Prevention of cataract by pyruvate in experimentally diabetic mice.
Previous studies have demonstrated that administration of pyruvate prevents cataract formation in diabetic rats. It is known that the induction of cataractous process in this case is initiated by aldose reductase (AR) catalyzed synthesis and accumulation of excessive sorbitol in the lens fibres and epithelium and their consequent osmotic hydration. Synthesis of this and other polyols is competitively inhibited by pyruvate. The objective of the present investigations was hence to determine whether pyruvate would have a similar protective effect in species where cataract formation is relatively independent of sorbitol synthesis such as in humans where the lens AR activity is extremely low, especially with glucose as a substrate. The Km of AR for glucose is known to be very high. The possible protective effect of pyruvate in the low AR models was conceived on the basis of our previous findings suggesting that it can also exert substantial antiglycating as well as antioxidant effects. The present studies have hence been conducted with mice, a species known to be low in lens AR, similar to that in humans. As stipulated, pyruvate administration has indeed been found to offer a significant protection against development of diabetic cataract in this model also. The effect correlated with the inhibition of protein glycation as well as of oxidative stress. The latter was apparent by the prevention of the loss of glutathione known to be associated with diabetes. Although there was a small but noticeable increment in the sorbitol content of the diabetic lenses, this was osmotically insignificant. Even this increase was prevented by pyruvate. The magnitude of the elevation in the contents of glycated proteins and the depression in the level of glutathione were, on the contrary, highly pronounced, suggesting a more prominent role of the latter factors. In addition, the possibility of a direct metabolic support it could offer to the tissue is also imminent by its effect on the maintenance of ATP, as shown earlier. The present studies are therefore considered more relevant to the pathogenesis of cataract in human diabetics and its possible prevention by endogenous compounds with antiglycating and antioxidant properties. Inhibition of cataract formation by pyruvate in an animal model with low lens AR, similar to that in humans, has been shown for the first time.
Hegde
K R
KR
Departments of Biochemistry and Ophthalmology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Varma
S D
SD
D000818:Animals; D002386:Cataract / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D006031:Glycosylation; D007908:Lens, Crystalline / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D011506:Proteins / Q000378:metabolism; D019289:Pyruvic Acid / Q000627:therapeutic use*; D013012:Sorbitol / Q000032:analysis / Q000378:metabolism
D011506:Proteins; D013012:Sorbitol; D019289:Pyruvic Acid