The effect of ponalrestat on sorbitol levels in the lens of obese and diabetic mice.
Sorbitol levels were determined in lens of genetically obese (ob/ob) and diabetic (db/db) mice, as well as in lean mice (+/db, +/ob) made diabetic by administration of streptozotocin (STZ). Treatment of lean mice with STZ resulted in hypoinsulinemia, whereas the ob/ob and db/db mice were hyperinsulinemic. Hyperglycemia was present in STZ-treated +/db and +/ob mice and in db/db mice, whereas relative euglycemia was observed in ob/ob mice and untreated +/db and +/ob mice. Sorbitol levels were elevated in lens tissue of db/db mice and STZ-treated +/db. In contrast, no changes in sorbitol content were observed in ob/ob mice and +/ob mice treated with STZ, suggesting that aldose reductase activity in lens of this animal model is considerably less than that present in db/db mice. Oral treatment of db/db mice and STZ-treated +/db mice with Ponalrestat reduced hyperglycemia-induced sorbitol accumulation significantly in lens, indicating that aldose reductase inhibitors may ameliorate long-term complications associated with sorbitol accumulation in diabetes.
Vicario
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Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey 07065.
Slater
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Saperstein
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D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007908:Lens, Crystalline / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity; D010793:Phthalazines; D013012:Sorbitol / Q000378:metabolism*; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*
D001786:Blood Glucose; D007328:Insulin; D010793:Phthalazines; C042829:ponalrestat; D013012:Sorbitol; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase