At present we do not know whether the increase in circulating Edn2 protein in mature Akimba mice is solely the result of a more severe retinal phenotype, whether it is due to the combination of RNV and long-term hyperglycaemia, or whether in fact DN also contributed to the elevation of serum Edn2 protein Future studies on animal models will be required to clarify these questions and to determine whether Edn2 might be part an early warning system to identify patients at risk of progressing from background DR to PDR. This evidence concerns the gene EDN2 and Hyperglycemia.