Lenticular and retinal glutathione metabolism and its role in the diabetic complications of the eye

This study has examined the key sequential changes in glutathione and intermediary metabolism of the diabetic rat lens. An in vivo streptozotocin-induced diabetic model and an in vitro hyperglycaemic incubation model have been used to evaluate the role glutathione maintenance plays in respect to oxidative processes and the ensuing pathological changes that occur in the diabetic lens and retina. In the in vivo model, the glutathione levels fall 3 days after the induction of diabetes, this is followed by a decrease in the NADPH and ATP. Manipulation of the in vivo model by treatment with verapamil, a calcium blocker, vanadate, which mimics insulin action and nicotinamide, a diabetogenic protective agent, have also been studied. The in vitro model, employing a 1 or 24 hour incubation, under normal and hyperglycaemic tissue culture conditions, showed similar changes to diabetes in lenticular glutathione levels and energy state. The effects of oxidative assault (hydrogen peroxide and altering oxygen tension) on these parameters was also studied. The results show that a depletion of glutathione is quickly followed by the fall in ATP and NADPH. These are important indicators of the development of cataracts. These results are discussed in relation to the competition between sorbitol formation and glutathione reduction, for NADPH. How pentose phosphate pathway activity and other metabolic routes of the lens are modulated by changes resulting from elevated glucose and depleted metabolites is discussed. In the in vivo lens, metabolism proceeds under anaerobic conditions, the metabolic profile in the air/CO2 and O2/CO2 incubations are quite different, indicating studies closer to the physiological condition, could provide information on the level of oxidative stress at which normal energy status can be sustained. A fall in glutathione appears to be one of the initial perturbations in cataract formation. Maintenance of the reduced sulphydryl environment is fundamental to lens clarity by maintaining an environment in which lens crystallins can provide the high refractive index necessary to focus light.