Overview
Diabetic retinopathy is a major complication of diabetes. It affects the blood supply to light-sensitive layer at the back of the eye (the retina). High blood sugar damages the blood vessels over time and can eventually cause sight loss or blindness.
Diabetes also causes complications in the heart, kidneys and nerves. Past research has shown that these organs develop an excess build-up of a toxic form of the metal copper. But the research team has found that a drug called trientine can remove excess copper and can slow down, or even reverse, complications from diabetes. Trientine is already used to treat Wilson’s disease.
So in this study the team is finding out whether there is excess copper in the retina and its blood supply in diabetes, whether it is important in diabetic retinopathy and what effect treatment with trientine has on the condition’s progress.
They are working with diabetic rats and with eye-tissue from human donors for now. But if trientine works, this study will pave the way for future clinical trials with a drug that has already proved safe enough to use in another condition. There have also been Phase I and Phase II clinical trials of the drug in people with diabetes and it has had some success in treating diabetic heart complications.
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Scientific summary
Does copper(II) overload contribute to the pathology of diabetic retinopathy?
There is clear evidence for an excess of copper(II) in diabetic tissues. This excess copper(II) is thought to be loosely bound to the extracellular matrix in diabetic tissues through interactions with advanced glycation end products (AGEs). The loosely bound copper(II) is redox active resulting in oxidative stress and tissue damage. Furthermore, it drives the production of more AGE and alters intracellular copper homeostasis.The copper(II) specific chelator trientine (which is used to treat Wilson’s disease) can remove the excess copper(II) from diabetic tissues including the heart, kidney and nerves resulting in decreased oxidative stress, normalisation of biochemical pathways implicated in diabetic complications, prevention of progression of complications and even, in some instances, reversal of complications. Here the team is investigating whether there is also excess copper(II) in the retinal vasculature and neuroretina leading to perturbed biochemistry and tissue damage, and whether this can be prevented with trientine treatment.
The levels of loosely bound copper(II) and AGE in isolated retinal vasculature and whole retina from diabetic rats and human post-mortem eye tissue are being measured using mass spectrometry. The streptozoticin rat model of diabetes is being used to determine whether trientine treatment can prevent damage to the retinal vasculature and neuroretina. The readouts for these studies are leakage from the retinal vasculature and the formation of acellular capillaries, along with biochemical markers of diabetes mediated damage. This work could pave the way for clinical trials of trientine for diabetic retinopathy.