Hill, Joseph A, MD, PhD
Forkhead transcription factors modulate insulin signaling and contribute to the pathogenesis of diabetic cardiomyopathy.
General Research Subject: Type 2 Diabetes
Focus: Insulin Action\Insulin Resistance
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2008
Project End Date: June 30, 2012
Patients with diabetes suffer disproportionately from heart disease. Indeed, cardiovascular disease is the leading cause of morbidity and mortality in these patients. Underlying causes are several, including coronary atherosclerosis ('hardening of the arteries') and high blood pressure. Recently, however, it has become clear that patients with diabetes develop heart disease independent of these factors, a condition termed 'diabetic cardiomyopathy.' Dr. Hill's lab has uncovered evidence implicating a set of molecules called FoxO in this process. FoxO is a family of transcription factors -- proteins that control the expression of genes within the nucleus -- that are normally turned off by insulin. Dr. Hill's group has found that these molecules can be inappropriately active in diabetic hearts, thereby antagonizing the beneficial actions of insulin.
Their proposed studies will elucidate mechanisms underlying this inappropriate FoxO activity and will determine the functional consequences in the heart. In so doing, they expect to define a novel mechanism contributing to heart disease in patients with diabetes.
Mentor: Joseph Hill, MD, PhD Postdoctoral Fellow: Pavan Battiprolu, PhD
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Cardiovascular disease, including heart failure, is the leading cause of morbidity and mortality in patients with diabetes. Whereas the underlying causes are multifactorial, recent work has emphasized the importance of ventricular dysfunction (inadequate pumping action of the heart) independent of atherosclerotic coronary artery disease or hypertension, a condition termed 'diabetic cardiomyopathy'. Our studies will explore the role of a class of transcription factors (proteins that govern the expression of genes in the nucleus) named FoxO in diabetic heart disease. We have amassed preliminary evidence to suggest that these proteins are inappropriately active, contributing to insulin resistance in the heart, and thereby participate in the pathogenesis of diabetic cardiomyopathy.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Patients with diabetes are disproportionately affected by heart disease and the catastrophic end-consequence, heart failure. For society as a whole, cardiovascular diseases are predicted to be the most common cause of mortality worldwide by 2020. Heart failure is already the most important cardiovascular disorder in the West from the perspectives of health care resource utilization. Annual expenditures for heart failure in the US are estimated at $20-40 billion.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Studies we have proposed will provide insights into a mechanism that has never been explored in the heart and which we believe to be an important factor in diabetic heart failure. As a physician who routinely cares for patients with diabetes, I am all too familiar with the ravaging effects it has on the heart. As a scientist who studies heart disease, I am in a position to harness state-of-the-art methodologies to uncover novel mechanistic insights into the failing, diabetic heart.
In what direction do you see the future of diabetes research going?
We are currently facing an epidemic of heart failure in western society, much of it occurring in the context of insulin resistance and/or diabetes mellitus. As most patients with diabetes ultimately succumb to heart disease, it is apparent that more work like this - designed to elucidate novel mechanisms of cardiac dysfunction in diabetes - are needed.
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