Researchers Explore Why Episodes of Low Blood Sugar Worsen Eye Disease in People with Diabetes

Researchers at Johns Hopkins Medicine say they have linked low blood sugar levels in people with diabetes with a molecular pathway that is turned on in oxygen-starved cells in the eye.

The study, published in the January issue of Cell Reports, involved animals with low glucose levels, human and mouse eye cells, intact retinas, and low sugar (low glucose) environments created in the lab.

“Temporary episodes of low glucose happen once or twice a day in people with insulin-dependent diabetes and often among people newly diagnosed with the condition,” Akrit Sodhi, MD, PhD, the Branna and Irving Sisenwein Professor of Ophthalmology at the Wilmer Eye Institute at Johns Hopkins Medicine, said in a news release. 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, resulting in an overgrowth of blood vessels and worsening diabetic eye disease."

According to Dr. Sodhi, the new study implies that persons with diabetic retinopathy may be more susceptible to low glucose levels, and maintaining stable glucose levels should be a key component of glucose control.

The Study

The researchers measured the amounts of proteins in intact retinas and human and mouse retinal cells that had been cultured in a low-glucose environment in the lab as well as in mice that occasionally experienced low blood sugar.

The scientists discovered that low glucose levels in the retinal cells of mice and humans triggered a series of biochemical alterations that may result in blood vessel enlargement. First, the scientists found that low glucose reduced the capacity of retinal cells to metabolize glucose for energy.

Artistic rendition of an immunofluorescent image of a mouse retina taken during a transient episode of low serum glucose demonstrating accumulation of a protein, Hypoxia Inducible Factor (HIF)-1 alpha(red), in inner retinal cells. A recent study from Guo et al., published in Cell Reports provides insight into how accumulation of HIF-1 alpha in retinal cells during these transient episodes of low serum glucose (i.e., hypoglycemia) can promote the expression of the angiogenic mediators that worsen diabetic retinopathy. Credit: Alexander Sodhi, McDonogh School.

The GLUT1 gene, which produces a protein that transports glucose into cells, was discovered to be more expressed in the so-called Müller glial cells, which are support cells for neurons in the retina and predominantly rely on glucose for energy production.

The scientists discovered that cells boosted their amounts of a transcription factor called hypoxia-inducible factor (HIF)-1 in response to low glucose. This activated the cellular machinery, including GLUT1, required to enhance their capacity to utilize the glucose that was already available, preserving the minimal oxygen available for retinal neurons' energy production.

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

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

The purpose of this research is to determine whether low glucose levels in diabetics may have an effect on similar molecular pathways in other organs, such as the kidney and brain.

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