ELEVATED GLUCOSE-LEVELS INCREASE RETINAL GLYCOLYSIS AND SORBITOL PATHWAY METABOLISM - IMPLICATIONS FOR DIABETIC-RETINOPATHY

Purpose. To assess effects of elevated glucose levels on retinal glyco lysis and sorbitol pathway metabolism. Methods. Freshly isolated retin as from normal male Sprague-Dawley rats were incubated for 2 hours at 37 degrees C, pH 7.45, in Krebs bicarbonate-Hepes buffer containing 5, 10, 20, or 30 mM glucose. Glycolytic metabolites, sorbitol, and fruct ose were measured in extracts of retina and medium. Results. Elevated glucose levels increased retinal levels of sorbitol and triose phospha tes, decreased sn-glycerol-3-phosphate levels, increased lactate and f ructose production, and increased the retinal lactate-pyruvate ratio ( indicative of an increased cytosolic ratio of free NADH-NAD(+) like th at induced by hypoxia). An inhibitor of aldose reductase (AL 4114) nor malized sorbitol, fructose, triose phosphates, and the lactate-pyruvat e ratio without affecting lactate production or sn-glycerol 3-phosphat e levels. Conclusions. Elevation of retinal glucose levels causes a hy poxia-like redox imbalance ''pseudohypoxia'' that results from increas ed oxidation of sorbitol to fructose in the second step of the sorbito l pathway. This redox imbalance provides a plausible explanation for i mpaired regulation of retinal blood flow (in the absence of vascular s tructural changes) in humans with diabetes and in nondiabetic acutely hyperglycemic animals. These findings, together with other observation s, suggest that this redox imbalance precedes, and may contribute to, hypoxic and ischemic retinopathy associated with diabetes.