Diabetes Complications: Retinal Disease
Research Models
Mark Vézina

Diabetes Complications: Retinal Disease

How advances in imaging technology and electrophysiology are spotlighting a leading cause of blindness.

Though cataracts and glaucoma are two possible complications of diabetes, diabetic retinopathy (DR) is by far the most severe complication that can occur with both type 1 and type 2 diabetes. Up to 45% of diabetics will develop some form of DR.

DR, a disease of the retinal blood vessels, is a leading cause of blindness in North America. It usually starts slowly, progressing undetected for several years until the person starts noticing blurry vision. There are four stages of disease, starting with the formation of microaneurysms—small bulges in the walls of the main vessels that can burst or cause blockages. Once a significant number of vessels become blocked, certain areas of the retina become hypoxic (oxygen-deficient) and start growing neovessels to try to restore circulation. Unfortunately, these neovessels lack order, and have fragile walls that tend to leak blood, serum, proteins or other particulates into the eye that should not be there and can cause inflammation.

It is this self-perpetuating cycle of more blockage, more fluid, more hypoxia and more neovessels known as the proliferative stage that leads to impaired vision in people with DR. And when fluid leaks into the macular area, where visual acuity is highest, it causes macular edema that, left untreated, leads to blindness. Until recently, treatment for DR largely came down to controlling blood sugar, cholesterol and blood pressure until the symptoms became severe enough to require laser surgery. In the past decade, however, the approval of drugs that block vascular endothelial growth factor (VEGF), a protein that causes blood vessels to proliferate and leak fluid into the eye, have provided a therapeutic alternative. Both surgical and therapeutic interventions have limitations, however.

For instance, laser scatter treatment, which uses a few thousand laser burns to shrink the neovessels in the periphery of the eye, also reduces peripheral vision. And because the anti-VEGF drugs have limited residence time in the eye, they need to be administered monthly with or without the laser therapy. Treatment of macular edema also involves laser burns, though in a much more focused manner. And when there is significant bleeding in the eye, a more invasive vitrectomy (removal and replacement of the gel-like vitreous humor) is performed.

So there is significant room for improvement in the treatment of DR, and animal models are doing their part to help scientists reach that goal. There are several models available: natural, diet- induced, pharmacologically- induced or transgenic, primarily in rodents, but also in some larger animal species. The details of these models are well described in the literature and too numerous to list here; however, the methods used to evaluate DR models are similar, and are also used in the diagnosis and follow-up of the human form of DR disease, making them especially useful in understanding the disease process.

The technology for the in-vivo evaluation of the eye has advanced significantly in recent years. Beyond the standard eye exam and classic photography of the retina, fluorescein angiograms, electrophysiological testing, visual acuity testing and optical coherence tomography imaging play important roles in the evaluation of DR in animal models.

  1. Fluorescein angiography is a test of the vessel integrity. Fluorescein dye is injected intravenously and the vessels are imaged to look for leakage, blockage or other abnormalities, such as microaneuryisms. Recent advances in technology have improved the resolution of these images so that the fine capillaries can be observed thus increasing the usefulness of the parameter.

  2. The electroretinogram (ERG) is an electrophysiological functional evaluation of the photoreceptor cells of the retina and transmission of a signal from the photoreceptors to the optic nerve (see Eureka blog). It is used in humans for early disease diagnosis. A reduction in retinal vessel circulation will reduce oxygen and nutrient delivery to the neural cells in the retina and will have an effect on function. The ERG is also sensitive to the number of functioning (live) cells; however, it cannot differentiate between functional deficit and absence of live cells. Therefore in animal models additional complementary parameters may be necessary depending on the objectives of the research.

  3. Optokinetics is a quantitative evaluation of visual acuity for rodents. In contrast to the strictly cellular level functionality evaluation provided by the ERG, optokinetics provides information on how well the animal can see (vision). While the ERG can provide early onset information (within days to weeks after diabetes onset), optokinetics is a more late stage evaluation requiring several months of diabetes before visual impairment is evident.

  4. Optical coherence tomography (OCT), specifically the newer spectral variety (SD-OCT) provides non-invasive serial cross sectional images of the retina at a microscopic level and allows for imaging of the same animal over a period of time (see Eureka blogs herehere and here). Serial imaging capability is an advantage for evaluating progression of the disease. SD-OCT can be used to measure retinal thickness (entire or even individual cell layers) and can be used in conjunction with the ERG to determine if changes are functional, degenerative or a combination of both. SD-OCT can also show conformational changes in retinal structure.

These advances in technology are allowing for more detailed analysis of retinal functions and structure in both animals and humans that can lead to more meaningful research in this field. And ultimately better treatments for people suffering from DR.