16 Jun Brigham Study Finds Diabetic Damage in the Eye May Precede Onset of Diabetes
MedicalResearch.com Interview with:
Ali Hafezi–Moghadam, Ph.D., M.D
Director, Molecular Biomarkers Nano-Imaging Laboratory (MBNI)
Associate Professor of Radiology, Harvard Medical School
Brigham and Women’s Hospital
MedicalResearch.com: What is the background for this study?
Response: “It is very easy to answer many fundamental biological questions” said Richard Feynman in his 1959 address, where he also offered his simple and ingenious solution: “you just look at the thing!”.
As a biologist, I am familiar with the challenges surrounding looking at things in the context of life. There is no single device or technology that lets me simply see the answers to my questions. How does diabetes harm the tissues in the body? When exactly does the pathology start and which molecules and cells are involved? Trying to answer these questions, I have spent the past two decades innovating new ways of quantifying expression of molecules in the living organism .
At the same time to study diabetes, we needed a realistic rodent model that mirrors the human disease. In collaboration with KC Hayes, we first introduced the Nile grass rat (NGR, Arvicanthis niloticus), a gerbil that recapitulates the main features of the human type 2 diabetes . For visualization of early changes, the eye offers a unique site. Much of my lab’s work focused on the first effects of diabetes in the retina, the site of the neurons that perceive light in the back of the eye , , . In recent studies, we focused on how diabetes affects the lens in the eye of our animals , .
Diabetes is a major risk factor for cataract formation, a condition during which the lens loses its original transparency to visible light. How diabetic cataracts are formed is not well understood. A popular and prevailing theory, termed “sugar cataracts”, has been around for over half a century. According to the sugar hypothesis of cataracts, the excess levels of the sugar molecule, glucose, in the lens are transformed through the polyol pathway into the sugar-alcohol sorbitol. The resulting osmotic dysbalance leads to swelling of the fiber cells and opacity of the lens. Even though the sugar hypothesis has never been proven, it was generally accepted and remained unchallenged for a very long time. That is where our latest experimental results became relevant.
MedicalResearch.com: What are the main findings?
Response: When we longitudinally examined the lenses in our animals from initially pristine condition until full cataracts was formed, we discovered as the very first signs certain microscopic lesions that had not been described previously. These dot-like microlesions were in a characteristic ring formation and were only visible through a special imaging technique, called stereo microscopy with dual light illuminations . We found that these novel microlesions preceded all the other varieties of the diabetic cataracts known to occur in individuals with diabetes. But most curiously, we detected in about half of the animals these microlesions before the animal’s blood sugar was above normal. This finding is at odds with the theory of sugar cataracts, a requirement of which is high blood sugar. While we found that high blood sugar was not necessary for the microlesions to form, the animals were in the prediabetic state and had higher than normal insulin levels. The next question then arose, what triggers the formation of the microlesions.
In a newly developed in situ microscopy technique, we found a subtype of immune cells wandering from the structures surrounding the lens, the so called ciliary bodies, along the zonular fibers that hold the lens in place, toward the lens capsule. Some of these immune cells attached to the lens capsule and seemingly attempted to pass through it. In those areas we found that the epithelial cells that cover the inner surface of the frontal part of the lens capsule had changed their characteristics. Some epithelial cells died, while others underwent epithelial mesenchymal transformation. These cells proliferated, abandoned their original places, and started migrating into the lens tissue. Analogous to the cells arising from the ciliary bodies, we found immune cells migrating the retina towards the lens. These findings introduce the novel role of immune cells in the formation of diabetic cataracts during the early prediabetic state.
MedicalResearch.com: How might these findings influence clinical medicine?
Response: Our study shows that diabetic damage in the eye may precede the onset of diabetes, currently defined as abnormally high blood glucose. If our findings also apply to humans, it would mean that a staggering number of individuals in the pre-diabetic state are at risk of having incipient damages in their eyes.
To reveal that an individual is in the prediabetic state, clinical tests such as the oral glucose tolerance test (OGTT) or plasma insulin measurements are needed. These tests however are not routinely performed for screening purposes, so that most individuals in the prediabetic state remain unaware of their condition. The hyper-reflective dot-like microlesions in the lens can be non-invasively detected and quantitated. They are also mechanistically involved in the disease process. These characteristics make them an ideal biomarker for early diagnosis of the prediabetic state.
The mechanistic role of the immune cells in the cataract formation opens the door to development of new treatments and prevention. Our finding that immune cells can instigate lens epithelial cells to undergo a transformation that makes them proliferate and migrate like cancer cells, gives invaluable cues how to intervene in this critical juncture. While cataracts can be surgically treated, a significant number of the patients will endure post surgical complications. From the patient’s perspective, but also in respect to the health care costs, it would be a major gain if cataracts could be medically treated or even prevented.
MedicalResearch.com: What recommendations do you have for future research as a results of this study?
Response: A scientific theory, regardless of how logical it may appear, has to be continuously challenged with new experiments. When experimental data contradicts an established theory, as it did in our study, then chances are we are experiencing a discovery. The sugar hypothesis was accepted for over half a century. In part because there was paucity of realistic models of diabetic cataracts. As a result, most studies were performed in acutely-induced hyperglycemia, where glucose does indeed cause the cataracts. Only after we had established the new model of type 2 diabetes in an animal that first becomes insulin resistant before becoming diabetic, it was possible to observe the changes in the eye before the animal’s blood glucose became abnormal.
Another reason, why little attention has been devoted to the study of diabetic cataracts could lie in the commonly practiced cataract surgery. But just because there is a treatment for the problem of diabetic cataracts, one must not stop trying to understand its mechanistic origins. With the new insights from the current study, we are at the advent of a new theory of diabetic cataract formation. What we learn from looking at the lens in our animals may also teach us about diabetic complications in other organs. Right now diabetes is defined as abnormally high blood glucose. But if the diabetic complications precede the abnormally high blood glucose levels, a rethinking of what constitutes diabetes will be needed.
MedicalResearch.com: Is there anything else you would like to add? Any disclosures?
Response: This work was supported by NIH Impact Award (DK108238‐01, AHM), and JDRF Innovation award (INO‐2016‐222‐A‐N, AHM).
I am grateful for the contributions of Ehsan Ranaei Pirmardan, Yuanlin Zhang, Aliaa Barakat, Marzieh Naseri, and Christoph Russmann in this study. My colleague and friend KC Hayes dramatically influenced my thinking about diabetes, especially through his invitation to work with him on the Nile grass rat.
None of the authors of the study has a conflict of interest to declare.
Ranaei Pirmardan, E., Zhang, Y., Barakat, A. et al. Pre-hyperglycemia immune cell trafficking underlies subclinical diabetic cataractogenesis. J Biomed Sci 30, 6 (2023). https://doi.org/10.1186/s12929-023-00895-6
 Department of Biology, Brandeis University, Waltham, Massachusetts, USA
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