Summary: People with diabetes suffer from diabetic retinopathy when their blood sugar levels are low.

Source: Johns Hopkins Medicine

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

Now researchers at Johns Hopkins Medicine have linked such low blood sugar levels to a molecular pathway that opens up in oxygen-starved cells in the eye.

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, is published in the January issue of Cell reports.

“Intermittent low glucose levels occur once or twice a day in people with insulin-dependent diabetes and more often in people newly diagnosed with the condition,” said Akrit Sodhi, MD, PhD, the Brana and Irving Seisenwein Professor of Ophthalmology at Johns Hopkins Medicine and Wilmer Eye. Institute.

In people who are not dependent on insulin, low glucose levels can occur during sleep. “Our results show that these chronically low glucose levels increase certain retinal cell proteins, which cause blood vessels to dilate and worsen diabetic eye disease,” Sodi added.

In the US, eye disease is one of the most preventable causes of blindness for people with diabetes. Diabetic retinopathy, which occurs in up to a third of people with diabetes, is characterized by the growth of abnormal blood vessels in the retina.

SODIE Current research suggests that people with diabetic retinopathy may be particularly vulnerable to periods of low glucose levels, and keeping glucose levels stable should be an important part of glucose control.

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

Low glucose levels in human and rat retinal cells caused molecular changes that caused blood vessels to overgrow, the researchers said. First, the researchers found that the low glucose levels caused a decrease in the retinal cells’ ability to use glucose for energy.

When the researchers looked at Müller glial cells, which are supporting cells for neurons in the retina and rely primarily on glucose for energy production, they found that the cells had increased expression of the GLUT1 gene. Glucose into the cells.

The researchers found that in response to low glucose, cells increased the amount of a transcription factor called hypoxia-inducible factor (HIF)-1α. This turned on cellular machinery—including GLUT1—that was supposed to improve their ability to use available glucose.

However, in low-oxygen environments, as occurs in the retinas of diabetic patients, this normal and physiological response to low glucose levels causes the HIF-1α protein to flood into the nucleus, the cell’s control center.

This in turn increases the production of proteins such as VEGF and ANGPTL4, which lead to the formation of abnormal and smaller blood vessels – a major cause of vision loss in people with diabetes.

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

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

So diabetes and visual neuroscience research news

Author: Press office
Source: Johns Hopkins Medicine
Contact: Press Office – Johns Hopkins Medicine
Image: The image is in the public domain.

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Preliminary study: Open Access.
“Accumulation of HIF-1α in response to transient hypoglycemia may exacerbate diabetic eye disease.“In Chuanyu Guo et al. Cell reports

Draft

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

Highlights

• Diabetic patients experience short periods of low glucose (hypoglycemia) every day
• Hypoglycemia stimulates HIF-dependent expression of GLUT1 in retinal glial cells.
• Hypoglycemia increases the expression of HIF-dependent angiogenic mediators
• This physiological response is paradoxically exacerbated by diabetic retinopathy

Summary

Tight glycemic control (TGC), the cornerstone of diabetes management, reduces the incidence and progression of diabetes mellitus. However, TGC can lead to transient hypoglycemia, which is associated with adverse effects in patients with diabetes.

Here, we show that low glucose induces hypoxia-inducible factor (HIF)-1-dependent glucose transporter, Glut1, in retinal cells.

The enhanced nuclear accumulation of HIF-1α is independent of its canonical post-translational stabilization but instead depends on its localization and induction of nuclear localization. In the presence of hypoxia, this physiological response to low glucose induced the development of diabetic retinopathy in HIF-dependent vasoactive mediators.

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