Vascular Complications of Diabetes

Detection of alterations in ocular vasculature

Almost half of adults with diabetes have vision impairments due to some form of diabetic retinopathy. The systemic effects of abnormal blood glucose concentrations greatly affect the vascular system of the eye. Over time, there may abnormal vessel growth and/or the leakage of blood through capillary walls. If this continues it often results in blindness. Indeed, diabetic retinopathy is the leading cause of blindness among adults in the United States. Early changes in the vascularization of the eye are not noticeable by the patient. By the time the patient recognizes severe alterations in their vision, the disease is already in an advanced stage. Therefore, Dr. Jennifer Kang Derwent and her colleagues are searching for ways to identify abnormal vascularization in the eyes of diabetics, and thus diagnose diabetic retinopathy before excessive vessel proliferation and clinical manifestation of disease.

Kang Derwent’s Retinal Vascular Research Laboratory is developing a technique to detect the slight alterations in the flow of blood through the vessels which are already present in the early stages of diabetic retinopathy. The technique, which is non-invasive, employs scanning laser opthalmoscope imaging to track fluorescent particles in the blood, and thus measure the flow rate through the vessels. The method has already been shown to detect changes before diabetic retinopathy was clinically manifested in research animals.

Ocular drug delivery

Currently, the medical options to prevent vision loss associated with diabetic retinopathy are limited. One treatment, which is also used in cases of age-related macular degeneration, is the local administration of antibodies or small molecules which interfere with the action of a protein called VEGF. VEGF promotes the growth of blood vessels (angiogenesis) by binding to VEGF-receptors on the cellular surface and initiating an intracellular signaling cascade. By blocking the action of VEGF with these ‘anti-VEGF’ agents, vessel growth can be effectively inhibited.

The delivery of anti-VEGF, however, is problematic. Because it needs to be supplied directly to the back of the eye, the current method is intraocular injection. And because of its relatively-short effect, it needs to be continuously injected every four to six weeks. With these invasive injections there is the risk of damage to the eye and the frequent administration is far from ideal. Thus, Kang Derwent and colleagues, including fellow CDRP researchers Drs. Victor Perez-Luna and Eric Brey, are looking for alternatives. One which shows promise is the encapsulation of anti-VEGF in a thermoresponsive hydrogel that is liquid at temperatures outside the body, but forms a gel at body temperature. When injected into the eye this newly-formed gel can slowly and regularly release VEGF over a prolonged period, so such frequent administration is not necessary.

Tissue ischemia

Many of the major complications in diabetes stem from changes in vascularization and blood flow throughout the body. Without therapy, these changes often result in heart disease and severe impairments in wound healing. There are methods available to promote neovascularization, but when used in diabetics they have not met with much success. Therapies are needed which specifically promote vascularization within the systems of diabetics and counter the changes which cause altered blood availability and Dr. Eric Brey and his colleagues are working to develop these.

Currently, the mechanisms behind vasularization changes in diabetics are not well-understood so Dr. Brey’s lab is examining both intracellular and extracellular alterations which are characteristic in diabetics. Much of their work focuses on the extracellular matrix, the structure which supports cells, their movement, and their interactions. In diabetics, the continual exposure to sugars results in excessive cross-linking of the elements in the extracellular matrix and Dr. Brey’s lab is determining how these unique changes influence vascularization. A better understanding of these cellular interactions is guiding the design of new synthetic and natural materials that enhance neovascularization in diabetic patients.

Cardiovascular disease

Atherosclerosis is a major cause of cardiovascular disease and can lead to both heart attack and stroke. Much research has focused on the conditions surrounding initial stages of atherosclerosis. Endothelial dysfunction has been identified as an early indicator of atherosclerosis. Endothelial dysfunction can expose otherwise buried vessel constituents to blood and induce endothelial expression of leukocyte adhesion molecules. Basement membrane constituents are known activate adherent platelets while increased surface concentrations of leukocyte adhesion molecules localize leukocytes to the area. Microparticles are small, lipid vesicles that have been shown to contain a number of physiologically active integral proteins that potentially bind to dysfunctional endothelium and impart procoagulant activity to the MPs. Blood borne MP populations, present in very small numbers under normal, healthy conditions, are elevated in many diseased states including obesity and diabetes. There is a possible role for these MPs in the advanced rate of atheroscerotic development in these disease states. Additionally, the interplay of the physical and chemical forces produced by blood flow with the biochemical interactions of platelets, leukocytes and possibly microparticles with the endothelium may result in the increased risk of cardiovascular disease in diabetic patients.