Diabetes is a major contributing factor in
cataract development. In animal models where
cataracts develop within days or weeks of diabetes it is well established that osmotic stress from the accumulation of
sorbitol leads to
cataract development. This mechanism might explain the rare cases of acute
cataract sometimes found in patients with uncontrolled sustained
hyperglycemia but cannot account for the vast majority of
cataracts that developed after years of diabetes. Thus, a model that can simulate diabetic slow-developing
cataract is needed. The contribution of osmotic and oxidative stress in
cataract development in
sorbitol dehydrogenase (SDH) deficient mice, a model for slow-developing
cataract in diabetic patients was determined. Contribution of osmotic stress was assessed by HPLC measurement of
sorbitol and by observing the effect of blocking
sorbitol accumulation by
aldose reductase (AR) null mutation in the SDH deficient mice. Contribution of oxidative stress was assessed by observing the effect of
vitamin E treatment and the effect of null mutation of
glutathione peroxidase-1 (Gpx-1) on
cataract development in these mice. Lenticular
sorbitol level was significantly increased in the SDH deficient mice, and blocking
sorbitol accumulation by the AR null mutation prevented
cataract development, demonstrating the contribution of osmotic stress in
cataract development. SDH deficiency did not affect lens oxidative stress status. However, treatment with
vitamin E significantly reduced the incidence of
cataract, and Gpx-1 deficiency exacerbated
cataract development in these mice. Our findings suggest that chronic oxidative stress impaired the osmoregulatory mechanism of the lens. This was not evident until modest increases in lens
sorbitol increased the demand of its osmoregulatory function. This osmoregulatory dysfunction model is supported by the fact that the activity of Na+/K+-
ATPase, the key regulator of cellular
ions and water balance, was dramatically reduced in the precataractous
lenses of the SDH deficient mice, and that treatment with
vitamin E prevented the loss of Na+/K+-
ATPase activity. This osmoregulatory dysfunction model might explain why diabetic patients who control their
blood glucose moderately well are still susceptible to develop
cataract.