| Goldberg, Ira J., MD Columbia University New York, NY Glucose metabolism in the lipotoxic heart Type of Grant: Mentor-Based Postdoctoral Fellowship Project Start Date: 07/01/2003 Project End Date: 06/30/2007 Diabetes Type: Both Type 1 and Type 2 Diabetes Research Description Diabetes is a major cause of heart failure. Moreover, patients with diabetes have a worse prognosis when they get heart diseases, i.e., heart failure or coronary artery disease. The reasons for this are unclear but likely relate to defects in energy utilization by the diabetic heart. It is widely believed that this results from over-dependence of the heart on fat metabolism for energy, since glucose metabolism is impaired. Dr. Goldberg's laboratory pursues several lines of research on diabetic heart disease complications: 1) Causes of increased atherosclerosis in diabetes and 2) Cardiac lipotoxicity and the pathophysiological basis of diabetic cardiomyopathy. This study is intended to uncover treatments for diabetic heart disease. Diseases of the heart and major blood vessels are the primary cause of death in patients with diabetes. Dr. Goldberg and Dr. Yokoyama hope to discover if expression or inhibition of certain genes will alter disease in an animal model. If successful, drug therapies could be developed that will mimic these gene changes. Other strategies, diets and perhaps drug treatments, might be directly applicable to humans. Thus, these studies might indicate strategies for human clinical trials. Researcher Profile What area of research does your project cover? What role will this particular project play in preventing,, treating and/or curing diabetes? We have created a lipotoxic heart model that in several ways resembles diabetic cardiomyopathy.These hearts have increased uptake of lipids (fats) due to overexpression of the enzyme lipoprotein lipase (LpL). The dilated cardiomyopathy is associated with increased enzymes of fatty acid oxidation (ACO, CPT1) and decreased glucose transporters (GLUT1 and GLUT4) in the heart. THat means, like in diabetes, the heart uses more fat and less glucose for the energy required to continuously contract and relax. The hearts of our mice do not contract normally. Biochemical indicators of this, heart failure genes, are increased. When we looked at the hearts using echocardiography, bouncing sound waves off the hearts, the hearts were dilated (stretched) and had decreased fractional shortening (they did not squeeze well). The objective of Dr. Yokoyama's work is to elucidate methods to alter the development of heart failure; methods that either increase or decrease the disorder are likely to provide insights into the pathophysiology of the disease. One of the first approaches that we have used is assess methods to reduce lipid content of the hearts. Two experimental approaches will be utilized. The cardiomyopathic transgene (heart LpL, hLpL) will be crossed with mice overexpressing human apoB. ApoB, the major protein component of LDL and VLDL, is expressed in the heart and it has been postulated that apoB will reduce cardiac lipid by allowing the heart to secreted lipoproteins. A second gene, apoAI the major protein in HDL, will be expressed using adenovirus. We will assess cardiac echocardiography, heart size and lipid, and expression of genes for heart failure, and fatty acid and glucose oxidation in these mice. A second approach will be to alter diets in these mice. In some models, high fat feeding and streptozotocin-induced diabetes accelerated heart failure. Both approaches will be used in the hLpL hearts. If a person with diabetes were to ask you how your project will help them in the future, how would you respond? Diabetes is a major cause of heart failure. Moreover, patients with diabetes have a worse prognosis when they get heart diseases, i.e. heart failure or coronary artery disease. The reasons for this are unclear but likely relate to defects in energy utilization by the diabetic heart. It is widely believed that this results from over-dependence of the heart on fat metabolism for energy, since glucose metabolism is impaired. Our study is intended to uncover treatments for diabetic heart disease. Diseases of the heart and major blood vessels are the primary cause of death in patients with diabetes. We hope to discover if expression or inhibition of certain genes will alter disease in an animal model. If successful, drug therapies could be developed that will mimic these gene changes. Other strategies, diets and perhaps drug treatments, might be directly applicable to humans. Thus, these studies might indicate strategies for human clinical trials. Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts? My laboratory primarily studies the regulation of plasma lipoproteins. However, as a clinical endocrinologist, a major focus of my clinical teaching and patient involvement is with patients with diabetes and their complications. This award will permit a fellow to specifically explore the development of cardiomyopathy in diabetes. The fellow, Dr. Yokoyama, was a diabetologist in Japan and specifically came to the Goldberg lab to study laboratory models of diseases that occur in patients with diabetes. In what direction do you see the future of diabetes research going? The approach to diabetes care and the future of diabetes research are parallel. Both involve a two pronged approach to 1) study regulation of plasma glucose, and 2) define the etiology and develop treatments for the complications of diabetes. In many ways, this latter objective will explore why these diseases, e.g. atherosclerosis and renal failure, occur more frequently in patients with diabetes. An alternative and complementary approach is to define the basic etiology of disease with research not specifically directed to diabetes, and then to apply the knowledge to the diabetic situation. The specific issue addressed in the research by the fellow supported by the ADA Mentored Award is the development of lipotoxicity. The model that we will use is one of lipid-induced cardiomyopathy. However, the future of the field is to define the mechanisms responsible for tissue dysfunction; these same pathways are likely to cause diabetic cardiomyopathy, fatty liver (NASH), islet cell failure, and muscle insulin resistance.
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