People with metabolic diseases such as diabetes type 1 or II who suffer periods of low blood sugar are more prone to develop diabetic eye damage. Researchers at Johns Hopkins Medicine have found that low blood sugar levels results in activation of a biochemical pathway in oxygen-starved retinal cells.
The research used entire retinas that were cultured in a low glucose environment, and low glucose levels. Low blood sugar is most common in people who use insulin or certain other diabetes medicines, including some patients diagnosed with type 2 diabetes, and how often it happens varies widely from person to person. Some episodes happen during sleep and may go unnoticed. The findings revealed that these intermittently low glucose levels help to promote an increase in specific retinal cell proteins, leading to an expansion of blood vessels and a deterioration of diabetic retinopathy.
What are Diabetic Eye Diseases?
Diabetic eye disease is a group of vision related disorders that affect people diagnosed with diabetes, and diabetic retinopathy is one of them. This group of conditions can include:
- Diabetic macular edema
- Cataracts
- Glaucoma
- Diabetic retinopathy
Over time, uncontrolled diabetes can result in damage to the eyes resulting in poor vision and eventually blindness. Diabetes-related eye diseases is are one of the most avoidable causes of blindness in the world and it is estimated that nearly 35% of people with diabetes develop complications such as diabetic retinopathy over time. This degenerative eye disease is characterized by the proliferation of aberrant blood vessels in the retina. Separately from this study, people with diabetes complications such as kidney disease (diabetic nephropathy) can be at higher risk of low blood sugar, and diabetic neuropathy may make its warning signs harder to notice, so avoiding both high and low glucose levels, with guidance from their diabetes care team, is an important part of diabetes management.
The researchers studied protein levels in human retinal cells and in whole retinas grown in the laboratory under low glucose conditions, designed to mimic the intermittent low blood sugar that some patients experience. Low glucose levels in retinal cells caused a cascade of molecular alterations that lead to blood vessel enlargement. The researchers observed that low glucose levels decreased the ability of retinal cells to convert glucose into energy. The expression of the GLUT1 gene, which produces a protein that transports glucose into cells, was shown to be enhanced in so-called Müller glial cells, which are cells that support the neurons of the retina and rely predominantly on glucose for energy production.
The research discovered that, in reaction to low glucose levels, the cells boosted their hypoxia-inducible factor (HIF)-1 levels which activated the Glucose transporter 1 proteins (GLUT1) that are required to utilize available glucose, conserving the minimal oxygen available for energy creation by retinal neurons. In low-oxygen situations, such as those found in the retinas of diabetic eye disease patients, this standard physiologic response to low glucose drove an influx of HIF-1 protein into the nucleus, the cell’s control center.
This led to an increase in the synthesis of proteins such as VEGF and ANGPTL4, which stimulate the formation of aberrant, leaky blood vessels which are the primary culprit of vision loss in persons with diabetic eye disease.
Stem Cell Treatment for Diabetic Eye Disease
The researchers also hope to investigate if low glucose levels in people with diabetes can influence comparable molecular pathways in other organs, including the kidney and brain. These findings on the Hypoxia-Inducible Factor (HIF)-1 regulatory pathway may help researchers develop new targeted drug treatments for patients with diabetic retinopathy.
