Research Grants for 2013
Cure for Type 1 Diabetes
A Program for the Cure of Type 1 Diabetes Using a
Generic Drug: Phase II
Researcher:
Denise L. Faustman, MD, PhD., Associate Professor
Harvard Medical School and Director Immunobiology Laboratory
Massachusetts General Hospital
Charlestown, MA
Purpose:
After a successful completion of the Phase 1 clinical trial which investigated
the safety of BCG vaccination in individuals with type 1 diabetes,
in 2011 Dr. Faustman’s lab launched the Phase II study which will
determine what doses will be needed to make BCG a functional type 1
diabetes therapy and how frequently this treatment will be needed to
maintain normal blood sugar levels. In August, 2012 publication of the
full Phase 1 trial showed that the pancreas of long-term diabetics was
able to transiently make insulin after two repeat injections of the generic
vaccine, BCG. Unlike other type 1 diabetes trials which focused only on
new-onset diabetics, this study is concentrating on reversing type 1 diabetes
in people with longstanding disease. The current Phase II trial will provide
more direction for turning BCG into a long-lasting treatment by identifying
the right dose and frequency of vaccination needed to sustain a therapeutic
response over several years.
Complementary / Nutrition Research
Stearidonic Acid As A Potential Nutritional Therapy For
Obesity And Type 2 Diabetes
Researcher:
Kevin W. Huggins, PhD
Associate Professor Dept. of Nutrition
Auburn University, AL
Purpose:
Increased consumption of n-3 polyunsaturated fatty acids (PUFA) have been
shown to have health benefits associated with obesity and type 2 diabetes.
The n-3 PUFA obtained from cold water fish and fish oils are the most effective
source for these effects; however, due to concerns regarding the safety and
sustainability with fish oils, there is need to identify alternative sources
of n-3 PUFA having similar biological properties. Stearidonic acid (SDA) is a
botanical n-3 PUFA that may have similar health benefits to fish oils. The
purpose of this research project is to determine if SDA can be used as
alternative to fish oil in the prevention of obesity and/or diabetes. The
overall hypothesis of this research is that SDA will aid in prevention of
adiposity, inflammation, and insulin resistance associated with obesity and
diabetes in a mouse model. The results from this research project will serve
to provide proof of principle for SDA as a therapeutic alternative for the
treatment of obesity and type 2 diabetes.
Role of Bile Acids in Diabetes Remission after Bariatric
Surgery
Researcher:
Blandine Laferrere MD
Principal Investigator
St. Luke’s-Roosevelt Hospital Center
Purpose:
Bariatric surgery often results in remission of type 2 diabetes (T2DM).
While weight loss is mainly responsible for the improved glucose metabolism,
other mechanisms have been implicated after gastric surgery, as glucose
levels improve rapidly, prior to any significant weight loss. In this proposal,
Dr. Laferrere wishes to characterize new mechanisms explaining type 2 diabetes
remission after gastric bypass surgery. Specifically, the role of bile acids
on the improved glucose and lipid metabolism and the improved gut peptide
release after gastric bypass surgery will be tested. Circulating bile acids
will be measured in samples from a cohort of obese patients with T2DM, before
and after gastric bypass and gastric banding surgery. Understanding the effects
of gastric bypass surgery on the action of bile acids will make it possible to
further characterize the benefit of therapies that manipulate the enterohepatic
cycle as treatments for T2DM.
Identifications of Novel Botanicals For the Prevention
and Treatment of Type 2 Diabetes
Researcher:
Dongmin Liu, PhD. Associate Professor
VA. Polytechnic Institute & State University
Blacksburg, VA.
Purpose:
The goal of this project is to identify low-cost bioactive compounds as
complementary and alternative approaches to prevent and treat type 2 diabetes
(T2D). T2D is a growing public health problem which is a result of chronic
insulin resistance and loss of functional B-cells (the only source of insulin
in our body). Thus, search for novel agents that simultaneously prevent insulin
resistance and protect B-cell mass could be a novel and more effective strategy
to prevent T2D. Dr. Liu discovered for the first time that baicalein, a flavonoid
compound isolated from a Chinese medicinal herb, ameliorates diabetes due to
protection of functional B-cell mass, while kaempferol, which is present in
various natural plants and citrus fruits, might be an insulin sensitizer in the
body. In this project Dr. Liu will explore whether the combination of treatment
with baicalein and kaempferol is more effective in preventing T2D development by
simultaneously preserving B-cell mass and improving insulin sensitivity in obese
T2D mice.
Comparison of Fructose and Table Sugar as Sources of Caloric Excess in a Drosophila Model of
Type 2 Diabetes
Researcher:
Laura Musselman, PhD. Research Instructor in Medicine
Washington Univ. School of Medicine
St. Louis, MO
Purpose:
Many of us have heard of the dangers of high fructose corn syrup, and of caloric
excess. Recently, science has shifted to place the blame for increased metabolic
disease on dietary sugar instead of fat (see the NY Times 60 Minutes, HBO).
Some scientists and dieticians suspect that fructose is worse for health than
other sugars. Dr. Musselman has developed a model of insulin resistance that
results from high sucrose feeding, where all dietary sugar consists of table
sugar. High levels of table sugar induce Type 2 diabetes-like phenotypes in
the fruit fly Drosophila. She has characterized the genomic, physiological,
and biochemical responses to insulin resistance in high sucrose-fed Drosophila.
What effects does fructose have? This study will compare fructose to sucrose
and glucose to try to understand the differences, if any, between different
sugar-containing diets.
Effect of Chromium Picolinate On Diabetic Vascular
Complications
Researcher:
Priya Raman, PhD. Assistant Professor
Northeast Ohio Medical University
Rootstown, OH
Purpose:
Diabetic patients are highly prone to vascular complications, substantially
impacting national health care expenditures. Despite significant advances,
no cost-effective alternative remedies are currently available for management
of diabetic macrovascular disease. Trivalent chromium (Cr3+) picolinate (CrP),
one of the largest-selling mineral supplements in the U.S., has a beneficial
role in glycemic and cardiovascular health. Although previous studies underscore
a protective role of Cr3+ in atherosclerosis, therapeutic value of CrP in
diabetic vascular disease and mechanism(s) underlying its effect remain unknown.
Dr. Raman’s preliminary data demonstrates that CrP decreases expression of
thrombospondin-1 (TSP-1), a protein implicated in initiation of atherosclerosis.
Dr. Raman proposes to test the central hypothesis that CrP alleviates diabetic
atherosclerotic complications by reducing TSP-1 expression in the vessel walls
and further uncover novel mechanisms underlying this effect. The proposed studies
will significantly impact our current understanding of CrP, as a beneficial
alternative and nutritional therapy for diabetes and its complications.
Vanadium and Cinnamon Derived Compounds as Therapies For Wound Healing in
Diabetes
Researcher:
Janice Zabolotny, PhD., Instructor in Medicine
Beth Israel Deaconess Medical Center
Boston, MA
Purpose:
Diabetic Foot Ulceration is a major complication of diabetes and the leading
cause of non-traumatic lower extremity amputation in the U.S. Despite the
clinical need for therapies for chronic diabetic wounds, there has been very
little basic research aimed at identifying molecular mechanisms that can be
augmented to overcome wound healing impairments in diabetes, hampering
development of effective treatments. Our data show that intracellular protein
tyrosine phosphatases (PTPs), negative regulators of growth factor action,
impede cutaneous wound healing. Blocking the action of PTP-1B accelerates
healing rate and closure of cutaneous excisional wounds in diabetic mice.
Vanadium and cinnamon derived compounds are well known potent inhibitors of
PTP-1B, which also improve glucose tolerance in diabetic patients and promote
healing of diverse experimental wounds in healthy animals. This study will
determine whether vanadium and cinnamon derived compounds are effective topical
therapies that can restore cutaneous wound healing in preclinical models of
chronic diabetic wounds.
Nephropathy (Kidney) Research
Neuroregulation of Diabetic Nephropathy
Researcher:
Babu J. Padanilam, PhD.
Associate Professor
University of Nebraska Medical Center
Omaha, NE
Purpose:
Diabetes affects 20.8 million people and is the fifth-deadliest disease in
the US. Type 2 diabetes (T2D) is ten times more prevalent than type 1 diabetes
(T1D) and its incidence is increasing in adults and in children due mostly to
the upsurge in obesity. Diabetic nephropathy (DN), one of its ominous
complications, is the leading cause of end-stage renal disease. Recent reports
indicate that sympathetic hyperactivity is common in chronic kidney disease
(CKD) and is shown to contribute to glomerular nephritis and induce proteinuria
both through and beyond its effect on blood pressure. Several recent reports
indicate that increased sympathetic activation is an early event in the
pathophysiology of CKD, rather than a consequence, and its sustained activity
has adverse clinical consequences. The objective of this proposal is to
determine if renal denervation prevents the pathophysiology of diabetic
nephropathy and define the mechanisms by which renal nerve activation instigates
inflammation and fibrogenesis in T2D kidneys. These proposed studies on the
neural regulation of renal fibrogenesis are paradigm-shifting as it has never
been reported and will have the potential to transform the way we investigate
fibroproliferative diseases. Elucidation of neural regulation in DN may provide
a conceptual framework for identifying novel therapeutic targets of this
disease.
Gene Research
Role of VGF in Beta Cell Function, Insulin Secretion,
and Glucose Homeostasis
Researcher:
Stephen R.J. Salton, M.D., PhD
Professor of Neuroscience and Geriatrics
Mt. Sinai School of Medicine
New York, NY
Purpose:
Germline ablation of the Vgf gene results in a lean and hypermetabolic knockout
mouse that is resistant to diet-, lesion- and genetically-induced obesity and
diabetes. Modulation of VGF levels or VGF signaling may therefore represent an
alternative means to regulate circulating glucose levels and insulin sensitivity.
Recent studies from the Newgard lab have demonstrated that the VGF-derived
peptide TLQP21 enhances insulin secretion, improves glucose homeostasis,
and preserves beta cell mass, through a mechanism that is similar to but
distinct from GLP-1R agonists. Utilizing previous Diabetes Action funding,
Dr. Salton has generated VGF mouse models that (1) express full length human
VGF(1-615), (2)express truncated VGF(1-524) that lacks the TLQP21 peptide, or
(3)have loxp recombination sites flanking the mouse VGF coding sequence. To
further investigate mechanisms by which VGF regulates glucose balance, Dr.
Salton will generate and characterize beta-cell conditional VGF knockout mice,
and lines expressing full length and truncated human VGF.
Beta Cell Research
Myeloid-Derived Suppressor Cells for Tolerance to
Islet Transplants
Researchers:
P.I., Luca Inverardi, MD, PhD
Research Professor of Medicine, Microbiology and Immunology
Co-P.I., Paola Serafini, PhD.
Asst. Research Professor, Dept. of Microbiology and Immunology
Alessia Zoso, PhD.
Diabetes Research Institute Foundation
Hollywood, Florida
Purpose:
Survival of transplanted insulin producing islet cells requires life-long
immunosuppressive drugs, which cause a number of undesirable side effects
including damage to the islets themselves. They also shut down the entire
immune system, leaving the patient susceptible to viruses and infections.
The critical need that this project addresses is to obtain a means of inducing
transplant tolerance- thus changing islet transplantation from a procedure with
serious side effects to a safe one. Myeloid-Derived Suppressor Cells (MDSCs)
naturally accumulate in certain areas of the body. Cancer researchers know that
these MDSCs are present in large numbers around tumors where they interfere with
the immune system’s ability to mount an attack against the cancer- essentially,
protecting the tumor. This study attempts to put MDSCs to work in our favor by
using them to interfere with the immune system’s ability to attack the
insulin-producing islet cells that we transplant to reverse diabetes.
Education
Lifestyle Intervention For Diabetes
Researcher:
Adam Bernstein, MD
Director of Research, Wellness Institute
Cleveland Clinic
Cleveland, Ohio
Purpose:
Although targeting low-income women for health care screening and interventions
has been a priority of the US Centers for Disease Control and Prevention for
the past 15 years, little is known on how to adapt and deliver evidence-based
lifestyle interventions for chronic disease to fit the needs of low-income,
urban populations. Dr. Bernstein proposes a pilot study of a lifestyle
modification program for overweight or obese African-American women with
diabetes. As recommended by the ADA, the program emphasizes diet, exercise,
and cognitive behavioral therapy. However, based on focus groups performed
with African-American women in the low-income community of East Cleveland,
Dr. Bernstin proposes the incorporation of mind-body practices that address
more inner and spiritual aspects of mental health to allow participants to
maintain the recommended lifestyle changes in a sustainable manner. If
successful, the proposed research has the potential to significantly affect
the health and quality of life of a large percentage of the population.
Coaching for Control: A Pilot Study of a Medical
Student Intervention to Promote Diabetes
Self-Care in High Risk Settings
Researcher:
Mercedes Carnethon, PhD, Assoc. Professor
Associate Chair for Mentoring & Faculty Development
Northwestern University
Chicago, IL
Purpose:
Diabetes poses a substantial burden to racial/ethnic minorities and in
populations with limited access to healthcare. However, there is a shortage
of healthcare providers available to help patients adopt the lifestyle
changes required for diabetes control. The goal of this study is to evaluate
the feasibility and effectiveness of a diabetes self-care intervention
delivered by medical students to patients with poorly controlled diabetes.
Training medical students to use proven communication techniques to help
patients identify and overcome barriers to adopting lifestyle changes in
diabetes is a novel but plausible strategy. Dr. Carnethon anticipates that
findings from this pilot study will be used to develop a larger study to
definitively test the program’s effectiveness. A long-term benefit of this
program is that future healthcare providers are practicing the skills needed
to promote positive lifestyle changes and provide care for chronic conditions
in diverse communities.
The Diabetes Center Summit: Operations, Management and
Quality Imperatives
Researcher:
Les Jebson, M.H.A.
Administrator, The Diabetes Center of Excellence
Univ. of Florida Academic Health System
Gainesville, FL
Purpose:
In 2009, approximately 1,406,000 adults in the state of Florida had been
diagnosed with diabetes. In 2009 approximately 87% of all adults in Florida
were overweight or obese and 41.6% were physically inactive. This summit will
focus on how to better manage the diabetes population in Florida, with the
intent being that its success and design can be used for other state level
or regional diabetes educational events in other geographic locations throughout
the country. This conference is unique by being designed for Administrators,
Managers, and Research Coordinators of Diabetes facilities throughout the region
and will be free of charge for attendees without any commercial/industry
funding. In order to better manage the exploding population of patients with
diabetes, it is critical that innovative ways of increasing coordination
among diabetes care providers be developed in this Symposium.
The Development of an Evidence-Based Smartphone Application
for Diabetes Self-Management
Researcher:
Ronald Tamler, MD
Director, The Mount Sinai Diabetes Center
Mt. Sinai School of Medicine
New York, NY
Purpose:
The goal of this project is to build a Smartphone application (app) based on
clinical evidence and established behavioral science that makes it easier for
people with diabetes to self-manage this chronic disease. The study will use
focus groups, the development team and a 3 month pilot study to develop the
efficacy and usability of the Smartphone app. Dr. Tamler hopes to make this
chronic disease management tool widely available on both the website and app
stores so that thousands of people with diabetes will be able to download the a
pp and self -manage their disease by monitoring their nutritional habits,
life style choices and medication adherence, among other features which
will empower patients with diabetes.
Heart Disease
Exploiting A Novel ATP-Regulated Molecular Switch To
Selectively Boost Akt2, But Not Akt1 Signaling In Diabetic Cardiomyopathy
Researcher:
Tung Chan, PhD., Assistant Professor of Medicine
Thomas Jefferson University
Philadelphia, PA.
Purpose:
Patients suffering from diabetes, in particular African-Americans, are at
increased risk of developing heart disease, even without high blood pressure.
Heart disease remains the leading cause of death in the US and despite
therapeutic improvements, outcomes in chronic heart failure remain poor
with a 5-year survival only around 50%. While moderately effective, current
treatment options for diabetic heart failure are limited. In this application,
Dr. Chan will help to develop a novel effective treatment for this condition
by restoring the function of a critical intracellular effector of insulin
action (Akt2) in cardiomyocytes. A second focus of this study is the development
of new assays that can be used in living human heart tissues or fat tissues
to study differences in response from heart failure and diabetes patients.
Chromatin Protein Complexes and Regulation of Cardiac
Hypertrophy
Researcher:
Susan Marsh, PhD., Assistant Professor
Washington State University
Spokane, WA
Purpose:
The heart undergoes changes in shape and strength (hypertrophy) in response
to hypertension, diabetes, and exercise training, although the remodeling
caused by these interventions results in differences in the shape, size, and
function of the heart’s muscle cells. Hypertension causes hypertrophy through
changes in protein interactions that regulate the winding and unwinding of
DNA, which, in turn, affects which genes are copied; this ultimately determines
the changes that occur in the muscle cells of the heart. Our preliminary
experiments indicate that these events also occur in exercise-trained and
diabetic hearts which is somewhat unexpected as exercise-trained hearts are
stronger and more efficient than hypertensive and/or diabetic hearts. The
studies in the proposal will investigate whether these changes are essential
for remodeling of the heart’s muscle cells.
Multidrug Resistance Protein-1 as an Essential Regulator
of Vascular Inflammation and Diabetic Restenosis
Researcher:
Manikandan Panchatcharam, PhD.,
Assistant Professor
Purpose:
Approximately 180 million people worldwide have diabetes and this figure is
expected to grow to 366 million in 2025, according to the Centers for Disease
Control and Prevention. Diabetes is a chronic disease in which a person has
high blood sugar, which leads to the classical symptoms of polyuria (frequent
urination), polydipsia (increased thirst) and polyphagia (Increased hunger).
Left unmanaged, diabetes can bring on complications such as heart disease,
problematic vision, kidney disease, nerve damage and loss of limbs. Drugs used
to treat uptake of sugar in cells are not effective due to the action of
multidrug resistance proteins, which are elevated during diabetic condition.
The major problem addressed here is to study the role of multidrug resistance
protein-1 in normal and diabetic condition, which would lead to a new window
for the therapeutic treatment by regulating multidrug resistance protein-1
levels in the diabetic patients.
Neuropathy
Reversal of Diabetic Neuropathy by a Ketogenic Diet
Researcher:
Charles Mobbs, PhD.
Professor, Neuroscience, Endocrinology, and Geriatrics
Mt. Sinai School of Medicine
New York, NY
Purpose:
Dr. Mobbs recently reported that a ketogenic diet reverses diabetic nephropathy
in mouse models of both Type 1 and Type 2 diabetes and that ketones are highly
protective of neurons in an in vitro model of diabetic neuropathy. Furthermore,
the ketogenic diet is clinically safe and effective in treating epilepsy in
humans and diabetic neuropathy appears to be at least partially reversible under
optimum conditions. Thus Dr. Mobbs hypothesizes that the ketogenic diet will
also at least partially reverse diabetic neuropathy by reducing glucose
metabolism more effectively than simply reducing blood glucose, as analyses
of bistable metabolic states suggest that even temporary but substantial
reduction in glucose metabolism may “reset” the metabolic state and produce
protective effects that persist after resumption of a normal diet. Thus, the
goal of this study is to assess if the ketogenic diet will reverse diabetic
neuropathy in a normal diet.
The Mechanism Approach of the Therapy For Diabetic
Neuropathic Pain
Researcher:
Yan Ping Zhang, PhD., Assistant Scientist
University of Miami
Miami, Florida
Purpose:
Diabetic Neuropathy is a nerve disorder caused by high blood sugar.
About 60-70% of people with diabetes have mild to severe forms of diabetic
neuropathy. Painful diabetic neuropathy (PDN) can have devastating effects
on a patient’s health and overall quality of life. High blood sugar causes
metabolic dysfunction triggering nerve damage in diabetes. Cells and tissues
damaged by high blood sugar in turn stimulate the natural immune defense
system to produce free radicals (highly reactive oxygen molecules that damage
tissues) and toll-like receptor 4 (TLR4) is critically important in regulating
these responses. In diabetes, Dr. Zhang hypothesizes that TLR4 activation
in the spinal cord plays a key role in perpetuating neuronal injury and the
symptoms of PDN. The proposed research will apply TLR4 antagonist to inhibit
potentially harmful natural immune responses, and protect from PDN.
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