What do age-related macular degeneration (AMD) and diabetic retinopathy have in common, other than they are both eye diseases? Glucose metabolism may contribute to the development of both conditions. Research projects at the National Eye Institute (NEI), part of the National Institutes of Health (NIH), and Wilmer Eye Institute, at Johns Hopkins Medicine are studying how glucose metabolism plays a part in these diseases.
Researchers at the NEI discovered that the way glucose is metabolized in the retina controls which genes get turned on and off in the light-sensing photoreceptors. Retinal photoreceptors need glucose, both for energy and structural maintenance. In this study, researcher focused on lactate, a byproduct of glucose metabolism, because it chemically tags DNA-packing proteins, known as histones in the photoreceptor cells. A specific tag, called H3K18 lactylation (H3K18La), rises and falls in response to the amount of glucose the retina is metabolizing. This gave researchers a readout of the retina’s metabolic state and the expression of vision-related genes
They studied the retinas of mice at different stages of development, measured the process that converts glucose to lactate, and mapped the locations of the H3K18La tags across the entire genome. By doing this, scientists confirmed the relationship between H3K18La tags and gene expression by growing mouse retinas in petri dishes. The retinas were exposed to either extra glucose or a drug that blocks glycolysis, and researchers measured how both the tags and gene expression reacted.
The results showed that more glucose led to more lactate, more H3K18La tagging, and increased expression of genes critical for vision. Blocking glycolysis showed the opposite effect. Namely, it stripped away the tags and suppressed gene expression. Scientists also found that H3K18La tags gather at the control switches of genes next to another activating mark, H3K27Ac, and that these tagged areas are recognized by a specific group of regulatory proteins. This suggests that H3K18La is part of a precise regulatory system, rather than a general metabolic side effect.
This suggests that metabolic disruptions associated with aging and disease may undermine the gene expression necessary to keep photoreceptors healthy. This research could lead to new ways to treat retinal diseases, like AMD.
What about when blood sugar is too low. How does hypoglycemia (low blood sugar) affect eye disease and what can be done about it?
Scientists at Johns Hopkins’ Wilmer Eye Institute found that hypoglycemia, may lead to the breakdown of the blood-retinal barrier. This important barrier regulates the flow of nutrients, waste, and water, in and out of the retina.
They studied diabetic mice in order to learn about the origins of diabetic retinopathy. Their research showed that a specific protein known as hypoxia-inducible factor (HIF) builds up in certain retinal cells during periods of low blood sugar. HIF has been linked to diabetic retinopathy and other eye diseases. It triggers a chain reaction by increasing the production of other proteins, leading to abnormal blood vessel growth and leakage in the retina.
Researchers wanted to better understand HIF’s role during hypoglycemia. They induced periods of low blood sugar in mice with and without diabetes. This experiment demonstrated that mice with diabetes had higher levels of HIF during hypoglycemia, which lead to the breakdown of blood-retinal barrier and leakage in retinal blood vessels. Mice without diabetes didn’t show higher levels of HIF.
Scientists also looked at an experimental drug, known as 32-134D, which inhibits the HIF protein. Some of the diabetic mice received 32-134D before an induced episode of hypoglycemia. Researchers found that treated mice had lower HIF levels, preventing the production of proteins that led to the breakdown of the blood-retinal barrier and reducing blood vessel leakage.
This study helps explain why diabetics who have a tight control on their glucose, as well as those who have fluctuating glucose levels, can develop severe diabetic eye disease. The findings suggest that therapies targeting HIF may provide an effective way to prevent or treat diabetic retinopathy.
These studies demonstrate that glucose is both good and bad when it comes to vision. Work at NIE showed that maintaining appropriate glucose levels helps photoreceptors function properly. Work at Johns Hopkins showed that hypoglycemia can lead breakdown of the blood-retinal barrier. Findings from both studies may lead to treatments that improve outcome for people with diabetic eye disease.
Of course, it never hurts to eat less sugar.