Sprague, Randy , MD
Effect of type 2 diabetes on the erythrocyte and vascular control
General Research Subject: Type 2 Diabetes
Focus: Clinical Therapeutics/New Technology\Pharmacologic Treatment of Diabetes or its Complications
Type of Grant: Basic Science
Project Start Date: January 1, 2011
Project End Date: December 31, 2013
Diabetes Type: Type 2 diabetes
Red blood cells (erythrocytes) carry oxygen to the organs in the body. Recently, we have shown that erythrocytes have another important function related to the control of blood flow. These cells can be stimulated to release a compound know as adenosine triphosphate or ATP. When ATP is released inside blood vessels, the vessels increase their diameter allowing more blood flow. Erythrocytes release ATP when they enter a region of tissue which oxygen need is increased, such as an exercising muscle, or when they are exposed to prostacyclin (PGI2) that can be released from blood vessels or administered pharmacologically to produce relaxation of blood vessels.
We have determined that the ability of erythrocytes to release ATP in response to low O2 is reduced in humans with diabetes mellitus, type 2 (DM2). In contrast DM2 erythrocytes release more ATP in response to PGI2. Interestingly, we have determined that the worse the control of blood sugar, the greater the defect in ATP release in response to low O2. However, ATP release in response to PGI2 actually increases when glucose control is poor.
In this project, we will establish that the failure of DM2 erythrocytes to release ATP in response to low O2 impairs the ability of this cell to relax blood vessels which interferes with the adequate delivery of oxygen to muscle. We will also determine if drugs that are used to treat vascular disease can restore the ability of human DM2 erythrocytes to release ATP, dilate blood vessels and deliver necessary oxygen.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Red blood cells carry oxygen to the organs in the body. Recently we have shown that these cells have another important function. They can also synthesize and release a compound known as adenosine triphosphate or ATP. This ATP helps blood vessels to relax. Red blood cell release ATP when they pass through organs that have increased usage of oxygen, such as an exercising muscle. We have determined that the ability of red blood cells to release ATP is decreased in humans with diabetes mellitus, type 2. In addition, we have shown that this defect in the red blood cell may be due to the failure to produce a protein that is in the membrane of the red cell and helps stimulate ATP release. Importantly, we have determined that the inability of the red blood cell to release ATP is inversely related to the degree of blood sugar control. This could contribute to the problems that these patients have with poor arterial circulation.
We have also found the red blood cell of humans with type 2 diabetes release increased amounts of ATP release compared to healthy humans in response to prostacyclin analogs. The latter studies suggest new strategies for the treatment of the vascular disease of diabetes. Recently, we have found that there may be ways to increases ATP release from red blood cells of humans with type 2 diabetes by using another group of drugs that are often avoided in type 2 diabetes, namely, phosphodiesterase 3 inhibitors. In the current project, we are studying new ways to pharmacologically restore the ability of red blood cells to release ATP and dilate skeletal muscle arterioles. This will provide new insights into the treatment of the peripheral vascular disease of type 2 diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The successful completion of the studies described in this proposal will give us new insights and novel strategies for the treatment of the vascular disease that is a major complication of type 2 diabetes. We believe that if we can correct defects in the release of a substance that relaxes blood vessels in red blood cells humans with type 2 diabetes (ATP), we will be able to improve, and perhaps even prevent, much of the associated vascular disease. It is possible that drugs that are already available to physicians could be used to help restore red blood cell function.
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, throughout my research career, tried to better understand the control of the circulation. This began with studies in the pulmonary circulation. We were among the first to establish that red blood cells are important determinants of vascular resistance in the lungs and, subsequently, in the peripheral circulation. I became interested in the role of the red blood cell in the vascular disease of diabetes when we realized that this cell is very important in directing blood flow to areas of increased oxygen need. I knew that in patients with diabetes the blood flow to the muscles, especially in the legs, is often inadequate. I reasoned that a part of the problem of reduced blood flow to these muscles could be due to abnormal red blood cell function. We have, indeed, found that the ability of red blood cell to release a substance that causes relaxation of blood vessels (ATP) is reduced in type 2 diabetes. This award will be instrumental in continuing our research. It is our ultimate goal to provide important new and novel approaches for the treatment and prevention of vascular disease in diabetes.
On a more personal note, both my grandfather and my mentor in science died of vascular complications of diabetes. I would like to hope that our work can help prevent or at least ameliorate this complication of type 2 diabetes.
In what direction do you see the future of diabetes research going?
I believe that studies aimed at the understanding of the mechanisms responsible for the complications of diabetes are essential and will yield new and useful information. However, equally important are studies designed to understand those mechanisms that lead to the development of both type 1 and type 2 diabetes. Thus, in my view, the critical directions are in development of strategies for prevention of diabetes and in the treatment and prevention of its complications.
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