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Glaser, Nicole,
MD
University of California Davis Medical Center, Sacramento,
CA
Cerebral edema and cerebral injury in pediatric
diabetic ketoacidosis
Focus: Type 1, Other
Type of Grant: Core\Basic Science
Project start Date: 01/01/2009
Project end date: 12/31/2011
Diabetes type: Both Type 1 and Type 2 diabetes
Research Description
Diabetic ketoacidosis (DKA) is a potentially
life-threatening complication of diabetes which may occur at onset
of diabetes, or during episodes of illness. During DKA, blood
glucose levels are high and fat breaks down rapidly, resulting in
high levels of fat breakdown products (ketones). Although most
children recover from DKA, approximately 1% develop cerebral edema
(brain swelling), which often causes permanent brain damage or
death. DKA-related cerebral edema is the most frequent
diabetes-related cause of death in children. Previous studies
by our group suggest that cerebral edema may result from poor blood
flow to the brain during DKA. Our data suggest that even a
modest decrease in brain blood flow may cause brain injury, if this
decrease occurs under the conditions present during DKA (elevated
blood glucose and ketone levels and acidosis). Exactly why the
conditions of DKA increase the damaging effects of a reduction in
brain blood flow is not known. In our proposal, we aim
to investigate which of the metabolic alterations occurring during
DKA predispose children to brain injury and brain
swelling. We plan to induce various metabolic
alterations in rats to determine which factor, or combination of
factors, leads to brain swelling. These data will allow us to
develop a more complete understanding of the mechanisms responsible
for cerebral edema and to determine which treatments might be used
to prevent cerebral edema. In addition, data from the
proposed studies are applicable to other common conditions which may
affect individuals with diabetes, such as stroke and head
trauma.
Researcher Profile
What area of diabetes research does your
project cover? What role will this particular project play in
preventing, treating and/or curing diabetes?
Diabetic ketoacidosis (DKA) is a potentially
life-threatening complication of diabetes which may occur at onset
of diabetes, or during episodes of illness. During DKA, blood
glucose levels are high and fat breaks down rapidly, resulting in
high levels of fat breakdown products (ketones). Although most
children recover from DKA, approximately 1% develops cerebral edema,
which often causes permanent brain damage or death.
DKA-related cerebral edema is the most frequent diabetes-related
cause of death in children. Previous studies by our group
suggest that cerebral edema may result from poor blood flow to the
brain during DKA. Our data suggest that even a modest decrease
in brain blood flow may cause brain injury, if this decrease occurs
under the conditions present during DKA (elevated blood glucose and
ketone levels and acidosis). Exactly why the conditions of DKA
increase the damaging effects of a reduction in brain blood flow is
not known. In our proposal, we aim to investigate which
of the metabolic alterations occurring during DKA predispose
children to brain injury and brain swelling. The data
gathered in our study will allow us to develop a more complete
understanding of the mechanisms responsible for cerebral edema and
to determine which treatments might be used to prevent cerebral
edema in children with DKA. In addition, data from this
study might help us to better understand other common conditions,
such as stroke and head trauma, which may affect people with
diabetes. The data will help us to determine how best to help
individuals with diabetes recover from these conditions.
If a person with diabetes were to ask you how
your project will help them in the future, how would you
respond?
Even individuals who are very careful about
their diabetes care can develop diabetic ketoacidosis (DKA) in some
situations, especially during episodes of illness. In
addition, people with new onset of diabetes often have DKA at the
time of diagnosis, especially children. DKA can cause injury
to the brain, but the mechanism behind this injury is not well
understood. The data gathered in our project will help us
learn how best to help people with diabetes recover from DKA without
damage to the brain. In addition, our project will help
us to understand how different factors affect the brain in people
with diabetes. At present, we do not have a good
understanding of how high glucose concentrations, elevated blood
ketone concentrations and other factors affect the brain's blood
flow and metabolism. These studies will help us to gain a
broader understanding of the effects of metabolic changes resulting
from diabetes on the brain and will help us to learn how best to
help people with diabetes recover from other brain injuries such as
stroke or traumatic injuries.
Why is it important for you, personally, to
become involved in diabetes research? What role will this
award play in your research efforts?
When I was doing my residency training in
pediatrics, a beautiful 2 year old boy was admitted to the pediatric
intensive care unit with cerebral edema resulting from diabetic
ketoacidosis. Tragically, he did not survive the
episode. Disheartened by the tragedy of this child's death, I
searched the medical literature to try to better understand why this
had happened to him and whether there was anything that could have
been done to prevent it. I was surprised to find out how
little was understood about how diabetic ketoacidosis effects the
brain and why cerebral edema sometimes occurs. The sense that
there was a gap in our understanding of diabetic ketoacidosis stayed
with me through my residency training in pediatrics and my
fellowship in pediatric endocrinology. When it came time
to choose a research path, it was clear to me what my path should
be. For the past 10 years, I have been studying
the effects of diabetic ketoacidosis on the brain. We
now have a large, multi-disciplinary group working on projects aimed
at understanding the changes in brain metabolism and blood flow that
occur during DKA and how best to prevent brain injury in this
setting. The current award will allow us to further
study the basic mechanisms underlying brain injury in DKA with the
ultimate goal of preventing brain damage or death in children with
DKA.
In what direction do you see the future of
diabetes research going?
For type 1 diabetes, I am hopeful that the
future will allow for early detection of the immune system
abnormalities responsible for causing the disease and intervention
at that stage to prevent type 1diabetes from occurring. Early
studies indicate that this could be possible in the
future. It would be a joy to be able to see type 1
diabetes become a condition of the past.
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University of Toledo Health Science
Campus, Toledo, OH
Prevention of TZD-induced bone loss
and improvement of TZD-affected bone fracture healing
Focus: Transcriptional Regulation,
Hormones
Type of Grant: Core\Basic Science
Project Start Date: 01/01/2009
Project end date: 12/31/2011
Diabetes type: Type 2
Research Description
Anti-diabetic drugs, thiazolidinediones (TZDs),
improve insulin sensitivity and glucose metabolism. Unfortunately,
these drugs may have a negative effect on bone in some of the
diabetic patients. They induce bone loss and increase the
frequency of bone fractures in older diabetic women. In mice, TZDs
cause bone loss and delay bone fracture healing. TZDs interact with
a single protein, named PPARgamma, which controls both sugar levels
and bone mass. In order to prevent TZD-caused bone loss and
improve bone fracture healing in diabetic patients on TZD therapy,
the following studies are proposed:
1) Examine whether anti-osteoporotic
drugs may prevent bone loss caused by TZD therapy
2) Improve bone fracture healing by
eliminating PPARgamma, the protein target of TZDs, exclusively in
the fracture site.
These studies will be performed in female mice
of different ages and estrogen status. Estrogen status will be
manipulated by removing ovaries in some mice to model a
postmenopausal state. These studies will provide information crucial
to developing therapies to prevent TZD-associated bone loss and
improve bone fracture healing in older diabetic women. These studies
are especially important because older diabetic women already have a
high risk of bone loss due to aging and a lack of estrogen
hormone.
Researcher Profile
What area of diabetes research does your
project cover? What role will this particular project play in
preventing, treating and/or curing diabetes?
My project focuses on researching
pharmacological methods to prevent bone loss which is associated
with a use of anti-diabetic drugs, thiazolidinediones (TZDs). TZDs
are very effective in lowering and controlling blood glucose levels
in patients with type 2 diabetes. Unfortunately, these drugs may
have a negative effect on bone in some of the diabetic
patients. TZDs induce bone loss and increase the frequency of
bone fractures in older diabetic women. They also may cause a delay
in healing of bone fractures. In order to prevent TZD-caused bone
loss and improve bone fracture healing in diabetic patients on TZD
therapy, the following studies are proposed:
1) Examine whether anti-osteoporotic
drugs, commonly used in clinics, may be used as an accompany therapy
to TZDs therapy to prevent bone loss in diabetic patients
2) Study the methods to improve
bone fracture healing in diabetic patients on TZD therapy by
stimulating bone formation exclusively in the fractured bone.
These studies will be performed in female mice
of different ages and estrogen status. Estrogen status will be
manipulated by removing ovaries in some mice to model a
postmenopausal state. These studies will provide information crucial
to developing therapies to prevent TZD-associated bone loss and
improve bone fracture healing in older diabetic women on TZD
therapy. These studies are especially important because older
diabetic women already have a high risk of bone loss due to aging
and a lack of estrogen hormone.
If a person with diabetes were to ask you how
your project will help them in the future, how would you
respond?
These studies will improve safety of the
patients, which are on TZD therapy. They will provide a means to
prevent bone loss in those patients, which are at a risk of
TZD-induced bone loss, especially older diabetic women. In general
diabetic patients, regardless of TZD use, are at increased risk of
bone fractures and TZD therapy may augment this risk. Our studies
are also addressing the question how to improve healing of fractured
bone in diabetic patients on TZD therapy.
Why is it important for you, personally, to
become involved in diabetes research? What role will this
award play in your research efforts?
I have a long interest in the research, which
investigates bone status in diabetic patients. I had started this
research in 1995 and had found that some of the anti-diabetic
therapies may increase bone loss in diabetic patients. This led me
to the conclusion that diabetes and osteoporosis may share common
mechanisms, which have to be addressed during development of new
anti-diabetic therapies. In light of the prevalence of diabetes and
osteoporosis in our society, I strongly believe that research which
integrates these two diseases will significantly contribute to the
better health care for patients which suffer diabetes. This is
my second research award from the American Diabetes Association to
investigate skeletal complications in diabetic disease. I am honored
and very grateful to the Association for its vision and dedication
to improve health of diabetic patients.
In what direction do you see the future of diabetes research going?
Diabetes is a very complex disease which
affects every organ in the body, including bone. I see the future of
diabetes research in developing interdisciplinary and system
physiology approaches, which will allow for development of the
therapies controlling not only blood glucose levels but being also
beneficial in controlling functions of other organs. Such approach
will improve the safety of already existing and newly developed
drugs to combat diabetic disease.
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Michigan State University, Ann
Arbor, MI
New therapeutic targets in diabetic
neuropathy
Focus: Neuropathy, Pharmacologic treatment
of diabetes or it complications, Animal Models
Type of Grant: Core\Basic Science
Project start Date: 01/01/2009
Project end date: 12/31/2011
Diabetes type: Both Type 1 and Type 2 diabetes
Research Description
The cells that line blood vessels are first in
line for injury when blood glucose and oxidized LDL increase in
diabetic patients. Injury to these cells causes broader damage
to the tissue the blood vessels are feeding by leaking and by
decreasing the availability of oxygen. This proposal aims to
define the mechanisms of injury to the blood vessel cells and to
explore the potential for fenofibrate to block these
mechanisms. Increased glucose overloads the energy-producing
component of a cell, the mitochondria. As mitochondrial
function decreases, a state known as oxidative stress occurs.
Enzyme systems are activated to protect the mitochondria including
NAD(P)H oxidase that attempts to remove the load on the
mitochondria. Oxidized LDL also activates NAD(P)H
oxidase. These injuries will be defined in cultured blood
vessel cells and in diabetic mice. Fenofibrate is used in type
2 diabetes to correct poor blood lipids. Recently, fenofibrate
was found to produce a broader range of effects. This proposal
will test the hypothesis that fenofibrate will directly prevent
oxidative stress and mitochondrial dysfunction as well as alleviate
diabetes. Understanding these mechanisms will permit
improvement to therapies to prevent not only hyperglycemia, but also
the complications of diabetes including neuropathy.
Researcher Profile
What area of diabetes research does your
project cover? What role will this particular project play in
preventing, treating and/or curing diabetes?
I am interested in understanding the mechanisms
that lead to sensory nerve injury in diabetic patients. This
type of nerve injury is the most common complication of diabetes and
can lead to chronic pain, or to the need for limb amputation.
My project is designed to investigate how increased levels of
glucose and/or blood lipids in diabetes cause injury to sensory
nerves. Both type 1 and type 2 diabetic patients experience
high blood glucose, but the additional importance of blood lipids in
diabetic nerve injury is becoming increasingly recognized.
Type 2 diabetes is commonly associated with increased blood lipids,
but the incidence of type 1 patients with elevated blood lipids is
increasing. The project also will evaluate a potentially
beneficial drug, fenofibrate. Fenofibrate is already used
clinically to improve blood lipid levels, but we contend that it may
be more broadly applicable to directly prevent nerve injury in
diabetic patients. In this regard, if our hypothesis is
correct, fenofibrate may be effective in both type 1 and type 2
diabetes to prevent sensory nerve damage.
If a person with diabetes were to ask you how
your project will help them in the future, how would you
respond?
As we dissect the mechanisms that lead to nerve
injury in diabetes, we can better design therapeutic
interventions. This is critically important for diabetic nerve
disease since this is the most common complication of diabetes, but
there are no approved treatments other than tight glycemia
control. The studies also will help us to understand which
patients are at risk for developing nerve disease and how they could
prevent the progression by altering their diet or by using a new
drug treatment.
Why is it important for you, personally, to
become involved in diabetes research? What role will this
award play in your research efforts?
The incidence of diabetes is growing at a
significant rate and it is critically important to prevent
complications to improve the quality of life for diabetic
patients. I have a broad experience of working in
neurodegenerative diseases and the role of oxidative stress.
My preliminary work in diabetes has established that mechanisms
leading to oxidative stress are the key to the development of
complications. My diabetes research efforts have grown from a
side project assisting other researchers to a strong desire to build
an independent research project in this area. This is the
result of compelling findings using the experimental systems
available- micro vascular endothelial cells, primary sensory neuron
cultures, and mouse models of both type 1 and type 2 diabetes.
I believe we can both understand and treat diabetes complications
and that this is a worthy research goal. This award is the
essential next step for me to begin to establish an independent
research program. It will establish my status as a researcher
and will permit me to produce important data on mechanisms of nerve
injury and protection. I will gain insight into the use and
validation of a mouse model of diabetic nerve disease and I intend
to further establish methods for the assessment of nerve disease in
these mice.
In what direction do you see the future of
diabetes research going?
Diabetes research will remain an important
field of endeavor, since our long-established knowledge of nutrition
and exercise has not prevented the current diabetes epidemic.
We have demonstrated that oxidative stress is central to the
development of complications, although an effective treatment is not
yet determined. In order to prevent or reverse complications,
we need to further characterize the mechanisms that produce
oxidative stress, as well as understand more fully the roles of
oxidative stress in the susceptible cell types. It is
increasingly clear that single antioxidant therapy is ineffective
because of the essential balance of regulatory systems.
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Mordes, John Peter, MD
University of Massachusetts Medical School Worcester,
Massachusetts
T cell receptor as a critical diabetes susceptibility gene
Focus: Genetics\Type 1 Diabetes
Type of Grant: Basic Science
Project Start Date: July 1, 2008
Project End Date: June 30, 2011
Research Description
Funded by the Order of
the Amaranth
The genes underlying juvenile diabetes (T1D) are not well
understood. Rat models now suggest that at least one member of the
T-cell receptor (TCR) 'beta chain family' of genes, Tcrb-V13, is a
powerful T1D gene. The Tcrb-V13 genetic haplotype of a rat predicts
if it is highly resistant or susceptible to T1D. This proposal seeks
to obtain functional proof of the role of Tcrb-V13 in T1D. We
hypothesize that Tcrb-V13 is an important T1D susceptibility gene in
the rat and that silencing it will prevent T1D.Rationale: The TCR
must play a role in T1D because it is a T-cell mediated disease, but
no one family of TCR genes has been thought to be particularly
important. 'Preferential TCR usage' is not a known risk factor for
human T1D, but previous studies have often not had the power to
address this issue directly. The goal of this proposal is 'to take a
fresh look at an old idea. Aim 1 will apply standard methods
(monoclonal antibodies, T-cell clones) to attack the problem. Aim 2
will use cutting edge 'RNA interference' to silence Tcrb-V13 in T
cells, preventing their ability to cause diabetes in a transfusion
model. Aim 3 will generate transgenic rats that lack expression
of Tcrb-V13 to prevent diabetes. Relevance: A positive outcome of
these rat studies will reveal much about a very fundamental,
structural component of this T-cell mediated disease. If our
hypothesis is confirmed in the rat, it will certainly justify 'fresh
look' studies in humans.
Reseacher Profile
What area of diabetes
research does your project cover? What role will this particular
project play in preventing, treating and/or curing diabetes?
This project is focused on understanding the genes that make an
individual, or in this case an animal, susceptible to type 1 (or
juvenile) diabetes. Although recent 'genome wide scans' have
revealed several areas within the human genome that are associated
with the disease, we still lack a comprehensive understanding of the
set of genes that are required for diabetes to occur.
For the past 12 years we have been mapping the genes that make
various inbred strains of rats susceptible to diabetes. We have
found one genetic locus in particular that seems to have a very
powerful effect, clearly distinguishing animals susceptible to
diabetes from animals that are not. Gene sequencing has revealed a
very surprising candidate, a member of a large family of genes
called T cell receptor beta chain genes. T cells are well know to
mediate type 1 diabetes, and the genes that encode T cell receptors
have long been suspected of playing a role in determining
susceptibility, but our model is the first to provide evidence that
they may in fact be very important.
This research is designed specifically to determine if one gene
called Tcrb-V13 is actually a diabetes susceptibility gene.
If a person with
diabetes were to ask you how your project will help them in the
future, how would you respond?
A positive outcome of these animal studies will reveal much about
a very fundamental, structural component of this T-cell mediated
'autoimmune' form of diabetes. That information in turn can be used
to help develop new tests to identify children at risk for diabetes.
The majority of children with juvenile diabetes has no relatives
with diabetes, and understanding this new predisposing genetic
element will help in the design of screening methods. In addition,
the additional understanding we gain should help to design therapies
to prevent the disease. Finally, the animal models we have not only
make it simpler to detect and identify predisposing genes, but they
also provide important platforms in which safely to test new
therapies for preventing or reversing juvenile diabetes.
Why is it important for
you, personally, to become involved in diabetes research? What role
will this award play in your research efforts?
This award represents the final stem in an effort to find this
gene that was begun 12 years ago. In close collaboration with other
colleagues, a meticulous program of genotyping and animal breeding
has brought us to the final steps necessary to identify the gene.
Proving that our gene is, in fact, Tcrb-V13 would represent the
culmination of much effort and investment. Most importantly, it
could redirect and enhance our thinking about how exactly how
juvenile diabetes starts and thereby how to prevent it.
In what direction do you
see the future of diabetes research going?
For type 1 or juvenile diabetes, the advent of genome wide
scanning together with the development of biomarkers of inflammation
promise to revolutionize our understanding of how the disease is
initiated, how it progresses, and how it might be stopped or
reversed. The number of genes associated with the disease has
increased perhaps ten fold in only two years, and the biomarker
technology is just in its infancy. Similar information has
revolutionized the therapy of other autoimmune diseases like Crohn's
disease and psoriasis, and the promise of comparable
immunotherapeutics for juvenile diabetes is very bright, as is the
promise of beta cell replacement therapy for those who are already
ill.
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Freemark, Michael, MD
Duke University Medical Center Durham, North Carolina
Beta cell growth and
function during pregnancy: The interactions of glucocorticoids,
cytokines, and lactogenic hormones
Focus: Islet Biology\Beta Cell Growth and Differentiation
Type of Grant: Basic Science
Project Start Date: July 1, 2008
Project End Date: June 30, 2011
Research Description
Funded by the Order of
the Amaranth
Gestational diabetes develops when the pregnant mother fails to
produce insulin in quantities sufficient to overcome the insulin
resistance that normally develops in late gestation. We propose that
the lactogenic hormones of pregnancy (placental lactogen and
prolactin, PRL) thwart the development of gestational diabetes by
increasing beta cell mass and insulin production and by limiting
beta cell damage caused by chronic exposure to glucocorticoids, and
fatty acids. We hypothesize that these effects are mediated through
suppression of key regulators of metabolism including FoxO1,
PGC1alpha, and PPARalpha, which are over-expressed in islets of
diabetic humans and mice. To test that hypothesis we will first
explore the interactions of PRL, glucocorticoids, and fatty acids in
the regulation of FoxO1, PGC1alpha and PPARalpha levels in
pancreatic islets and insulinoma cells. We will then determine: (a)
if the effects of PRL on beta cell growth and function are abolished
by genetic over-expression of FoxO1; (b) if islets of PRL-resistant
mice have increased expression of FoxO1, PGC1alpha, PPARalpha, and
CPT-1, which regulates fatty acid metabolism, and if genetic
silencing of FoxO1 can restore normal function to PRL-resistant beta
cells; and (c) if PRL-resistant islets are hypersensitive to the
toxic effects of fatty acids. Since PRL prevents the development of
diabetes in mice and maintains beta cell mass during postnatal life
as well as pregnancy, our studies have important implications for
the prevention and treatment of beta cell failure in types 1 and 2
diabetes as well as gestational diabetes.
Reseacher Profile
What area of diabetes
research does your project cover? What role will this particular
project play in preventing, treating and/or curing diabetes?
The research funded by this grant focuses on the development of
diabetes in pregnant women (gestational diabetes). Gestational
diabetes develops when the pregnant mother fails to produce insulin
in quantities sufficient to maintain normal sugar metabolism. We
propose that the 'lactogenic hormones' of pregnancy (the placental
hormone placental lactogen and the pituitary hormone prolactin)
prevent the development of gestational diabetes in most women by
increasing the mass of pancreatic beta cells and their production of
insulin and by limiting beta cell damage caused by maternal cortisol,
fatty acids, and inflammatory proteins. We hypothesize that these
effects are mediated through suppression of key regulators of
metabolism including the transcription factors FoxO1, PGC1a, and
PPARa, which are over-expressed in islets of diabetic humans and
mice. To test that hypothesis we will explore the interactions of
prolactin (PRL), glucocorticoids, and fatty acids in the regulation
of FoxO1, PGC1a and PPARa levels in pancreatic islets and insulinoma
cells. We will then determine: (a) if the effects of PRL on beta
cell growth and function are abolished by genetic over-expression of
FoxO1; (b) if islets of PRL-resistant mice have increased expression
of FoxO1, PGC1a, PPARa, and CPT-1, which regulates fatty acid
metabolism, and if genetic silencing of FoxO1 can restore normal
function to PRL-resistant beta cells; and (c) if PRL-resistant
islets are hypersensitive to the toxic effects of fatty acids. Since
PRL prevents the development of diabetes in mice and maintains beta
cell mass during postnatal life as well as pregnancy, our studies
have important implications for the prevention and treatment of beta
cell failure in types 1 and 2 diabetes as well as gestational
diabetes.
If a person with
diabetes were to ask you how your project will help them in the
future, how would you respond?
Pregnancy is a 'diabetogenic' state; this means that pregnant
women are predisposed to developing diabetes. Gestational diabetes
has deleterious effects on the metabolism and growth of the
developing baby and places the child at risk for obesity and
diabetes later in life. Diabetes in pregnancy increases the risk to
the mother as well; she herself is more prone to serious
complications during gestation and is at higher risk for developing
type 2 diabetes after delivery. Our project, which focuses on the
hormonal control of the mother's metabolism, has important
implications in three areas. First, a fundamental understanding of
the roles of hormones and nutrients in the control of maternal
metabolism may in the future enable us to prevent gestational
diabetes and/or to treat it more effectively if it develops. Second,
our studies may in the long-term help to limit the danger to the
developing infant and reduce his/her long-term risks of obesity and
type 2 diabetes. Finally, our studies may also provide important
clues to understanding why most pregnant women do not develop
gestational diabetes. This may provide new approaches to preventing
or treating type 2 diabetes in non-pregnant men, women, and
children.
Why is it important for
you, personally, to become involved in diabetes research? What role
will this award play in your research efforts?
As a pediatric endocrinologist I have cared for thousands of
children with types 1 and 2 diabetes during the past 25 years. My
close relationships with these children and their families provide
the incentive for understanding the fundamental causes and
complications of the disease so that they might be ameliorated or
prevented in the future. In this sense my laboratory research
represents a natural extension of my clinical pursuits. Our research
group has a longstanding interest in the mechanisms by which
hormones and nutrients control insulin production. We have focused
on the pregnancy lactogens (placental lactogen and prolactin),
because these are the major determinants of beta cell mass and
insulin production during gestation. Our previous studies showed
that the actions of these hormones are essential for maintaining
insulin production during postnatal life. The studies supported by
this grant will enable us to dissect the molecular mechanisms by
which these hormones regulate beta cell development and function and
should shed light on the pathogenesis of glucose intolerance in
diabetic states.
In what direction do you
see the future of diabetes research going?
I envision three major trends. First, there will be increasing
delineation of the interactions of genetic, hormonal, nutritional,
and environmental factors in the pathogenesis of beta cell failure
in both types 1 and 2 diabetes. Such studies will identify subjects
at highest risk for the development of disease and may suggest novel
approaches to diabetes prevention. Second, there will be increasing
understanding of the mechanisms controlling the development of
complications of diabetes. Such studies will no doubt reveal complex
interactions of genetic, hormonal, nutritional, and environmental
factors in the pathogenesis of diabetic neuropathy, nephropathy,
retinopathy, and cardiovascular disease. Third, long-term studies
will identify those therapeutic approaches that can ameliorate or
prevent complications of diabetes and/or prevent or reverse the
disease itself.
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