Barrett, Eugene , MD, PhD
The cell biology of trans-endothelial insulin transport
General Research Subject: Insulin Resistance Pre Diabetes
Focus: Insulin Action\Insulin Resistance, Integrated Physiology\Muscle, Signal Transduction (Non-Insulin Action)\Cytokines and Apoptosis
Type of Grant: Basic Science
Project Start Date: January 1, 2011
Project End Date: December 31, 2013
Diabetes Type: Type 2 diabetes
Skeletal muscle is an important site for insulin-stimulated glucose uptake following a meal. Multiple experiments have shown that the rate limiting step for insulin action to promote muscle glucose uptake involves getting insulin from the circulating blood through the blood vessel wall into the extracellular fluid within muscle. In humans this process has a halftime of ~ 40 min whereas insulin, once it reaches the muscle cell, stimulates glucose uptake with a halftime of ~ 3 min. Insulin resistance has seen with obesity or diabetes further slows insulin movement from blood to muscle tissue. We have preliminary evidence that insulin does not passively leave the plasma by simple diffusion but rather promotes its own movement across the blood vessel wall.
This is not surprising as insulin is a relatively large molecule and the vascular wall cannot simply be leaky to proteins of the size of insulin. To get across the vessel wall insulin appears to bind to its receptor, and then activate a transport process that utilizes small vesicles or packages that move across the lining cells (endothelium) of the blood vessel and deposit the insulin in the extracellular space around muscle. This process is complex and we propose to identify the regulated processes that are responsible for insulin's ability to promote its own movement out of the vasculature and to define how this is affected by insulin resistance. This potentially will provide a whole new series of targets for therapeutics directed at improving insulin sensitivity.
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 been very interested in studying the mechanism by which insulin leaves the vascular compartment and enters into skeletal muscle. This interest is provoked by observations that indicate that this escape of insulin from the vascular compartment into muscle is the rate limiting step for insulin's metabolic action in muscle and that the rate of this process is impaired in states of insulin resistance. We have strong preliminary data indicating that insulin moves across the endothelium via a vesicular trafficking system involving caveolae.
Very little is known about the regulation of this process. However, since it is rate limiting for insulin delivery to a major target tissue it appears to us important to define the biological processes involved. Success at this should provide us with the opportunity to consider various targets for new therapies for type 2 diabetes. These might improve muscle insulin resistance by acting within the vasculature that slows insulin's trans-endothelial movement. It is also possible that we will be in a position to identify interventions which will prevent the development of insulin resistance at the outset and prevent therefore the onset of a significant fraction of cases 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?
Most current research suggests that in type 2 diabetes insulin resistance is a major causative factor. We think that this insulin resistance occurs in many tissues including blood vessels. When present within blood vessels, insulin resistance impairs the ability of insulin to get to metabolic target tissues like skeletal muscle and fat. Currently we don't know nearly enough about the process by which blood vessels allow insulin to be delivered across the blood vessel wall into target tissues.
We do have reasonable data to suggest that this process is slowed by insulin resistance and this may contribute to both postprandial and fasting hyperglycemia. It is also important to understand this process when we consider treating patients with insulin since this process will impact the rate at which insulin can act in an individual. Finally, by understanding this process we will have the opportunity to consider novel interventions that will reduce blood sugar and improve insulin resistance.
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 interests have been focused on diabetes for more than two decades. I have also been involved as a volunteer and officer in the ADA, my clinical practice is essentially entirely patients with diabetes both type 1 and type 2 and I have several members of my family with diabetes. This award allows my laboratory to probe in a very deliberate way a poorly understood aspect of insulin physiology that appears to be extremely important for the kinetics of insulin action in humans.
In what direction do you see the future of diabetes research going?
I think we will be developing an increasing understanding of the genetics of both type 1 and 2 diabetes and how these genetic factors interact with our environment. On the clinical investigations by I think it is becoming increasingly clear that in as much as the majority of the morbidity and mortality of diabetes is related to vascular disease we need to understand better just how diabetes and insulin resistance impact blood vessels. We then we'll be in a position to target directed therapies to reverse abnormalities in vascular function and hopefully prevent long-term complications that afflict patients with both forms of diabetes i.e. myocardial infarction, stroke, amputations.
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