sorbinil and Glycosuria

To evaluate the role of excessive polyol pathway activity in the pathogenesis of nerve disorders in diabetes mellitus, nerve conduction velocity was measured in motor nerves of diabetic dogs given an aldose reductase inhibitor (Sorbinil) or placebo, and also in non-diabetic dogs made experimentally galactosaemic. The nerve conduction velocity slowly declined in the diabetic placebo group, becoming significantly less than normal by the fifth year of the study, and the decline was prevented by administration of the aldose reductase inhibitor. Non-diabetic dogs made galactosaemic by consuming a 30% galactose diet developed erythrocyte and nerve polyol concentrations many times greater than that of diabetic or normal animals, but the nerve conduction velocity remained normal throughout 5 years of study. These results in dogs suggest that aldose reductase inhibitors may prevent defective nerve conduction in long-term diabetes, and raise the possibility that excessive accumulation of polyol itself is not sufficient to produce the nerve defect in the absence of excessive polyol utilization.

Topics: Aldehyde Reductase; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dogs; Erythrocytes; Galactosemias; Glycated Hemoglobin; Glycosuria; Imidazoles; Imidazolidines; Neural Conduction; Time Factors; Ulnar Nerve

Proteinuria was diminished by concomitant oral administration of sorbinil, an aldose reductase inhibitor to streptozotocin-induced diabetic rats. Animals were placed in one of three groups: control, diabetic, sorbinil-treated diabetic. For a period of 10 weeks, 24-hour urine samples were analyzed weekly for volume, glucose, ketone, total protein (Pesce-Strande) and individual protein components having molecular weights between 15,000 and 120,000 daltons. The latter were examined by polyacrylamide gel electrophoresis and quantitated by laser densitometric analysis. Results indicated that controls excreted albumin (68,000 daltons) and low-molecular weight proteins between 15,000 and 20,000 daltons. Throughout the 10-week period of diabetes, there was a 7- to 12-fold increase in total urinary protein excreted in 24 h. Diabetic-induced proteinuria primarily resulted from excretion of newly detected proteins having molecular weights of 30,000-100,000 daltons and an increase amount of albumin. Sorbinil treatment prevented approximately 70% of the increase in total protein excretion despite persistent hyperglycemia, glycosuria and ketonuria. Laser densitometric analysis indicated that the aldose reductase inhibitor decreased by 70% the excretion of newly detected proteins and albumin while maintaining the 15,000- to 20,000-dalton proteins. These results suggest that the polyol pathway is implicated in diabetic-induced proteinuria and inhibition of aldose reductase may represent a therapeutic approach for management of diabetic nephropathy.

Topics: Aldehyde Reductase; Animals; Diabetes Mellitus, Experimental; Glycosuria; Hyperglycemia; Imidazoles; Imidazolidines; Ketone Bodies; Male; Proteinuria; Rats; Rats, Inbred Strains; Sugar Alcohol Dehydrogenases