King, George L., MD
Identification and Validation of Protective Factors for Diabetic Retinopathy and Nephropathy
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Clinical Therapeutics/New Technology, Clinical Therapeutics/New Technology\Pharmacologic Treatment of Diabetes or its Complications, Complications, Complications\Nephropathy, Complications\Ocular
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2012
Project End Date: June 30, 2016
Funded by the Z Gallerie/Zeiden Family Research Award
The goal is to identify protective factors against the development of diabetic eye and kidney diseases which could be used for new therapy. This is possible since we have studied over 700 type 1 diabetic patients (Joslin Medalist patients) who have had the disease for 50 years or longer. Over 35% of the Medalists do not have significant eye or kidney diseases. Using the retinas and kidneys donated from these patients after death, we have identified 10 and 14 potential protective factors for diabetic eye and kidneys, respectively, using proteomic analysis. Our laboratory is presently determining whether these potential protective factors can prevent the toxic effect of hyperglycemia in cell culture models of diabetic eye and kidney disease. Top candidates from these cell-based assays will be tested using specific gene delivery methods to diabetic eye and kidneys to determine whether they can prevent the onset of diabetic eye and kidney pathologies in mouse models of diabetes. The positive results from these studies can then be used in clinical trials as potential treatments for diabetic eye and kidney diseases.
Mentor: George L. King, MD Postdoctoral Fellow: Kyoungmin Park, PhD
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Our laboratory has identified multiple pathways that are important for the development of diabetic complications induced by hyperglycemia and insulin resistance. In this project, we are proposing to identify biomarkers that could yield a measurement of possible damage to the retinal pericytes and endothelial cells, leading to diabetic retinopathy (DR) and endothelial dysfunction. These studies will identify proteins that have been changed by high glucose levels or loss of insulin’s effects in culture cells. Once potential targets have been identified in culture cells, we will determine whether they are changed in diabetic mice. Those that showed change in the retina and arteries of diabetic mice will be studied in diabetic patients with and without long-term diabetes. Diabetes mellitus is a disease characterized by increased blood glucose and loss of insulin actions. Diabetic patients suffer from various chronic complications, which can severely impair many organs. Because complications play the most primary role for causing death of diabetic patients, many studies are focused on the mechanism of the onset and development of complications. In many cases, the onset of diabetic complications are often regarded as originating from damaged blood vessels of organs, which may result from the abnormal changes of some specific proteins such as signaling molecules in the cells of blood vessels caused by metabolic disorders. Our project will identify early biochemical markers of DR and atherosclerosis.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Complications are most likely to threaten or impair quality of life in diabetic patients and can also affect many organs including the heart, brain, blood vessels, eyes, kidneys, and nerves. Many epidemiological investigations show the risk for loss of eyesight, heart attack, kidney failure, stroke and amputation in diabetic patients as several-fold higher compared to people without diabetes. Preventing complications of diabetes is the primary goal of diabetes lifestyle interventions and medical therapy. The only way we can improve our approach to preventing diabetic complications is to better understand the mechanisms by which complications develop. We have focused our research to pinpoint new and better approaches to prevent and cure diabetic complications. Our study will identify markers that could potentially lead to predicting early changes that lead to diabetic eye disease. If these early markers can be identified, we could have an ability to predict who will develop diabetic eye disease and will allow us to develop early treatments that could prevent the onset of diabetic eye disease and the need for laser treatment for diabetic eye diseases.
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 been involved in diabetes research since 1978, focused on the development of new treatments for diabetic eye, kidney and heart diseases. Diabetes has affected family members, many who passed away from complications. Thus, it would be very important for me personally to contribute to the development of new treatments for diabetic complications. In addition, the American Diabetes Association has provided support during multiple stages in my career, continuing to this day. This award will allow me to work and mentor young investigators in this area. One of my most rewarding experiences has been to work with fellows and develop them into both clinical and basic researchers over the past 29 years. With this award, I will be working with Dr. Jennifer Gong, a clinical fellow at Joslin Diabetes Center and Beth Israel Deaconess Medical Center of Harvard Medical School. We will be investigating potential biomarkers that could be used to protect pericytes, key cells in the eye. The damage to pericytes in the eye is believed to be the most specific and earliest marker that leads to the development of diabetic eye disease. This support will allow us to identify potential markers for pericyte damage using culture cell, animal and human studies. These studies reflect the true idea of translational and clinical studies.
In what direction do you see the future of diabetes research going?
The prevalence of diabetes is increasing at an epidemic rate all over the world, including the USA. Complications of diabetes are a major cause of blindness, kidney failure, heart disease, strokes, limb amputations and many other medical problems. Almost all of these complications are either linked with high levels of glucose or insulin dysfunction. Thus, future research in the area of diabetes needs to focus on developing new treatments to prevent these important complications, which are the major causes of death and suffering in diabetic patients. In order to develop new treatments to prevent or stop diabetic complications, we need to understand the ways by which high glucose level and insulin resistance are causing damage in the blood vessels in the eye, kidney, brain and peripheral limbs, including the various arteries. Once we have some understanding on the mechanism by which high glucose and insulin resistance are causing vascular damage, then we can design new treatments to nullify the actions of hyperglycemia and improve the actions of insulin on the blood vessels. These are the most important areas of diabetes research to prevent complications.
What else can the American Diabetes Association do to assist investigators in their efforts to prevent, treat and/or cure diabetes?
Studies for prevention of diabetes and its complications are critical in order to decrease the epidemic prevalence rate of diabetes. Prevention of diabetes is possible due to landmark government-sponsored studies from the US, Finland, China and India. However, the translation of these results preventing diabetes in the community level has not shown dramatic improvement. Thus, new treatments for the translation of prevention methods for the development of diabetes need to be developed. In addition, pharmacological approaches for diabetes and the prevention of its complications are clearly needed. For example, pharmaceutical intervention to lower cholesterol and treat hypertension contributed significantly to the decline in cardiovascular diseases and hypertension in the general population of the United States. Thus, we need to develop new methods in order to implement the changes in lifestyle and diet in order to prevent diabetes and its complications. We also need to develop new pharmaceutical treatments for the prevention of diabetes and its complications as well.
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