specifi cally, Kuphal is
intrigued by how regular exercise might
help diabetic women who endure disease-
related pain. Studies show about half of
all diabetic patients suffer from neuropa-
thy – a sometimes painful abnormality of
the nervous system. Of those managing a
neuropathic condition, 13 percent report
pain that is so acute that women with
diabetes say it keeps them from perform-
ing self-care behaviors like exercise and
foot care, both known to minimize disease-
related complications.
When Kuphal discovered that women
with diabetes experience chronic pain more
often than men, she wondered if exercise
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35
Unlocking the Secrets of D
iabetes
might play a role in helping women
alleviate the pain.
“If you look at research, it shows
that females with diabetes consist-
ently report more pain than males.
They use analgesic medications more
often than males, report lower pain
thresholds and higher pain ratings
when exposed to noxious stimuli,”
explained Kuphal, who is an assist-
ant professor in the Department of
Physical Therapy and Rehabilitation
Science.
As an exercise physiologist who
did post-doctoral training in neuro-
science, Kuphal set out to fi nd what
role, if any, physical fitness might
play in helping reduce chronic pain.
“I wanted to know if exercise could
lessen a patient’s dependence on pain
medication,” she said.
The number of women facing
diabetes-related, neuropathic pain
will only increase in the coming years,
Kuphal pointed out. New projections
from the American Diabetes Associa-
tion estimate the number of people
with diabetes will rise to
30 million by 2030.
“If we can reduce
pain through exercise,
maybe it will lead to
improved self-care behav-
iors,” Kuphal stated.
With funding from the Building
Interdisciplinary Research Careers
in Women’s Health K12 (BIRCWH)
program, Kuphal is now investigat-
ing the effects of exercise training on
the sensitivity of animals experienc-
ing neuropathic pain. This animal
model, she hopes, will shed light on
the role exercise might play in manag-
ing chronic pain in humans.
As part of her research, Kuphal
surgically alters part of the sciatic
nerve of test rats, which causes the
a n i m a l s t o
develop hyper-
sensitivity in
the a f fec ted
paw. She then
conducts behav-
ior tests on the
rats to measure
their response
to having their
affected paw
touched by coarse
hair bristles and thermal stimuli.
To determine how regular exercise
Karen Kuphal, PhD
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affects the rats’ response to painful
stimuli, Kuphal has divided the
animals into two groups. One group
is housed in cages without exercise
wheels. The other group, kept in
cages with exercise wheels, gets the
benefi t of a nightly run.
“Our computers track the rats
24-7 and record the revolutions of the
wheel,” Kuphal noted.
Every few days during the 30-
day study period, Kuphal conducts
behavioral tests on both groups to see
how they react to pain. Even though
she is still collecting data, Kuphal has
already determined that gender does,
in fact, play a role in pain sensitivity.
“We see lower pain thresholds in the
female rats,” she said. “Although, we
are currently analyzing data on the
effect of exercise on pain, right now
we can tell that exercise is not exac-
erbating painful symptoms, which is
hopeful. Ongoing experiments will
determine if we can reduce the pain
or increase thresholds.”
Next year, Kuphal hopes to
translate her animal model find-
ings into a pilot research program
using humans.
“Pending the results of the non-
clinical data, I want to take a pilot
group of female patients and have
them engage in a structured exer-
cise program to see how it affects
their overall pain rating and to
see if it could benefit their cardio
fitness levels,” she explained. “I
don’t believe exercise will cure the
pain. But if it helps alleviate pain
and helps their general health, it’s a
win-win situation.”
The University of Kansas Medical Center
has been supportive of the diabetes research taking place in the School of
Allied Health. These researchers moved together into a new, state-of-the-art
biomedical research building where they are all located in close proximity. This
will foster more collaborative research projects. In addition, the University has
started a new Diabetes Institute that will serve the Midwest.
Through these and other studies, the School of Allied Health researchers are
leading the way in the development of the Institute. Together, they continue to
strive to unlock the secretes of diabetes, and eventually, hope to minimize the
devastating effects of the disease.37
Unlocking the Secrets of D
iabetes
82,000lower-limb amputationsfrom diabetes in 2002 alone