Manipulating rat lens glucose metabolism with exogenous substrates

Diabetic lens glucose metabolism in vivo can be altered by a number of exogenous substrates. We have chosen two, one a glucose epimer (mannose) and the other a glycolytic intermediate (pyruvate), to demonstrate the possibility of this approach. D(+)-Mannose is a D(+)-glucose epimer but in lenses incubated in 35.5 mM mannose, no mannitol (the sorbitol equivalent) was detected, while both lactate production and 31P profile appeared normal. Mannose therefore is a good glucose substitute causing no polyol formation. Mannose metabolism in the rat lens in vivo was then examined. Diabetic rats fed mannose-enriched diet over a period of 14 days showed retardation of changes in 31P metabolites, specifically the levels of phosphorylcholine and glycerophosphorylcholine, suggesting a protective effect. Rat lenses incubated in 35.5 mM glucose in the presence of 5 mM pyruvate (pyr) showed 50% lower sorbitol than without pyr. With 5 mM pyr in the drinking water, i.e. pretreatment in vivo during a 3-day diabetes induction period, the diabetic rat lens accumulated acetate and alanine when incubated in the presence of pyr. The decrease in sorbitol was most likely due to a lower glucose flux rather than an increased polyol dehydrogenase activity. Increasing glucose concentration from 5.5 to 35.5 mM or provision of exogenous pyr both caused an intermediate increase in O2 consumption in the normal lens; a maximal activity was reached with both 35.5 mM glucose and 5 mM pyruvate in the incubating medium. In the diabetic lens, O2 consumption could reach the intermediate but not the maximal level. Dietary pyr pre-treatment also prevented normal and diabetic lenses from maximal pyr-stimulated O2 consumption. The NMR and O2 consumption data together indicated activation of alanine dehydrogenase and saturation of Krebs cycle. It appears that dietary supplement of mannose can preserve 31P membrane metabolites in the diabetic lens. Mannose can be used in conjunction with hypoglycemic therapy for the management of diabetic cataract. In addition, pyruvate may be effective in enhancing lens energy metabolism and lower sorbitol production.