Diabetic retinopathy and glutamate

Protects retinal neurons in diabetic rats by inhibiting reactive oxygen species and blocking tyrosine nitration. Tyrosine nitration may inhibit glutamine synthetase (GS), causing glutamate accumulation and leading to further neuronal cell death. We propose to test the hypothesis that diabetes-induced glutamate accumulation in the retina is associated with tyrosine nitration of GS and that CBD treatment inhibits this process.


Diabetes reduces glutamate oxidation and glutamine synthesis in the retina. The Penn State Retina Research Group


Retinas of diabetic individuals develop early functional changes measurable by electrophysiological and psychometric testing. Using a rat model of diabetes, we previously identified diabetes-induced alterations in metabolism of the neurotransmitter glutamate which may ultimately lead to accumulation of glutamate in the retina (Diabetes, 47: 815, 1998). We therefore investigated the function of enzymes that mediate the synthesis and breakdown of glutamate in retinas from rats made diabetic by injection of streptozotocin. De novo synthesis of nitrogen-containing amino acids including glutamate, glutamine and aspartate was assessed by measuring the rate of carbon fixation in freshly dissected retinas, and was unchanged by diabetes. In contrast, the oxidation of glutamate was significantly reduced in retinas from diabetic rats (62%, P < 0.05). Furthermore, diabetic retinas were less susceptible to inhibition of glutamate oxidation by the transaminase inhibitor aminoxyacetate (80%, NS), compared to the significant decrease seen in control rats (61%, P < 0.001). The activity and content of glutamine synthetase were also significantly reduced in retinas from rats diabetic for 2-6 months [range of 48% (P < 0.005) to 83% (P < 0.05) compared to control]. The activity of glutamine synthetase was normalized by acute injections of insulin, but not by reducing blood sugar levels with injections of phlorizin. These results indicate two enzymatic abnormalities in the glutamate metabolism pathway in the retina during diabetes: transamination to alpha-ketoglutarate and amination to glutamine. The reduced flux through these pathways may be associated with the accumulation of glutamate. These results are also consistent with the possibility that some of the glial changes in the retina during diabetes may be caused by hypoinsulinemia rather than hyperglycemia.



Neurodegeneration: An early event of diabetic retinopathy.



Diabetic retinopathy (DR) has been classically considered to be a microcirculatory disease of the retina caused by the deleterious metabolic effects of hyperglycemia per se and the metabolic pathways triggered by hyperglycemia. However, retinal neurodegeneration is already present before any microcirculatory abnormalities can be detected in ophthalmoscopic examination. In other words, retinal neurodegeneration is an early event in the pathogenesis of DR which predates and participates in the microcirculatory abnormalities that occur in DR. Therefore, the study of the mechanisms that lead to neurodegeneration will be essential to identify new therapeutic targets in the early stages of DR. Elevated levels of glutamate and the overexpression of the renin- angiotensin-system play an essential role in the neurodegenerative process that occurs in diabetic retina. Among neuroprotective factors, pigment epithelial derived factor, somatostatin and erythropoietin seem to be the most relevant and these will be considered in this review. Nevertheless, it should be noted that the balance between neurotoxic and neuroprotective factors rather than levels of neurotoxic factors alone will determine the presence or absence of retinal neurodegeneration in the diabetic eye. New strategies, based on either the delivery of neuroprotective agents or the blockade of neurotoxic factors, are currently being tested in experimental models and in clinical pilot studies. Whether these novel therapies will eventually supplement or prevent the need for laser photocoagulation or vitrectomy awaits the results of additional clinical research.



Diabetes-induced dysfunction of the glutamate transporter in retinal Müller cells.




A decrease in the ability of Müller cells to remove glutamate from the extracellular space may play a critical role in the disruption of glutamate homeostasis that occurs in the diabetic retina. Because this amino acid is toxic to retinal neurons and is likely to exacerbate oxidative stress, elucidation of the mechanisms by which glutamate levels are elevated in diabetes may help in the understanding of the pathogenesis of diabetic retinopathy. This study tested the hypothesis that the function of the glutamate transporter in Müller cells of the diabetic retina is compromised by a mechanism involving oxidation.


Müller cells were freshly isolated from normal rats and those made diabetic by streptozotocin injection. The activity of the Müller cell glutamate transporter, which is electrogenic, was monitored by the perforated-patch configuration of the patch-clamp technique.


Four weeks after the onset of hyperglycemia, a significant dysfunction of the Müller cell glutamate transporter was detected. After 13 weeks of streptozotocin-induced diabetes, the activity of this transporter was decreased by 67%. Consistent with oxidation’s causing this dysfunction, exposure to a disulfide-reducing agent rapidly restored the activity of the glutamate transporter in Müller cells of diabetic retinas.


Early in the course of diabetic retinopathy, the function of the glutamate transporter in Müller cells is decreased by a mechanism that is likely to involve oxidation.




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