News & Research

    University of Alabama at Birmingham, Birmingham, Alabama

The role of PPARdelta signaling in diabetic cardiomyopathy

General Research Subject: Type 1 Diabetes

Focus: Complications\Hypoglycemia, Integrated Physiology, Integrated Physiology\Fatty Acid Metabolism, Obesity, Obesity\Animal Models

Type of Grant: Basic Science

Project Start Date: July 1, 2012

Project End Date: June 30, 2015

Research Description

It has been well documented that chronic diabetes mellitus (both type 1 and type 2 diabetes) can result in heart problems with no discernible coronary artery disease. The heart in diabetes usually has disturbed metabolism and inflammation. However, the precise molecular mechanisms of the heart problems in diabetes remain obscured, and effective therapies are still lacking. Previous studies have documented the crucial roles of Peroxisome Proliferator Activated Receptor and delta in regulating metabolism in the heart and suppressing inflammation. Our preliminary studies revealed that the expression of PPAR delta in the heart was decreased in animal models of type 1 diabetes.

Considering the crucial roles of PPAR delta in regulating metabolism and inflammation, we proposed to determine the essential role of PPARdelta in protecting the heart from diabetic damages and the therapeutic potential targeting PPAR delta for heart problems found in type 1diabetes. We hypothesize that PPAR delta plays a protective role in the heart in type 1 diabetes. We will test this hypothesis with the following specific aims using animal models with genetic manipulations so that we could see whether the decreased expression of PPAR delta in the heart of diabetic animal is harmful. We will also test whether an increase of PPAR delta in the heart or in the whole body would be beneficial. Finally, we will carry out studies to unravel the underlying mechanisms of the PPARV effects in the heart. The knowledge gained from these studies will have translational impact given that PPARV specific ligands are currently under phase II clinical trial.

Research Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?

This project covers the area of diabetic cardiomyopathy, the complication often seen in patients with type 1 and type 2 diabetes. It has been well documented that chronic diabetes mellitus (both type 1 and type 2 diabetes) can result in heart problems with no discernible coronary artery disease. The heart in diabetes usually shows disturbed metabolism and inflammation. However, the precise molecular mechanisms of the heart problems in diabetes remain obscured, and effective therapies are still lacking.

In this project, we focus on the crucial role of Peroxisome Proliferator Activated Receptor (PPARdelta), an important factor that regulates gene expression, in regulating metabolism in the heart and suppressing inflammation. We will examine whether the decreased expression of PPAR? in the heart of diabetic animal is harmful. We will also test whether an increase of PPARdelta in the heart or in the whole body would be beneficial. The knowledge gained from these studies will have translational impact given that PPARdelta specific ligands are currently under phase II clinical trial.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

I would explain to them why research in this project may help to uncover crucial mechanisms underlying the development of heart disease in patients with diabetes and how the study may lead to better therapeutic strategy. Since synthetic compounds that can activate PPARdelta signaling are now actively studied in basic and clinical settings, the likelihood of a new therapy using these compounds to treat the heart complication related to diabetes is quite high. However, I would also remind them that the synthetic compounds could have unwanted off-target effects that may delay the process. The difference between mice and humans may represent another potential hurdle for the implementation of the finding. The proposed study will further clarify these potential issues and provide preclinical insights into the future therapeutic value of PPARdelta activation.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?

My research has been related to diabetes since I started my own lab. My research interests originally focus on how the energy status of the heart changes during various pathological developments. In these research efforts, we found that energy metabolic disorder in the heart is a crucial factor determining the development of heart problems, especially those found in patients with diabetes. This finding is highly relevant in the personal level, because I have quite a few colleagues and friends are suffering from diabetes. Dr. Craig A. Johnston, who was my former mentor and dear friend, passed away last year at the age of 56 due to complications of diabetes. I consider my research effort is the best way I could come up to memorize him. This award will help me to fulfill this wish and to expand my research efforts in this area.

In what direction do you see the future of diabetes research going?

Research in diabetes will have to focus more on preclinical and clinical studies that could be translated into therapies in a faster pace.