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

30

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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