Cells within retinal blood vessels are endowed with a previously unappreciated ability to acquire resistance against the damaging effects of hyperglycemia in patients with diabetes mellitus, researchers report in The American Journal of Pathology

Culturing primary human retinal endothelial cells under hyperglycemic conditions initially compromised their mitochondria. The cells respond by adapting, which includes clearance of the dysfunctional mitochondria via mitophagy. Such adaptation is a plausible contributor to the underlying mechanism responsible for the long delay between the onset of diabetes and the manifestation of diabetic retinopathy. Furthermore, loss of adaptation may be a prerequisite for the development of retinopathy in patients with diabetes. CREDIT The American Journal of Pathology

About one third of patients with diabetes mellitus (DM) develop diabetic retinopathy (DR), a leading cause of blindness in working-age individuals. DR typically develops after many years of DM, and some patients do not develop DR for more than 50 years. New research suggests that an endogenous system that protects human retinal endothelial cells from harmful effects of the hyperglycemia (an excess of blood sugar) may be responsible for the delayed onset of DR. Furthermore, degradation of this protective system over time may set the stage for development of DR. The new study appears in The American Journal of Pathology, published by Elsevier.

“The prevailing understanding of what causes DR predicts that it will develop soon after the onset of DM,” explained lead investigator Andrius Kazlauskas, PhD, Departments of Ophthalmology and Visual Sciences and Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA. “Yet this is not the case. Although the long delay from the onset of DM to the development of DR is a well-known clinical phenomenon, there is relatively little effort to investigate the underlying reason for this delay. Uncovering this information constitutes an exciting opportunity to improve current approaches to prevent DM from progressing to DR.”

Exposing cultured cells, such as vascular endothelial cells, to high glucose is a common in vitro model of DR. The investigators cultured human retinal endothelial cells in either normal glucose or high glucose–containing media. Unexpectedly, they found that prolonged exposure to high glucose was beneficial, not detrimental. After one day, the health of the cells declined, but as the duration of exposure was prolonged, the cells recovered and acquired resistance to DM-related damage such as inflammation and death.

The investigators found that the adaptation was associated with improved mitochondria functionality. Mitophagy is the process in which cells remove damaged mitochondria, and disruption of this intrinsic quality control system is associated with many diseases. Though initially compromised, mitochondrial functionality was improved after 10 days of exposure to high glucose, with increased clearance of damaged mitochondria. Interfering with the mitochondrial dynamics compromised the cells’ ability to endure high glucose. Susceptibility to cell death increased, and responsiveness of vascular endothelial growth factor deteriorated.

Dr. Kazlauskas said these observations indicate the existence of an endogenous system that protects human retinal endothelial cells from the deleterious effects of hyperglycemia. “The compelling role of mitochondrial dysfunction in the development of DR supports our central concept of a hyperglycemia-induced mitochondrial adaptation (HIMA) system, the purpose of which is to preserve the functionality of mitochondria. We posit that the loss of HIMA sets the stage for advancing to DR.”

An important component of the HIMA concept is that improving the functionality of a subset of retinal cells will be beneficial for the whole retina. Previous research has found even a small reduction in degree or type of insult to the retina can protect animals that have DM from developing DR. Together these discoveries suggest that the development of DR involves a relatively small shift in the balance between exogenous insults and the endogenous systems that prevent DM-driven damage and drivers of pathogenesis. 

Dr. Kazlauskas observed that the increasing incidence of DM, and consequently of DR, around the world exacerbates the need for effective approaches to protect patients from this serious complication. “Does HIMA exist in vivo, does it protect patients from DR, and is its demise a prerequisite for progression to DR? Our ongoing research is focused on answering these open questions,” he concluded.

A: Multicolor widefield SLO image of the right fundus of a 65-year-old man with PDR showing multiple hemorrhages in a wide area of the fundus. B: Blue SLO image shows a hyporeflective area in the mid-periphery to periphery of the fundus. C: Widefield FA image shows widespread NPAs in the mid-periphery to periphery. Neovascularization is also seen in the superior pole of the eye. D: Magnified image of image B shows hyporeflective areas in the lower temporal quadrant. E: Magnified FA image of image C shows NPAs in the same quadrant of image D. F: The hyporeflective areas in image D are outlined by white dots. G: The NPAs in image E are outlined by blue dots. The outline of white dots in image F is located inside the outline of blue dots image G. (Horie S, Ohno-Matsui K et al. Asia Pac J Ophthalmol (Phila). 2021 Aug 27; 10(5):478-485) CREDIT Department of Ophthalmology and Visual Science, TMDU

Just as bright light can illuminate the depths of a darkened room, researchers in Japan have found that blue light can be used to probe the depths of the eye and uncover areas affected by diabetic retinopathy (DR), a leading cause of blindness.  

In a new study published in Asia-Pacific Journal of Ophthalmology, researchers from Tokyo Medical and Dental University (TMDU) have revealed that blue images obtained by multicolor widefield scanning laser ophthalmoscopy (SLO) may be used to identify areas of DR-induced damage in a more extensive portion of the eye compared with previous methods. 

Current eye imaging methods include fluorescein angiogram, which involves the injection of dye into the eye. SLO is a non-invasive approach that does not require dye, and multicolor widefield SLO represents an advancement of this technique in which red, blue, and green lasers are used to simultaneously capture images of a wide portion of the eye. Previous research has shown that blue images captured by conventional SLO may reveal hyporeflective areas in the eye indicative of damage associated with DR. Researchers at TMDU sought to further evaluate this finding using widefield SLO.

In this retrospective study, the researchers compared blue widefield SLO images and fluorescein angiogram images taken in people with diabetes. The morphology of the retina was also evaluated in some individuals with DR.  

“We found that the hyporeflective areas in the blue widefield SLO images appeared to correspond with areas of ischemia in the fluorescein angiogram images of patients with DR,” explains Kyoko Ohno-Matsui, senior author. “We were pleased to find that the rate of concordance was high.” 

Further evaluation of patient images showed that ischemic areas (i.e., areas of reduced blood flow) appeared to correspond with parts of the retina that were thin and partially disorganized. 

“It’s possible that the blue wavelength of light can pass more easily through these thinned areas of the retina, which presents as hyporeflective areas in the SLO images,” says Horie.

This study confirms the utility of blue widefield SLO as a simple and non-invasive tool for the detection of DR-associated damage in the eye. This technique may serve as an important means of screening and monitoring disease progression in individuals with DR. 

A complication of diabetes that affects the eyes. It’s caused by damage to the blood vessels of the light-sensitive tissue at the back of the eye (retina).

The four stages of diabetic retinopathy include:

1. Mild Nonproliferative Retinopathy. This beginning stage is often where swelling begins in the retina’s blood vessels. …

2. Moderate Nonproliferative Retinopathy.

3. Severe Nonproliferative Retinopathy.

4. Proliferative Retinopathy. Early symptoms include floaters, blurriness, dark areas of vision and difficulty perceiving colours. Blindness can occur.

Ophthalmology Exam of Patient with Diabetes CREDIT Beetham Eye Institute/Joslin Diabetes Center

As they age, people with diabetes are more likely to develop Alzheimer’s disease and other cognitive disorders than are people without diabetes. Scientists at Joslin Diabetes Center now have shown that routine eye imaging can identify changes in the retina that may be associated with cognitive disorders in older people with type 1 diabetes.

These results may open up a relatively easy method for early detection of cognitive decline in this population, providing better ways to understand, diagnose and ultimately treat the decline, said George L. King, MD, Joslin’s Chief Scientific Officer and senior author on a paper about the study in the Journal of Clinical Endocrinology & Metabolism.

Previous research had demonstrated an association between proliferative diabetic retinopathy (PDR, a complication of diabetes that can severely damage eyesight) and cognitive impairment in people with type 1 diabetes. “Since we knew that there were cellular changes in the retina that might reflect changes in the brain, we were interested to see whether imaging techniques that visualize those changes in the retina might be reflective of changes in cognitive functions,” said Ward Fickweiler, MD, a Joslin postdoctoral fellow and first author on the paper.

The scientists drew on eye scans routinely gathered from patients as part of normal vision care at Joslin’s Beetham Eye Institute. One set of scans was based on optical coherence tomography (OCT, a technique employing light to provide cross-sections of the retina). A second set of scans employed OCT angiography (OCTA, an extension of OCT technology that examines blood vessels in the retina). Both types of scans are non-invasive and widely available in eye clinics in the United States, and can be performed within minutes.

The study enlisted 129 participants in the Joslin Medalist Study, which examines outcomes among people who have had type 1 diabetes for 50 years or longer. These volunteers took a series of cognitive tests that included tasks probing memory function as well as psychomotor speed (assessing the time it took to arrange objects by hand).

Strikingly, the researchers found very strong associations between performance on memory tasks and structural changes in deep blood vessel networks in the retina. “Memory is the main cognitive task that is affected in Alzheimer’s disease and cognitive decline, so that was exciting,” Fickweiler said.

The Joslin team also discovered strong associations between PDR and psychomotor speed. This finding reinforced earlier outcomes that had been identified among a smaller group of Joslin Medalists, and provided details about related changes in retinal structure. Additionally, the researchers saw that PDR was associated with memory performance among the larger group of Medalists.

While these results need to be confirmed in larger clinical investigations, the routine eye exams do seem to detect the cognitive changes happening in people with diabetes, said Fickweiler.

Currently, other ways to detect conditions such as Alzheimer’s disease such as MRI scans are difficult and expensive. People typically are tested only when they’re showing symptoms of cognitive decline and treatments at that stage generally don’t offer much help.

“If you can detect the condition at an earlier stage, when they’re still asymptomatic, that may benefit patients,” Fickweiler said. Earlier detection also could aid the quest to develop better therapies for neurocognitive diseases.

The Joslin team plans to launch a larger prospective study to confirm the potential of eye imaging to pick up signs of cognitive decline over time. This research will include people with type 1 diabetes who are younger and haven’t had the disease for as long as the Medalists. The scientists also will analyze MRI brain images and postmortem brain samples donated by Medalists.

Additionally, the investigators will look for common mechanisms that may inflict damage on brain and retina tissues, which share much of their early embryonic development pathways. Likely suspects in people with diabetes include impaired blood vessels and high or low levels of blood glucose. The autoimmunity that drives type 1 diabetes also might inflict other forms of harm, King said.

Notably, Joslin Medalists often display relatively low levels of the complications that can afflict those with long-term type 1 diabetes. For instance, almost half of Medalists don’t develop advanced eye disease, and only one of the 129 Medalists in the eye-scan study may have Alzheimer’s disease. “It is possible that in the Medalists, a shared mechanism alters the progression of the early stages of retinal and brain neurodegeneration, and provides protection against both PDR and Alzheimer’s disease,” Fickweiler speculated.

In addition to follow-up work in type 1 diabetes, King and his team plan to perform a similar study for people with type 2 diabetes. PDR also is associated with cognitive decline in this much larger group of patients, who also get OCT and OCTA eye scans as part of their regular vision care.