Research - 2014
Cure for Type 1 Diabetes
A Program for the Cure of Type 1 Diabetes Using a Generic Drug: Phase II
Denise L. Faustman, MD, PhD., Associate Professor
Harvard Medical School and Director Immunobiology Laboratory
Massachusetts General Hospital
After a successful completion of the Phase I 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 I 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
Exploring the role of branched-chain fatty acids as a diabetes-prevention neutraceutical
Thomas Jetton, Ph.D., Assistant Professor of Medicine
University of Vermont and State Agricultural College
Recent clinical evidence suggests reduced risk of type 2 diabetes (T2D) and its prime risk factor, the metabolic syndrome, in diets rich in whole milk products. The principal components responsible are thought to be the bioactive lipids (fats) that protect against metabolic derangements. The nature of this protection is unknown. Recently, we have identified the specific milk-derived lipid likely responsible for these effects (15 methyl-hexadecanoic acid). Whereas the mechanisms by which specific lipids influence the tissues regulating glucose uptake (skeletal muscle, adipose, liver) have been well studied, less is known on how these lipids impact the health of the insulin-secreting pancreatic B-cell. Beta cell failure or loss is the underlying cause of all forms of diabetes. This pilot proposal seeks to determine the molecular mechanisms by which specific milk-derived lipids may preserve the function and survival of rat and human B-cells in culture.
Characterization of Adiponectin During Ketogenic Diet Administration
Robert L. Judd, Ph.D.
Chair, Boshell Diabetes and Metabolic Diseases Research Program
Auburn University, AL
Ketogenic diets (KD) are classically defined as diets containing high-fat, adequate protein and low carbohydrates. In rodent models and humans, KDs are effective in obesity and type 2 diabetes due to their ability to produce weight loss, reduce insulin resistance, lower serum triglyceride concentrations and raise HDL-cholesterol concentrations. In addition, ketogenic diets in rodent models and humans have been associated with increased plasma adiponectin concentrations. Adiponectin is an adipokine with insulin-sensitizing, anti-inflammatory and anti-atherogenic properties. However, the role of adiponectin in the metabolic improvements observed with a ketogenic diet is unclear. Therefore, the objective of this application is to serially profile changes to adiponectin during a ketogenic diet in lean and obese mice. This study will delineate important information on the metabolic changes induced by a ketogenic diet, which will provide additional support for further clinical usage.
Control of Type 1 Diabetes by Herbal CAM
Kamal Moudgil, MD, Ph.D., Professor
University of Maryland
Alternative treatments based on natural plant products and herbal mixtures are increasingly being used in the US by patients with diverse autoimmune diseases, including Type 1 diabetes (T1D). However, the mechanisms of action of many of these products are poorly defined, or not at all. Celastrus is a traditional Chinese medicine and its constituents possess anti-inflammatory and anti-oxidant properties. In this study based on the non-obese diabetic (NOD) mouse model of human T1D, we propose to examine whether oral administration of the ethanol extract of Celastrus modulates the immune response of these mice to heat-shock protein 65, one of the disease-related target protein antigens in pancreatic islets. If successful, Celastrus extract could be further explored for the treatment of T1D patients.
Vanin 1 and Diet-Induced Obesity and Insulin Resistance: Therapeutic Roles for Cystamine and Pantothenic Acid
Ann Marie Schmidt, MD
The Iven Young Professor of Endocrinology, Professor of Medicine, Pharmacology & Pathology
NYU School of Medicine
New York, NY
The rapid rise in obesity and diabetes throughout the world dramatically threatens health and well-being. Established therapies are not uniformly successful and/or uniformly safe, indicating that there is an urgent need for new therapeutic strategies. We have discovered novel roles for the vanin 1 pathway in high fat diet induced obesity. Our data, including that in human subjects, suggest that in high fat feeding, insufficient upregulation of vanin1 is a consequence, thereby causing major disruption and derailment of beneficial metabolic pathways. Pharmacologic strategies to augment the vanin1 pathway, including cystamine and pantothenic acid treatment, are readily available. Thus Dr. Schmidt will use pharmacological and genetic modification approaches in mice to test the hypothesis that augmentation of the vanin1 pathway will modulate the course of high fat diet induced obesity and its key consequences of type 2 diabetes. If successful, this work can be immediately translated into human clinical trials.
Testing of new intervention to treat Type 1 diabetes-induced kidney failure
Kai Y. Xu, Assoc. Professor
University of Maryland
Type 1 diabetes causes kidney failure in which the kidneys are no longer able to remove waste from the body.( Na+and K+)-ATPase (NKA)) is found in large amounts of kidney and plays a crucial role in kidney function. Studies have shown that significant reduction of the NKA activity is strongly associated with type 1 diabetes-induced kidney failure, indicating that NKA activity is an essential basis for kidney function. Dr. Xu has developed a NKA activator which markedly increases NKA activity. Dr. Xu hypothesizes that protecting kidney NKA activity through NKA activator may offer a new disease-modifying intervention to prevent and treat type 1 diabetes-induced kidney failure. The purpose of this study is to test whether the NKA activator protects kidney function against the progression of kidney failure. If the hypothesis is supported by the experimental results, this study will transform basic research findings into medical technology for better treatment of type 1 diabetes-induced kidney failure.
P62/TRAF6 in Type 2 Diabetes
Ramesh Jeganathan, Ph.D.
Auburn University, AL
Deletion of the sequestosome 1/p62 gene in mice resulted in obesity and progressed to insulin, leptin resistance, type 2 diabetes. Recently, from my lab, we have shown that p62 interacts with IRS-1 and participates in insulin signaling pathway. TRAF6, ubiquitin ligase is known to interact with p62. Our goal is to determine if p62 and TRAF6 can connect IRS-1 and Akt, which in turn will lead to ubiquitination, activation, and membrane recruitment of Akt, thereby inducing GLUT4 translocation. Findings from these studies will be an important breakthrough in understanding the role of p62/TRAF6 complex in type 2 diabetes, and provide new prospects for prevention and treatment of type 2 diabetes.
Functional Characterization of Glv(972)Arg mutation of Insulin Receptor Substrate 1 (IRS1) Influencing Kidney dysfunction
Farook Thameem, Ph.D., Asst. Professor
Univ. of Texas Health Science Center
San Antonio, Texas
Glomerular filtration rate (GFR), an estimate of kidney function facilitates the diagnosis, evaluation and management of chronic kidney disease in patients with type 2 diabetes (T2DM) and in general population. GFR varies in patients with T2DM and in general population and is influenced by both environmental and genetic factors as well as their interactive influences. While there has been some progress in identifying genes which, when mutated, influence individual risk of disease, the genes involved in susceptibility to kidney dysfunction have yet to be identified. Our objective and long term goals are to identify gene(s)/mutation(s) responsible for susceptibility to the development and or progression of kidney dysfunction. The aim of this proposal is to perform the functional structure/function studies to determine the cellular and molecular mechanisms by which one of the genetic mutation that we identified, the Gly(972)Arg variant of IRS1, influences decline in GFR, a strong risk factor for the progression to ESRD and associated cardiovascular morbidity and mortality. Understanding and identifying the functional mechanism underlying the pathophysiology of kidney dysfunction may help developing new and more sensitive biomarkers for early diagnosis, and identifying pathogenic signaling pathway that can be specifically targeted for preventive and therapeutic efforts.
Beta Cell/Pancreas Research
Importance of regulatory T cells in Sertoli cell immune protection of transplanted pancreatic islets
Jannette M. Dufour, Ph.D., Assoc. Professor
Texas Tech University Health Sciences Center
Transplantation of insulin-producing pancreatic islets is a promising treatment for type 1 diabetes. However, to prevent immune rejection this treatment requires immunosuppression, which increases the risk of infections and cancer. Immunen-privileged Sertoli cells (SC) could be used to improve islet transplantation since they protect islets when transplanted across immune barriers without immunosuppression. However, the protection is variable and the mechanism of protection is unknown. Thus, there is an urgent need to investigate the mechanism(s) of SC immune protection. Recently, we observed a correlation between regulatory T cells (Treg), cells involved in graft protection, and SC graft survival. This study will test the importance of the Tregs in SC protection of transplanted islets. Dr. Dufour will also examine the mechanism(s) by which SC induce Tregs. Understanding the mechanism(s) of islet protection by SC is an important step towards translating this research into a clinically useful treatment (without immunosuppression) for diabetes.
Non-Invasive Assessment of Pancreatic Volume as a Tool to Augment Risk Stratification in Patients at Risk for Type 1 Diabetes
Michael J. Haller, MD, Associate Professor
University of Florida
Type 1 diabetes is characterized by a progressive destruction of insulin producing beta cells, resulting in lifelong dependence on exogenous insulin. While beta cells make up less than 1% of the pancreas, studies have demonstrated that T1D is associated with a marked reduction of pancreatic mass at diagnosis and as the disease progresses. As such, if pancreatic volume assessment, by ultrasonography (US) or MRI (Magnetic Resonance Imaging), could be utilized as a markerof beta cell function in high risk patients, non-invasive pancreatic imaging could become an important part of staging diabetes risk. Thus the primary goal of this study is to measure pancreatic volume and compare differences in volume between new onset T1D patients, antibody positive subjects at risk for diabetes, and antibody negative individuals.
Hybrid Bioprinting of Insulin Producing Cell Aggregates with Vascular Towards a Miniature Artificial Pancreas
Ibrahim Ozbolat, Ph.D., Asst. Professor
The University of Iowa
Iowa City, IA
Diabetes is a devastating disease but can effectively be treated with cadaveric organ transplantation; however, cadaveric organs are scarce and not widely available to patients on the waiting list. This proposal focuses on establishing a novel protocol for 3D glucose sensitive pancreatic miniature organ fabrication by assembling human insulin producing cell aggregates with new printable vasculature. Successful completion of the proposed study, which aims to combine state-of-the-art 3D bioprinting, stem cells and tissue engineering technologies, would justify the initiation of developing of an alternative therapy for diabetes.
DIAbetes teLehealth (DIAL) study
Erinn Rhodes, MD, MPH
Director Inpatient Diabetes Program
Boston Children’s Hospital, Boston, MA
Adolescents with type 1 diabetes are at risk for poor blood glucose control. This can put them at further risk for preventable hospitalizations and chronic complications. Telehealth (videoconference) interventions can facilitate contact with the care team allowing barriers to adherence to be addressed, education to be reinforced, care plans to be updated, and diabetes specific family support to be provided. This study is a randomized, controlled trial of the impact of a 6 month telehealth intervention on blood glucose control for high-risk adolescents in sub-optimal control recruited from the Diabetes Program at Boston Children’s Hospital. The intervention will be implemented by a diabetes nurse educator and social worker. They will use a diabetes action plan and remotely downloaded blood glucose data and follow an educational curriculum adapted for low health literacy, if identified through screening, and will evaluate the impact on hospitalizations, emergency room use, and adherence to treatment.
Loss of mitochondrial DNA as an early indicator of insulin resistance in Type 2 diabetes
Robert Gilkerson, Ph.D., Assistant Professor
Departments of Biology and Clinical Laboratory Sciences
University of Texas-Pan American
Type 2 diabetes is increasing in prevalence, both nationally and world-wide. The Rio Grande Valley of South Texas has an incidence of diabetes almost twice the national average. Increased understanding of the biology of insulin resistance provides exciting new approaches to detecting and fighting Type 2 diabetes. Specifically, cytokines, small proteins that activate inflammation, cause sustained insulin resistance; strikingly, cytokines damage mitochondria , the subcellular network that provides energy to the cell. Mitochondria have their own DNA (mtDNA), separate from the chromosomal DNA in the nucleus. MtDNA is damaged by cytokines, suggesting that MtDNA damage may occur prior to the development of insulin resistance. This study seeks to utilize this knowledge to explore mtDNA and associated factors as potential biomarkers of insulin resistance, providing a new, exciting approach to the early detection of diabetes in the Rio Grande Valley, a region that is hard hit by diabetes and metabolic disease.
Functions and regulatory mechanisms of class IIa histone deacetylases in adipocyte differentiation
Biao Wang, Ph.D., Assistant Professor
University of California
San Francisco, CA
Type 2 diabetes mellitus accounts for majority of all cases of diabetes, afflicting an estimated 6% of the adult population in Western society. Obesity, one major determinant of type 2 diabetes, is characterized as massive adipose mass due to high calorie intake and/or lack of physical activity. In addition to fat storage, adipose tissue secretes a wide range of circulating hormones to regulate systemic energy homeostasis, which is also frequently dysregulated in obesity. Formation of new functional adipocytes requires actions of extracellular stimuli and intrinsic transcriptional programs, and dysfunction of this process contributes to the development of obesity. This study aims to decipher a novel signal cascade to regulate adipocyte development, but also provide potential drug targets for obesity and type 2 diabetes.
A New Role for Metformin in the Treatment of Diabetes
Yun Yan, MD, Assistant Professor
The Children’s Mercy Hospital
Kansas City, MO
Metformin is the first line and the only FDA approved oral medication for management of pediatric patients with type 2 diabetes but has not been used in the patients with type 1 diabetes. There is new evidence to suggest that metformin can suppress vascular oxidative stress in addition to its effect of lowering blood glucose. Endothelial cell dysfunction induced by oxidative stress in poorly controlled diabetes plays an important role in the development of chronic complications including retinopathy, nephropathy and cardiovascular disease. Recent data has shown that patient risks for developing complications in diabetes differ even when patients have the same mean blood glucose, as measured by HbA1c. Fluctuating glucose levels cause more oxidative stress than sustained high glucose. This proposed study compares the effects of metformin in suppressing oxidative stress and protecting of endothelial cell function under experimental conditions of both blood glucose fluctuation and sustained high glucose.
Reversal of Diabetic Neuropathy by a Ketogenic Diet
Charles Mobbs, PhD.
Professor, Neuroscience, Endocrinology, and Geriatrics
Mt. Sinai School of Medicine
New York, NY
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 mouse model of Type 2 diabetes and if these protective effects persist even after a return to a normal diet.
Exercise as an Intervention for Reversing Myostatin-Induced Skeletal Muscle Insulin Resistance in Type 2 Diabetes
Leslie Consitt, Ph.D., Asst. Professor
Heritage College of Osteopathic Medicine
The majority of insulin-mediated glucose uptake takes place in skeletal muscle, making it the ideal tissue to identify cellular mechanisms that contribute to Type 2 diabetes. Our preliminary research suggests that myostatin, a member of the transforming grown factor-B (TGF-B) super- family, impairs insulin signaling in primary human skeletal muscle cells. Despite this knowledge, little is known regarding the cellular mechanisms through which myostatin functions. This study will examine the myostatin-mediated mothers against decapentaplegic homolog (SMAD) path- way to determine if it is up-regulated in the skeletal muscle of obese and Type 2 diabetics. This study will also use an acute bout of exercise to determine if antagonists of the SMAD pathway can be up-regulated in obese and Type 2 diabetic muscle to rescue initial impairments in insulin signaling. This study will use a combination of in vivo and in vitro to answer these questions.
Interleukin-20 as a target for therapies aimed at improving diabetic wound healing
Phillip J. Finley, Ph.D.
(in collaboration with Laurie Shornick, Ph.D.)
Senior Research Scientist
Wound and Burn Research
Impaired wound healing in diabetic patients is a significant health problem that leads to over 80,000 amputations per year. Unfortunately, the mechanism for impaired diabetic healing is not understood. In recent preliminary data we observed a pro-inflammatory protein (interleukin-20) was expressed at much higher levels in diabetic wounds compared to non-diabetic wounds. Previous literature has shown elevated IL-20 expression also linked to other inflammatory skin pathologies. Therefore, IL-20 may play a critical role during skin inflammation and in part sustain chronic wounds in diabetic patients. In collaboration with Laurie Shornick, PhD, the primary purpose of this research is to determine the extended time-course for IL-20 expression during diabetic and non-diabetic wound healing. This study may lead to a better understanding of the mechanisms of wound healing, thus potentially reducing amputations and improving the quality of life for many diabetic patients.
Importance of local microcirculation to the healing of foot ulcer in Diabetes after revascularization
Jie Zheng, Ph.D., Assoc. Professor of Radiology
Mallinckrodt Institute of Radiology
St. Louis, MO
Foot ulcers are an important complication of diabetes mellitus and often precede lower-extremity amputation. Insufficient perfusion of the tissues around ulcers may be the major cause to prevent wound healing. However, it is historically very difficult to assess the distal leg and foot perfusion accurately. The objective of this study is to apply a newly developed non-contrast MRI technique to evaluate local skeletal muscle microcirculation in patients with diabetes, before and after revascularization. In this study, a specific aim will determine how pre-surgical and post surgical measures of skeletal muscle microcirculation are related to wound healing following vascular surgery in patients with and without diabetes. It is hypothesized that patients with higher pre-surgical microcirculation will have accelerated wound healing. Accelerated healing will also be associated with a larger post-revascularization increase in the ulcer region’s microcirculation. The completion of this study will, for the first time, provide a foundation for determining the role of muscle perfusion as an important indicator to select diabetes patients for early intervention so that future amputation could be avoided.