Biochemical evidence of glucose toxicity was found in the retinal and corneal layers of diabetic rabbits. It can be reasonably assumed that the observed changes are causally related to the morphological and physiological diabetic pathologies of the retinal and corneal cells. Intracellular glucose is greatly increased, and the polyol pathway activity appears to be enhanced, resulting in an accumulation of intracellular sorbitol, which can be assumed to be oxidized to fructose. Accompanying the alterations of glucose metabolism are disturbances in myoinositol and Na+ handling by the affected structures. The detailed relationship of the observed metabolic effects of hyperglycemia to changes in cellular ion handling and the observed morphological and functional disturbances has yet to be elucidated. The morphologically and functionally discrete populations of RPE and CEN cells, which are readily amenable to experimental manipulation in situ and in cell culture may serve as unique models for systematic examination of the causes and the consequences of diabetes leading to ocular complications in particular and to the complications of other more complex tissues such as nerve and kidney. The present data show that the findings in one population of cells may not be completely reproducible in another as can be seen in the diverse myoinositol responses of the retinal and corneal layers to diabetes mellitus. The diverse responses perhaps reflect unique adaptive capabilities of individual tissues to the diabetic condition. It is a challenge for complications research to fully appreciate diverse responses of various tissues to persistent glucose intoxication and to delineate meticulously the time courses of such heterogeneous responses, which might result in debilitating pathology in certain cases but in a compensated chronic disease state in others. The corneal endothelium and the RPE are relatively resilient structures compared with the mural and endothelial cells of the retinal microvessels which are destroyed by the diabetic condition. Factors and components that protect tissues against the persistent effects of hyperglycemia need to be uncovered. Success in such an endeavor could be of benefit in the management of diabetic complications.