Why low blood sugar episodes make eye disease worse in people with diabetes

Summary: People with diabetes who experience hypoglycemia are more likely to have worsening diabetic retinopathy.

Source: Johns Hopkins Medicine

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

Now researchers at Johns Hopkins Medicine claim to have linked these low blood sugar levels to a molecular pathway that is activated in oxygen-deprived eye cells.

The research, involving human and mouse eye cells and intact retinas grown in a low-sugar (low-glucose) environment in the laboratory, as well as low-glucose mice, was published in the issue of January of Cell reports.

«Temporary episodes of hypoglycemia occur once or twice a day in people with insulin-dependent diabetes and often in newly diagnosed people,» says Akrit Sodhi, MD, Ph.D., Branna Professor of Ophthalmology and Irving Sisenwein at the Wilmer Eye Institute at Johns Hopkins Medicine.

Low glucose levels can also occur during sleep in people with non-insulin dependent diabetes. «Our results show that these periodic low glucose levels cause an increase in certain retinal cell proteins, leading to proliferation of blood vessels and worsening of diabetic eye disease,» adds Sodhi.

Eye disease in people with diabetes is among the most preventable causes of blindness in the United States. Diabetic retinopathy, which affects up to a third of people with diabetes, is characterized by the proliferation 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 maintaining stable glucose levels should be an important part of blood sugar control.

For the study, the researchers analyzed protein levels in human and mouse retinal cells and intact retinas cultured in a low-glucose environment in the laboratory, as well as in mice that occasionally exhibited hypoglycemia.

The researchers found that low levels of glucose in human and mouse retinal cells cause a cascade of molecular changes that can lead to blood vessel proliferation. First, the researchers found that low glucose led to a decrease in the ability of retinal cells to break down glucose into energy.

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

It shows an eye
Low glucose levels can also occur during sleep in people with non-insulin dependent diabetes. Image is in public domain

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

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

This led to an increase in the production of proteins such as VEGF and ANGPTL4, which cause the growth of abnormal and leaky blood vessels, the main culprits of vision loss in people with diabetic eye disease.

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

Sodhi says the HIF-1α pathway can serve as an effective target for developing new treatments for diabetic eye disease.

About this diabetes research and visual neuroscience news

Author: Press office
Source: Johns Hopkins Medicine
Contact: Press Office – Johns Hopkins Medicine
Picture: Image is in public domain

See also

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Original research: Free access.
«HIF-1α accumulation in response to transient hypoglycemia may worsen diabetic eye disease» by Chuanyu Guo et al. Cell reports


Accumulation of HIF-1α in response to transient hypoglycemia may worsen diabetic eye disease

Strong points

  • Diabetic patients experience brief episodes 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 worsening 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 cause transient episodes of hypoglycaemia, which have been associated with adverse effects in diabetic patients.

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

The increased nuclear accumulation of HIF-1α was independent of its canonical post-translational stabilization, but rather dependent on the 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 HIF-dependent vasoactive mediators that promote diabetic retinopathy.

Our results provide a molecular explanation of how early glycemic control, together with glycemic variability (i.e., swing in serum glucose levels), contributes to diabetic eye disease. These observations have important implications for optimizing glucose management in diabetic patients.

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