Cardiovascular Complications of Obesity, Insulin Resistance and Diabetes
Cardiovascular complications (heart attack and stroke) are among the most common and most devastating disorders that occur in association with obesity, insulin resistance, and diabetes. The risk of cardiovascular complications is greatest among individuals with elevated blood levels of LDL cholesterol and triglycerides, reduced levels of HDL cholesterol, and hypertension. Each of these risk factors is known to increase cardiovascular risk, and each is common in individuals with obesity and diabetes. Indeed, more than 65% of people with diabetes die from cardiovascular complications, according to the American Diabetes Association. Similarly, obesity and insulin resistance are major risk factors for cardiovascular complications.
Heart attack and stroke are caused by advanced lesions of atherosclerosis in the blood vessel wall. These lesions develop gradually over time, and eventually can become unstable and rupture or fissure. This in turn can lead to a sudden blockage of the blood vessel, resulting in heart attack or stroke depending on the site of the lesion. At the cellular level, atherosclerotic lesions contain a variety of immune cells and vascular smooth muscle cells, as well as endothelial cells that line the blood vessel. Each of these cell types plays a unique and important role in atherosclerosis and each is negatively affected by obesity, insulin resistance, and diabetes.
Normal and Lesioned Vessels
Section of a blood vessel from a mouse without atherosclerosis (top left). The normal vascular wall consists of smooth muscle cells (red) held together by elastin filaments (black). Beginning atherosclerosis in a mouse fed a high-fat diet. Immune cells (light purple) have infiltrated the vascular wall (top right). With time, the atherosclerotic lesion can grow and almost completely occlude the blood vessel (bottom left). These advanced lesions consist of immune cells (light purple, in the center), and areas containing dead cells and cholesterol. Advanced lesions can also show signs of bleeding, demonstrated as an intense red stain (bottom right). Bleeding (hemorrhage) into advanced atherosclerotic lesions is believed to contribute to cardiovascular events, such as heart attack and stroke. Images courtesy of the laboratory of Karin Bornfeldt, PhD.
Scientists at the Diabetes and Obesity Center of Excellence (D&O) are deciphering the cellular and molecular mechanisms underlying vascular complications of obesity, insulin resistance, and type 1 and type 2 diabetes.
One area of research, spearheaded by Dr. Francis Kim, focuses on inflammatory changes in the blood vessel wall in response to obesity and insulin resistance. Dr. Kim’s research suggests that vascular inflammation develops early in the course of obesity in animal models, and that this response causes endothelial dysfunction and vascular insulin resistance. Dr. Kim’s studies have demonstrated that toll-like receptor 4 (TLR4) signaling plays a critical role in vascular insulin resistance and inflammation, and his current work investigates whether endothelial dysfunction contributes to insulin resistance in key tissues for blood glucose control, such as liver and skeletal muscle.
The goal of another area of research, pursued by Dr. Karin Bornfeldt, is to identify factors that accelerate atherosclerosis in patients with type 1 diabetes and insulin resistant states. These studies have demonstrated that in a mouse model of type 1 diabetes, early lesions of atherosclerosis occur much more quickly than in non-diabetic mice, and their progression to advanced lesions is also greatly accelerated. She has also shown that the development and progression of these lesions in type 1 diabetes can be prevented by aggressive lipid-lowering therapy, and she is currently working to clarify the role of vascular inflammation, circulating fatty acids, and intracellular signal transduction pathways in atherosclerosis associated with type 1 diabetes. Similar studies in mice with insulin resistance/type 2 diabetes are also being pursued.
A related and very active area of research in the D&O Center focuses on the link between obesity, diabetes and abnormal lipid metabolism, which is described under “Lipid Metabolism and Inflammation”.