News & Research

    University of Virginia, Charlottesville, Virginia

Angiotensin II regulation of endothelial surface area and insulin delivery in humans

General Research Subject: Type 2 Diabetes

Focus: Insulin Action\Insulin Resistance, Insulin Action\Metabolism, Integrated Physiology\Muscle

Type of Grant: Novo Nordisk Clinical Research

Project Start Date: January 1, 2011

Project End Date: December 31, 2013

Diabetes Type: Type 2 diabetes

Research Description

Patients with type 2 diabetes are prone to suffer cardiovascular diseases such as heart attack, heart failure, stroke and kidney failure; all cause significant morbidity and mortality. The underlying mechanisms remain unclear. Patients with type 2 diabetes have decreased responses to insulin, a condition called insulin resistance in both small blood vessels and skeletal muscle which has been implicated in the development of cardiovascular complications in diabetic patients. Insulin acts on the skeletal muscle to stimulate glucose use. However, in order for insulin to act on the skeletal muscle it has to be delivered to the muscle first. It is in the small blood vessels in muscle where insulin passes through the vessel wall to reach muscle cells. Expansion of the small blood vessels increases the delivery of insulin, together with oxygen and nutrients to the skeletal muscle. It is unclear whether in the insulin resistant states that expansion of the small blood vessel volume would increase insulin sensitivity by increasing insulin delivery to the muscle.

Diabetes is associated with many biochemical abnormalities which are capable of causing insulin resistance and abnormal vascular function in the skeletal muscle. In this proposal, we plan to examine whether selectively activation of a hormone receptor, called angiotensin II type 2 receptors, would increase insulin sensitivity in the muscle by increasing muscle small blood vessel volume and insulin delivery in the insulin resistant states. We will use a state-of-the-art technique called contrast-enhanced ultrasound (CEU) to non-invasively measure small blood vessel volume in the human skeletal muscle. Results from the proposed studies should shed light to our understanding of the relationship between type 2 diabetes, insulin resistance, and cardiovascular complications in humans and open a whole new avenue for future mechanistic, diagnostic and/or therapeutic studies.

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?

Patients with type 2 diabetes are prone to suffer cardiovascular diseases such as heart attack, heart failure, stroke and kidney failure; all cause significant morbidity and mortality. The underlying mechanisms remain unclear. Patients with type 2 diabetes have decreased responses to insulin, a condition called insulin resistance in both small blood vessels and skeletal muscle which has been implicated in the development of cardiovascular complications in diabetic patients. Insulin acts on the skeletal muscle to stimulate glucose use. However, in order for insulin to act on the skeletal muscle it has to be delivered to the muscle first. It is in the small blood vessels in muscle where insulin passes through the vessel wall to reach muscle cells. Expansion of the small blood vessels increases the delivery of insulin, together with oxygen and nutrients to the skeletal muscle. It is unclear whether in the insulin resistant states that expansion of the small blood vessel volume would increase insulin sensitivity by increasing insulin delivery to the muscle.

Diabetes is associated with many biochemical abnormalities which are capable of causing insulin resistance and abnormal vascular function in the skeletal muscle. In this proposal, we plan to examine whether selective activation of a hormone receptor, called angiotensin II type 2 receptors, would increase insulin sensitivity in the muscle by increasing muscle small blood vessel volume and insulin delivery in the insulin resistant states. We will use a state-of-the-art technique called contrast-enhanced ultrasound (CEU) to non-invasively measure small blood vessel volume in the human skeletal muscle. Results from the proposed studies should shed light to our understanding of the relationship between type 2 diabetes, insulin resistance, and cardiovascular complications in humans and open a whole new avenue for future mechanistic, diagnostic and/or therapeutic studies.

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 at a very high risk of having microvascular complications and do not respond well to insulin. Activation of the type 2 receptor of angiotensin II is able to dilate blood vessels to promote tissue perfusion, thus increasing the delivery of insulin, nutrients and oxygen to various tissues. This project will help us to better understand the underlying mechanisms of insulin resistance and microvascular complications, and potentially make it possible for future development of therapeutic agents to protect various tissues from ischemic injury and to decrease the associated morbidity and mortality, especially in patients with diabetes.

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

I am a board certified endocrinologist and have strong interest in diabetes. In my practice, more than 50% of my patients have diabetes and many of them have diabetes-related complications, including coronary artery disease. Therefore, it is very important for me to become actively involved in diabetes research to better serve my patients. This research award will provide extremely important momentum for my research effort by providing much needed resources and protected research time. It will also help me to generate more data for future research funding applications in diabetes research.

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

With better understanding of the molecular and cellular mechanisms of diabetes, the future of diabetes research is likely going to focus on the application of bench top research findings in the clinical setting to explore the cure of diabetes.