Clinical issue

More than 2.5 million people in the world are blind as a consequence of diabetic retinopathy (DR). One of the most common clinical complications of diabetes, DR results from abnormal changes in the vascularisation of the retina, coupled to neurodegeneration. Current therapies target the advanced proliferative stage of the disease, stunting the inappropriate growth of new blood vessels, after much damage has already been done; treatment is not curative and has serious side effects. A better, potentially curative, approach might be to target the earlier non-proliferative stage of DR, and to protect the endangered retinal neurons. However, the progression of DR in its early stages is not well understood, as human data typically originate from post-mortem tissue at advanced stages, and animal models have given conflicting results. Important issues include which retinal neurons are affected in DR, when neuronal damage occurs, and whether neuronal damage depends on vascular injury.

Results

This paper suggests that zebrafish can successfully model non-proliferative DR, using a protocol in which hyperglycaemia is induced by adding glucose to tank water every other day for a month. Retinas from zebrafish subjected to this oscillating hyperglycaemia display many of the pathophysiological aspects of human DR. Vascular changes include thickening of the basal membrane, disturbance of the retinal blood barrier, and dilation of retinal capillaries. Interestingly, hyperglycaemia also induces pronounced neurodegeneration of cone photoreceptors without drastic effects on other retinal cell types, whereas treatment with mannitol, which causes hyperosmolarity but not hyperglycaemia, induces vascular changes without cone photoreceptor damage.

Implications and future directions

In this zebrafish model, hyperglycaemia induces cone receptor dysfunction, and hence neuronal damage, at early stages in DR, independently of vascular defects, and before the proliferative stage of the disease. Future work needs to confirm whether cone photoreceptors are particularly susceptible to damage by hyperglycaemia in humans and other higher mammals. Such findings would revise DR treatment strategies to include neuroprotection of cone photoreceptors in addition to inhibiting vascular pathology.