EFFECT OF PYRUVATE ON LENS MYOINOSITOL TRANSPORT AND POLYOL FORMATIONIN DIABETIC CATARACT

In diabetic cataract, sorbitol pathway flux perturbs intracellular met abolism by two putative mechanisms. The osmolyte hypothesis implicates the aldose reductase enzyme. increased rate of reduction of glucose t o sorbitol and reciprocal osmoregulatory depletion of organic osmolyte s (myo-inositol). Redox hypothesis favors alterations in the ratios NA DP+/NADPH and/or NADH/NAD+ as the primary cause of glucose-induced ald ose reductase related defects. Increase in NADH/NAD+ promotes increase d oxidation of sorbitol to fructose by polyol dehydrogenase; potential normalization of this ratio by coadministration of pyruvate (which re oxidizes NADH to NAD(+) via lactate dehydrogenase reaction) was invest igated. Effects of exogenous pyruvate on lens polyol formation and sod ium-dependant myo-inositol (MI) cotransporter using two in vitro model s of sugar cataract were determined. Rat lenses were incubated for 16 h in either normal (5.5 mM) or high sugar medium, 35.5 mM glucose or 3 0 mM galactose. Then lens MI influx was compared to polyol. MI and fru ctose content, Pyruvate did not affect MI influx or sorbitol content i n lenses incubated in control medium, In 35.5 mM glucose, coadministra tion of pyruvate maintained lens MI influx at 76% of control values vs . 43% for lenses without pyruvate. Furthermore, pyruvate treatment dim inished lens sorbitol content by 50% and increased lens sugar content (myo-inositol. fructose. lactate) and media lactate levels. Lenses inc ubated in high galactose medium formed galactitol with a corresponding decreased MI content. Coadministration of pyruvate had no effect on e ither lens sugar content (galactitol, myo-inositol, fructose) or MI in flux? consistent with the fact that galactitol was not metabolized to fructose. In conclusion, pyruvate did net exert a direct effect on the MI co-transporter or prevent galactitol inhibition of MI influx. Coad ministration of pyruvate with high glucose altered lens metabolism and promoted reduction of pyruvate to lactate, increased fructose, decrea sed sorbitol, enhanced MI influx, maintained lens MI content, implicat ing both osmotic and redox systems.