The influence of diabetes on glutamate metabolism in retinas.

P>Excised retinas from euglycemic and diabetic Sprague-Dawley rats were studied to evaluate differences in glutamate metabolism related to diabetes. Reports suggest, neuronal cell death possibly caused by glutamate excitotoxicity, is an early consequence of diabetes. To monitor the influence of diabetes on glutamate metabolism, we measured glutamatergic neurotransmission, anaplerotic glutamate synthesis from 14CO(2) and pyruvate as well as rates of glutamate cataplerosis ([U-14C]glutamate to 14CO(2) and 14C-pyruvate). The data suggest the presence of a glutamate buffering anaplerotic/cataplerotic metabolic cycle in controls which is uncoupled by diabetes. For cycle operation, anaplerosis is initiated by a small pyruvate pool which is also the product of cataplerosis. In the cataplerotic pathway, glutamate conversion to alpha-ketoglutarate and then to CO2 and pyruvate is reduced by 90% in diabetic retinal Muller cells because glutamate transamination by branched chain aminotransferase is competitively inhibited by branched chain amino acids (BCAAs). BCAAs, but not the ketoacids, were almost twice as high in diabetic compared to euglycemic rat retinas. The data suggest the hypothesis that glutamate levels in retinal Muller cells from diabetic rats are elevated because of the presence of excess BCAAs, and that elevated glutamate in Muller cells causes glutamate excitotoxicity.