*6.2. Diabetic Retinopathy*

Studies have demonstrated a correlation between serine deficiency and systemic diabetes [77]. Inflammation potentially increases the expression and activity of SRR, and consequently increases the availability of D-serine for receptor binding [40]. The elevated levels of D-serine contribute to glutamate toxicity and induce RGC apoptosis [40]. More precisely, as more D-serine binds to NMDARs, an excitotoxic response is induced [40]. As part of glutamate signal propagation in the retina, NMDAR excitation may be involved in decreasing neurotransmitter sensitivity [40]. Nevertheless, when D-serine levels are substantially elevated, the NMDAR-mediated excitation has a toxic e ffect in the retinal environment and induces cell death in RGCs [40]. In SRR null models with streptozocin (STZ) induced DR, degeneration of RGCs appeared attenuated, there was a reduction in neovascularization and the retina appeared significantly healthier than the control [40]. Most interestingly, multiple studies have found that if diabetic patients are treated with a serine supplement, blood glucose levels were reduced [77,82]. Currently, no mechanism is known to explain how this happens. But it is known that upon onset of diabetes, similar to serine deficiency, toxic sphingolipid accumulation starts occurring [83]. In fact, deoxysphingolipids have been shown to be potent biomarkers for diabetes mellitus [84]. As in IRD, DR results in similar toxic build-up of these aberrant sphingolipids, but this occurs far before any retinopathic complications start to develop [25]. These ceramides can actually be used as an early indicator of disease. It appears as if serine deprivation and toxic ceramide accumulation occur concomitantly. Perhaps, as the retina relies most heavily on serine, any deficiencies may cause the tissue to exhibit the first signs of disease in DR.
