Why episodes of low blood sugar worsen eye disease in people with diabetes

Overview: People with diabetes who experience low blood sugar are more likely to have worsening diabetic retinopathy.

Source: Johns Hopkins Drug

People with diabetes who experience periods of low blood sugar — a common occurrence in those new to blood sugar control — are more likely to have worsening diabetic eye disease.

Now researchers at Johns Hopkins Medicine say they have linked such low blood sugar levels to a molecular pathway that is turned on in deoxygenated cells in the eye.

The study, which involved human and mouse eye cells and intact retinas cultured in a low-sugar (low-glucose) laboratory, as well as low-glucose mice, was published in the January issue of Cell reports.

“Transient episodes of low glucose occur once or twice a day in people with insulin-dependent diabetes and often in people recently diagnosed with the condition,” says Akrit Sodhi, MD, Ph.D., the Branna and Irving Sisenwein Professor of Ophthalmology at the Wilmer Eye Institute of Johns Hopkins Medicine.

Low glucose levels can also occur during sleep in people with non-insulin dependent diabetes. “Our results show that these intermittent low glucose levels cause an increase in certain retinal cell proteins, resulting in overgrowth of blood vessels and exacerbation of diabetic eye disease,” Sodhi added.

Eye disease in people with diabetes is one of the most preventable causes of blindness in the U.S. Diabetic retinopathy, which affects up to a third of people with diabetes, is characterized by the overgrowth of abnormal blood vessels in the retina.

Sodhi says the current study suggests that people with diabetic retinopathy may be particularly vulnerable to periods of low glucose, and keeping glucose levels stable should be an important part of glucose regulation.

For the study, the researchers analyzed protein levels in human and mouse retinal cells and intact retinas grown in the lab in a low-glucose environment, as well as in mice that experienced intermittent low blood sugar.

The researchers found that low glucose levels in human and mouse retinal cells triggered a cascade of molecular changes that can lead to blood vessel overgrowth. First, the researchers saw that low glucose caused a decrease in the ability of retinal cells to break down glucose for energy.

When the researchers looked specifically at so-called Müller glial cells, which are support cells for neurons in the retina and rely primarily on glucose for energy production, they found that the cells increased the expression of the GLUT1 gene, which makes a protein that transports glucose in cells.

This shows an eye
Low glucose levels can also occur during sleep in people with non-insulin dependent diabetes. The image is in the public domain

The researchers found that, in response to low glucose, the cells increased levels of a transcription factor called hypoxia-inducible factor (HIF)-1α. This turned on the cellular machinery, including GLUT1, needed to enhance their ability to use available glucose, thus preserving the limited oxygen available for energy production by retinal neurons.

However, in low-oxygen environments, such as occurs in the retinas of patients with diabetic eye disease, this normal, physiological response to low glucose triggered a rush of HIF-1α protein into the nucleus, the cell’s control center.

This resulted in an increase in the production of proteins such as VEGF and ANGPTL4, which trigger the growth of abnormal, leaky blood vessels – the main culprit of vision loss in people with diabetic eye disease.

The researchers plan to investigate whether low glucose levels in people with diabetes can affect similar molecular pathways in other organs, such as the kidneys and brain.

Sodhi says the HIF-1α pathway could be an effective target for developing new treatments for diabetic eye disease.

About this news about diabetes and visual neuroscience research

Writer: Press Office
Source: Johns Hopkins Drug
Contact: Press Service – Johns Hopkins Medicine
Image: The image is in the public domain

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Original research: Open access.
“HIF-1α accumulation in response to transient hypoglycemia may exacerbate diabetic eye disease” by Chuanyu Guo et al. Cell reports


HIF-1α accumulation in response to transient hypoglycemia may exacerbate diabetic eye disease


  • Diabetic patients experience short periods of low glucose (hypoglycemia) every day.
  • In retinal glial cells, hypoglycemia promotes HIF-dependent expression of GLUT1
  • Hypoglycemia increases the expression of HIF-dependent angiogenic mediators
  • This physiological response causes a paradoxical exacerbation of diabetic retinopathy


Tight glycemic control (TGC), the cornerstone of diabetes management, reduces the incidence and progression of diabetic microvascular disease. However, TGC can also lead to transient episodes of hypoglycaemia, which have been associated with adverse outcomes in patients with diabetes.

Here we show that low glucose levels result in hypoxia-inducible factor (HIF)-1-dependent expression of the glucose transporter, Glut1, in retinal cells.

Enhanced nuclear accumulation of HIF-1α was independent of its canonical post-translational stabilization, relying instead on stimulation of its translation and nuclear localization. In the presence of hypoxia, this physiological response to low glucose resulted in a marked increase in the secretion of the HIF-dependent vasoactive mediators that promote diabetic retinopathy.

Our results provide a molecular explanation for how early glucose regulation, as well as glycemic variability (i.e., oscillating serum glucose levels), contribute to diabetic eye disease. These observations have important implications for optimizing glucose management in patients with diabetes.

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