Research challenges the “sugar hypothesis” of the day

image: Immune cell traffic in diabetic cataract formation. (A) New in situ visualization technique for studies of immune cell trafficking in the eye. (B) Immune cell passing through the epithelial cells of the ciliary body. (C) Microstructural lesions in the early stages of diabetic cataract formation.
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Credit: Images provided by Hafezi-Moghadam et al.

New discoveries from researchers at Brigham and Womens Hospital, a founding member of the General Brigham Mass Health System, contradict previous notions about the role of sugar in the onset of diabetic cataracts. Using an animal model that more closely recapitulates type 2 diabetes in humans, the research team found early signs of eye damage before the onset of type 2 diabetes, suggesting that diabetic complications may begin during the pre-diabetic state. The results are published in Journal of Biomedical Sciences.

A pitfall in the scientific process is not that a theory can be false, but that it is taken for granted when it seems logical and not challenged with new experiments,” he said. Ali Hafezi-Moghadam, MD, PhDdirector of Molecular Biomarkers Nanoimaging Laboratory (MBNI) in Department of Radiology at Brigham and an associate professor at Harvard Medical School. “The evidence we’ve collected here calls into question the long-held theory about diabetic cataracts, begging us to re-examine the current dogma that has been used to explain diabetes-associated cataracts.”

Cataracts – the clouding of the lens of the eye – is the number one cause of blindness worldwide and is a common complication of type 2 diabetes. The current hypothesis behind the development of diabetic cataracts is called the “sugar hypothesis” and suggests that high blood sugar – a hallmark of diabetes – precedes the development of cataracts. The working assumptions underlying the sugar hypothesis describe higher levels of glucose in the lenses of people with diabetes converted into a sugar alcohol molecule called sorbitol, which induces structural changes in the lens of the eye that precede the development of cataracts. While unproven, researchers rarely investigate this theory due to the treatable nature of cataracts.

Hafezi-Moghadam and his colleagues studied the Nile grass rat, a model they originally reported that spontaneously develops type 2 diabetes when kept in captivity and closely mimics the condition in humans. Like humans with type 2 diabetes, these animals first develop insulin resistance and high blood insulin levels before their blood glucose rises above normal. Using a specialized technique called bright-field dual-illuminated stereoscopic microscopy, researchers observed the development of dot-like microlesions, which predispose to cataract formation, in the inner cortical regions of the lens. Unexpectedly, they noticed that in nearly half of the animals tested, these microlesions appeared before the animals developed hyperglycemia, or high blood sugar, suggesting that it was not the high blood glucose levels that led to the development of cataracts.

Instead, the researchers identified that immune cells were migrating from specialized structures in the eye called ciliary bodies towards the lens. In these areas, where immune cells break through the lens capsule, they found that the epithelial cells that normally cover the inner surface of the lens capsule changed identity and behaved differently. These changes, also known as epithelial-mesenchymal transformation (EMT), were followed by apparently disorganized cell growth, cell death, and cell migrations into the lens body. In some regions, the newly transformed cells simply left their original positions and entered the lens. Such cellular changes, although small in size, significantly compromise lens function.

While it’s still too early to say what exactly causes immune cells and epithelial cells to behave the way they do, the researchers conclude that their study requires further investigation of prevailing theories. It may also bring the medical community closer to understanding the cellular mechanisms underlying the origins of diabetic complications during the pre-diabetic stage of the disease. And once we understand the pathogenesis, predicts Hafezi-Moghadam, we can start looking at how to prevent people with diabetes from developing cataracts and potentially other complications elsewhere in the body.

“While cataracts are now easily removable with surgery, this procedure carries risks of complications and is expensive, both for individuals and our healthcare system,” said Hafezi-Moghadam. “With over 500 million people worldwide and 37 million Americans with diabetes, the vast majority of whom have Type 2, there is an incentive to try to find non-surgical ways to prevent, delay or even reverse this complication. Perhaps one day it will be possible to completely avoid performing these surgeries. And that requires us to get back to the fundamentals of the cellular processes that underlie the development of cataracts.”
Financing: This work was supported by the NIH Impact Award (DK108238-01, AHM) and JDRF

Innovation Award (INO-2016-222-AN, AHM).

Cited document: Hafezi-Moghadam and others “Prehyperglycemic immune cell trafficking is the basis of subclinical diabetic cataratogenesis.” Journal of Biomedical Sciences DOI: 10.1186/s12929-023-00895-6

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Research challenges the “sugar hypothesis” of the day

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