Glomerular Polyol Accumulation in Diabetes and its Prevention by Oral Sorbinil

Although enhanced activity of the polyol pathway has been implicated in the pathogenesis of certain complications of diabetes, evidence that aldose reductase activity and sorbitol content are increased in the characteristic tissue site of the diabetic renal lesion has been lacking. We therefore measured polyols in glomeruli isolated from control and streptozotocin-diabetic rats, and assessed whether changes in diabetic glomeruli could be prevented by oral administration of the aldose reductase inhibitor sorbinil. Compared with control, polyol content of glomeruli isolated from diabetic rats was increased 10-fold and fourfold at 6 and 9 wk, respectively, after induction of diabetes, but was unchanged in glomeruli from rats treated with sorbinil throughout the experimental periods. In contrast, glomerular myo-inositol content was reduced in diabetic samples; this fall in myo-inositol levels was also completely prevented by sorbinil. These results establish that glomeruli contain aldose reductase activity and provide the first demonstration that glomerular polyol content increases while myo-inositol content decreases in diabetes and that oral sorbinil prevents these changes despite persistent hyperglycemia.