Novel imaging technology reveals role of immune cells in early diabetic cataract development

Scientists have detected early signs of damage in the eye before the onset of type 2 diabetes, suggesting that diabetic complications may start during the pre-diabetic state.

This new research conducted by the Brigham and Women’s Hospital, Harvard Medical School and the Health Campus Göttingen contradicts previous notions about sugar’s role in the onset of diabetic cataracts.

Cataracts — the clouding of the lens of the eye — are the number one cause of blindness worldwide and are a common complication of type 2 diabetes.

The current hypothesis behind cataract development is coined “the sugar hypothesis” and suggests that high blood sugar — a hallmark of diabetes — precedes cataract development.

The working assumption underlying the sugar hypothesis describes that higher levels of glucose in the lenses of individuals with diabetes converts to a sugar alcohol molecule called sorbitol, which induces structural changes to the lens of the eye that precede cataract development.

While unproven, researchers rarely investigate this theory further due to cataracts’ treatable nature.

Lead author Dr Ali Hafezi-Moghadam said: “A theory can survive for a long time, if it is unchallenged.

“For over half a century, the sugar hypothesis provided an explanation for how the lens becomes opaque, when the blood sugar in an animal is experimentally raised but this does not have to be how things work in human cataracts.”

To unravel the origins of tissue damage in diabetes, Dr Hafezi-Moghadam’s team broke tradition with the existing models.

Instead, it conducted it’s studies in the Nile grass rat, a model that they originally reported spontaneously develops type 2 diabetes when kept in captivity and closely mimics the condition in humans.

Fellow author Dr Christoph Rußmann said: “The advanced imaging technology we used in this study helped us see for the first-time dot-like microlesions that would not have been visible otherwise. This is where advanced medical technology helps bring novel mechanistic insights.”

The newly found micro-lesions preceded all forms of diabetic cataract. But unexpectedly in nearly half of the animals, the micro-lesions appeared before the animals entered hyperglycemia, or high blood sugar.

Dr Ehsan Ranaei Pirmaradan said: “It became clear that there was more complexity than the sugar hypothesis was able to explain.

“We found immune cells in the vicinity of the lens and in the lens capsule. That drew our focus to a completely new direction.”

The researchers identified that immune cells migrated from specialised structures in the eye called the ciliary bodies toward the lens.

In these areas, where the immune cells traversed the capsule of the lens, they found that the epithelial cells that normally cover the inner surface of the lens capsule changed their identity and behaved differently.

These changes, also referred to as epithelial-mesenchymal transformation (EMT), were followed by seemingly unorganised cell growth, cell death, and cell migrations into the body of the lens.

In some regions, the newly transformed cells simply vacated their original positions and made their way into the lens.

Such cellular changes, however small in dimensions, significantly compromise the function of the lens.

Dr Rußmann said: “It was fortuitous that our imaging technology had just high enough resolution to see such microscopic lesions in the living organism. A future direction will be to turn this knowledge into early clinical diagnosis.”

Dr Hafezi-Moghadam noted: “Our study raises exciting new questions, which will preoccupy us in the foreseeable future. We need to understand why the immune cells and the lens epithelial cells behave the way they do before the blood glucose becomes higher than normal.

“This will bring us closer to understanding why diabetic complications may start during the pre-diabetic stage of the disease. We can start to search for how to prevent people with diabetes from developing cataracts and potentially other complications elsewhere in the body.”

Dr Hafezi-Moghadam added: “While cataracts today are easily removable with surgery, this procedure comes with the risk of complications. With over 500 million people worldwide having diabetes, there is an urgent need for trying to find non-surgical ways of preventing, slowing, or even reversing this complication.

“Perhaps one day it will become possible to avoid performing these surgeries altogether, and that requires that we return to the basics.”

To read the full study, click here.