Current Research - 2018
Diabetes Action is committed to funding promising and innovative diabetes research with a special interest in alternative, complementary, integrative, and nutritional therapies to prevent, treat, and cure diabetes and its complications.
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
In August 2012, publication of the Phase I trial showed that the pancreas of long-term diabetics was able to transiently make insulin after two doses of the Bacillus Camlette-Guerin (BCG) vaccine. All Phase I clinical trial subjects who received the BCG vaccine were followed for 8 years. In 2018 a follow-up report of the 232 participants, published in the journal Vaccines, showed positive results in normalizing blood sugars after 8 years from the initial treatment with the BCG vaccine. In order to meet the goal of reversing advanced type 1 diabetes, the Phase II clinical trial was approved by the FDA in June, 2015 and that trial is now fully enrolled with 150 participants who have received at least 2 doses of the BCG vaccine or placebo. Also ongoing are over five double blinded randomized clinical trials with BCG/placebo administrations to over 200 long term diabetic subjects. In order to meet the ultimate goal of bringing BCG to market with an approved indication for treating type 1 diabetes, it is necessary to obtain funding to track these patients for an additional 5 years.
Establishment of tolerance to proinsulin to prevent or reverse type 1 diabetes
Teresa DiLorenzo, PhD, Professor
Albert Einstein College of Medicine
New York, NY
Beta cells in the pancreatic islets are responsible for making insulin, which is essential for controlling how sugar is used in the body. Type 1 diabetes is an autoimmune disease that occurs when the T cells of the immune system kill the beta cells and insulin can no longer be made. Suppressing all of the T cells of the body could prevent, or even reverse, type 1 diabetes. However, suppression of all the T cells would lead to serious side effects such as an increased susceptibility to infections and cancer. This alternative approach seeks to suppress only those T cells that are responsible for destroying the beta cells. The researchers also hope to facilitate the development of T cells that can suppress the remaining disease-causing T cells.
Using an Antigen Specific Monoclonal Antibody to Modulate Islet Autoimmunity and Reprogram the Development of Type 1 Diabetes
Li Zhang, MD, Ph.D., Assistant Professor
Baylor College of Medicine
Type 1 diabetes (T1D) is an islet specific autoimmune disease; insulin is a key self-antigen of T1D in humans. Our hypothesis is that a monoclonal antibody targeting insulin, the most important self-antigen, is able to modulate the development of T1D. Previously we successfully generated a mouse-anti-human insulin specific monoclonal antibody, MAb1E7, and confirmed that mAb1E7 suppresses disease associated auto-reactive lymphocytes of T1D patients. In order to decrease the immunogenic of the mAb1E7, here we propose to humanize the mAb1E7 by replacing its non-functional fragments with human amino acid sequences. We will modify the mAb1E7 to a human IgG so that the antibodies may be used for humans. We will test the ability of the humanized mAb1E7 to inhibit disease associated auto-reactive lymphocytes of T1D patients. If this project is successful, 50-60% of T1D patients who have specific high risk gene may benefit from this therapeutic modality.
Development of a Macrocell (Islet) Encapsulation Device to Cure Diabetes
Douglas Sobel, MD
Professor of Pediatrics, Chief Pediatric Endocrinology
Although islet transplantation is a promising approach to cure type 1 diabetes, the need for toxic drug therapy impedes its use. The subcutaneous administration of a macroencapsulated cell device could safely cure diabetes without immunotherapy, but the sensitivity of human islets to the low oxygen environment in the subcutaneous space has been a major obstacle. However, Dr. Sobel's lab has constructed a Membrane Device which, when loaded with MIN, (mouse insulin secreting cells) and transplanted subcutaneously, cures diabetes in mice. Further, this Implanted Device loaded with even human islets and growth-factor cures diabetes in nude mice. They propose to improve the Device by determining (1) which membrane materials best support MIN cell growth in vitro, and in vivo (2) which of these membrane devices best cures diabetic mice (3) which device also prevents the rejection of transplanted human islets. This work will be a major step towards safely curing people of diabetes through transplanted islets.
Complementary / Nutrition Research
Influence of activation of CB2 receptors on Cerebrovascular Function
William G. Mayhan, Ph.D., Professor and Dean
University of South Dakota-Sanford School of Medicine
In addition to producing abnormalities to the peripheral circulation, diabetes also has profound effects on the brain. Cognitive function is decreased and the incidence of stroke is increased by diabetes. Although the precise mechanisms responsible are not clear, the researchers suggest that impaired dilation of cerebral arterioles may contribute. Normally, cerebral blood flow will match metabolic demand (neurovascular coupling). However, during diabetes there is impaired vasodilation, and thus impaired neurovascular coupling. The researchers believe this scenario contributes to ischemic stroke during diabetes. Activation of cannabinoid receptors (CB2) has been shown to be protective in non-diseased models, but their potential protective role in the cerebral circulation during diabetes remains unknown. These studies will be the first to examine how activation of CB2 receptors may influence cellular pathways responsible for brain damage during diabetes. The researchers speculate that their studies will reveal a novel therapeutic approach for the treatment of cerebrovascular disorders during diabetes.
Exploring the role of cocoa derived epicatechins on beta cell growth, function and survival
Jeffery S. Tessem, Ph.D., Assistant Professor of Nutrition Science
Brigham Young University
The incidence of diabetes is increasing rapidly, with decreased functional Beta-cell mass critical for disease progression. Interventions that increase Beta-cell mass could be used as a treatment for both type 1 and type 2 diabetes. Dr. Tessem’s lab has shown that cocoa epicatechins are protective against obesity-induced diabetes by decreasing body weight, improving glucose clearance and increasing B-cell function. Although these phenotypes are observed, these compounds have limited intestinal absorbance and are not observed in circulation. Dr. Tessem’s lab hypothesized that cocoa epicatechins may be metabolized by intestinal bacteria to absorbable compounds that can enhance beta cell function. They have shown that the metabolites 5-phenylvaleric acid, homovanillic acid and hippuric acid enhance beta cell proliferation, survival and insulin secretion. The aim of this project is to determine the molecular mechanisms by which intestine derived cocoa epicatechin metabolites improve functional B-cell mass, and to use this to develop treatments for patients with diabetes..
Prevention of amylin amyloidosis in type 2 diabetes by botanical balcalein
Bin Xu, Ph.D., Assistant Professor
Virginia Polytechnic Institute and State University
The goal of this project is to investigate the novel functions of a natural product, baicalein, in the prevention and treatment of diabetes and its complications. Due to a rapidly aging population and the modern sedentary lifestyle, type 2 diabetes and related neurodegeneration are reaching epidemic proportions and they are among the fastest growing diseases in America and worldwide. Currently, there is no known cure for these diseases. One potential molecule link between these two diseases is a molecule call amylin. Excessive secretion of this molecule in type 2 diabetes patients can lead to the formation of toxic aggregates, which can deposit in the pancreas and in other organs such as the brain and cause damages in these tissues. The researchers discovered that baicalein potently inhibits amylin aggregation and reduces amylin-induced toxicity. The researchers will determine how baicalein can inhibit amyloid formation and test how effective baicalein is in a diabetic animal model.
Diabetic Wound Healing
THE FUNCTIONAL ROLE OF MICROENVIRONMENTAL CROSS- TALK IN MESENCHYMAL STROMAL CELL MEDIATED DIABETIC WOUND HEALINg
James Ankrum, Ph.D., Assistant Professor
University of Iowa
Iowa City, IA
Diabetic wounds are a complication of diabetes resulting from years of tissue, vascular, and nerve damage caused by advanced glycation end-products (AGEs) and afflicts both type 1 and type 2 diabetic patients. Historically, patients with type 1 diabetes have had a lower incidence of diabetic complications compared to patients with type 2 diabetes. However, the incidence of limb amputation, the end-stage of chronic diabetic wounds, is similar among both groups of patients. Furthermore, in the past decade the average weight of patients with type 1 diabetes has increased, resulting in more type 1 diabetic patients with obesity as a co-morbidity. Obesity, in these patients was associated with increased HbA1c, indicating elevated levels of damaging AGEs and likely puts these patients at elevated risk of developing diabetic complications. The goal of this project, to develop an improved therapy to treat diabetic wounds using the products of mesenchymal stromal cells (MSCs) is equally applicable to treating both type 1 and type 2 diabetic patients. In addition, Dr. Ankrum proposes future milestones for the second year that will focus our attention on in vitro and in vivo models that more closely mimic type 1 diabetes.
Understanding the role of KSRP in control of insulin signaling
Ching- Yi Chen, Ph.D., Associate Professor
University of Alabama at Birmingham
Insulin plays an important role in maintaining normal blood glucose levels by activating a series of actions referred to as the insulin signaling pathway in insulin target tissues. Defects in this pathway result in insulin resistance which predisposes an individual to the development of type 2 diabetes. Detailed understanding of how the insulin signaling pathway is regulated and how this pathway is disrupted during the progression of type 2 diabetes should provide a better way to reduce insulin resistance. The researchers plan to determine how a protein called KSRP controls the insulin signaling pathway and identify factors that are regulated by KSRP and involved in this pathway. These studies are expected to identify new factors in control of insulin signaling pathway which may serve as useful targets for drug development. Thus, much more effective therapeutic methods may be developed to increase insulin sensitivity in individuals with type 2 diabetes.
Obesity/Bariatric Surgery Research
Targeting the underlying inflammation in obesity-associated metabolic syndrome
Guianglong He, Ph.D., Assistant Professor
University of Wyoming
As an emerging epidemic in the US and worldwide, obesity is associated with a constellation of metabolic disorders including insulin resistance, glucose intolerance, type 2 diabetes, hypertension and cardiovascular abnormalities. As a hallmark feature, obesity is accompanied with chronic inflammation leading to potential cell damage and organ dysfunction. Furthermore, obesity is associated with increased lipid accumulation in many tissues. Therefore, understanding the underlying mechanisms responsible for obesity-associated chronic inflammation and the consequences on myocardial dysfunction is significant. The overall goal of this study is to determine the upstream signals that activate the pro-inflammatory responses and their consequences on myocardial dysfunction in high fat diet-induced obesity. With the critical knowledge obtained from these studies, potential pharmacological interventions may be possible aiming at inhibiting the deregulated lipolysis process and the pro-inflammatory responses associated with high fat diet-induced obesity.
Luminal Coating of the Intestine for Reduced Glucose Absorption
Jeffrey M. Karp, Ph.D., Associate Professor
The Brigham and Women’s Hospital
Roux-en-Y gastric bypass (RYGB) surgery is regarded as the gold standard treatment of obesity and obesity-related type 2 diabetes. However, its invasive and non-reversible nature has limited its application to small patient subgroups. Surgical isolation of the proximal bowel following this surgery is thought to be a critical driver of the observed clinical benefits. The study aims to develop an orally administered gut-coating formulation that provides a transient barrier to nutrient contact with the proximal intestinal mucosa, thus recreating an important aspect of the surgical procedure non-invasively. Through screening candidates for barrier formation the researchers identified sucrose octasulfate aluminum complex and further engineered it to rapidly form an effective transient physical coating in-situ within the duodenum. Here the researchers aim to further engineer the gut coating agents and validate that oral administration of this gut-coating formulation provides an effective barrier to glucose absorption and lowers postprandial blood glucose concentration.
Effect of exercise and caloric restriction on immune health insulin resistance in bariatric patients
Steven K. Malin, Ph.D., Asst. Professor
Director Applied Metabolism & Physiology Lab
University of Virginia
Bariatric surgery is increasingly being used as a therapeutic option to combat rising rates in obesity and, in some cases, also treat diabetes and cardiovascular risk factors. However, recent work suggests that not all individuals respond the same way. In fact, some people appear to have higher risk of complications during the procedure than others. The reason for this finding is unclear but pre-operative health related to adipose tissue immune health and insulin resistance appear important. This research will test the effectiveness of pre-operative exercise and/or diet on improvements in immune health and insulin resistance to determine if health improvements before surgery drive greater changes in patient outcomes after the procedure. This study has clinical and public health relevance since determining the best lifestyle approach pre-operatively may minimize surgical difficulty and enhance the effectiveness of surgery on obesity related disease in the future.
ISLET CELL RESEARCH
BIOPRINTING OF ENGINEERED PANCREATIC ISLETS INTO A PERFUSION BED
Ibrahim T. Ozbolat, Assoc. Professor
Penn State University
University Park, PA 16802
Dr. Ozbolat previously demonstrated the micro-vascularization of engineered pancreatic islets in fibrin constructs under static conditions, where capillaries sprouted into the constructs facilitating intravascularization in engineered islets as well as capillary network around the islets. In this project, Dr. Ozbolat will bioprint pre-vascularized pancreatic islets made of mouse insulinoma cells and rat heart microvascular endothelial cells into a perfusion bed in order to create a perfusable platform for microcirculation of the engineered islets. Dr. Ozbolat will test the hypothesis that perfused tissue constructs improve islet viability and function through performing LIVE/DEAD assays, immunostaining and glucose challenging tests.
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 the 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 1diabetes-induced kidney failure.