Impact of Glucose Fluctuations on DR Progression

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Why is tight glycemic control—the cornerstone of diabetic manage­ment—sometimes linked to worsening of diabetic retinopathy (DR)? A multicenter team of researchers set out to investigate this question in a murine study. Their findings linked low blood sugar levels with a molecular pathway that is turned on in oxygen-starved retinal cells.¹

Tight glycemic control can involve transient episodes of hypoglycemia, noted Akrit Sodhi, MD, PhD, at Wilmer Eye Institute in Baltimore. And these fluctuating glucose levels “cause an increase in certain retinal cell proteins, which can contribute to the develop­ment of abnormal blood vessels and worsening diabetic eye disease,” he said. Given the findings, he said, “We believe this study has important implications for optimizing glucose management in patients with diabetes.” It also could have implications for diabetic nephrop­athy and diabetic neuropathy.

“Importantly, this study does not undermine the importance of tight glu­cose control,” Dr. Sodhi added. “But it suggests that transient episodes of low glucose can, by themselves, exacerbate diabetic retinopathy.”

MICROVASCULAR INJURY. Artistic rendition of a fluorescein angiographic image demonstrating abnormal, leaky retinal blood vessels in a patient with DR. Tight glycemic control, as well as fluctuating serum glucose levels, appear to exacerbate DR.

Observing a cascade of events. The researchers analyzed protein levels in human and mouse retinal cells and intact mouse retinas cultured in low glucose. They also evaluated mice that had transient hypoglycemia.

They found that in response to low glucose, the retinal cells increased the levels of nuclear hypoxia-induc­ible factor (HIF)-1α. (HIF-1 plays an essential role in the cellular response to low oxygen.) This increase in HIF-1α _activated the cellular machinery—in­cluding glucose transporter Glut1 as well as key glycolytic enzymes in retinal Müller glial cells—needed to improve the cells’ ability to use available glucose. These responses preserve the limited oxygen available for energy production by retinal neurons.

In the presence of hypoxia, as can occur in patients with DR, this physio­logic protective response in Müller cells to low glucose resulted in a synergistic increase in the levels of nuclear HIF-1α _and the production of vasoactive me­diators such as VEGF and ANGPTL4, which promote the growth of abnor­mal, leaky blood vessels.

Target for new therapeutic treat­ments. Dr. Sodhi said that several potential therapeutic interventions may help prevent the pathologic consequenc­es of HIF-1α _accumulation in response to hypoglycemia. Currently, his lab is investigating signaling pathways that link hypoglycemia to the accumulation of HIF-1α. These pathways could be vulnerable targets for patients newly di­agnosed with diabetes, and for patients with diabetes and high glycemic vari­ability. His lab is also trying to develop therapies that directly target HIF-1α.

Dr. Sodhi cited several other poten­tial therapeutic interventions, including preventing episodes of hypoglycemia and directly targeting the HIF-1–regulated gene products that pro­mote DR. In the meantime, he said, “Ophthalmologists should encourage patients to discuss with their endocri­nologist strategies to minimize episodes of hypoglycemia.”

—Miriam Karmel

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1 Guo C et al. Cell Reports. 2023;42(1):111976.

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Relevant financial disclosures: Dr. Sodhi—HIF Therapeutics: PS; NIH: S; Research to Prevent Blindness: S; TEDCO: S.

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