Role of Aldose Reductase and Effects of Aldose Reductase Inhibitors in Ocular Tissue Aging Phenomena in the Diabetic Rat

Abstract

Studies of the role of aldose reductase in sugar cataractogenesis have been aided by the synthesis and characterization of inhibitors of this enzyme which can prevent lens opacification in galactosemic or diabetic rats^1,2. The anti-cataract activity of aldose reductase inhibitors correlates with inhibition of polyol accumulation in the lenses of treated galactosemic or diabetic animals; in untreated diabetic rats, lens sorbitol levels may be elevated 100-fold over the normal value³. Hyperglycemia produces an increase in glucose content of tissues not responsive to insulin. Due to increased substrate availability, the rate of sorbitol formation by action of aldose reductase is greatly accelerated relative to conversion of this metabolite to fructose via sorbitol dehydrogenase¹:

$$ Glucose\quad + \quad NADPH\quad + \quad {H^{ + }}\;\xrightarrow{{Aldose\,Reductase}}\;Sorbitol\quad + \quad NAD{P^{ + }} $$

(1a)

$$ Sorbitol\quad + \quad NA{D^{ + }}\;\xrightarrow{{Sorbitol\;Dehydrogenase}}\;Fructose\quad + \quad NADH\quad + \quad {H^{ + }} $$

(1b)

.

Since polyols such as sorbitol are poorly transported across cell membranes, an early effect of intracellular sorbitol accumulation appears to be increased osmolality¹. Compensatory responses of cells to an osmotic insult include water uptake and swelling, which, if sustained chronically, produce membrane damage and other alterations that progress eventually to end-stage nuclear cataract^1,2.