Twenty-three nonobese KK mice with abnormal tolerance to glucose, hyperinsulinemia with insulin resistance and human diabetic-like nephropathy were treated with either saline (12 mice) or glipizide, an oral hypoglycemic compound, 1 mg/kg, (11 mice) from 120 to 360 days of age. These mice develop significant increases in mesangial volume and matrix by 40 days of age. Oral glucose tolerance (OGTT), glucosyltransferase and N-acetyl-beta-glucosaminidase (enzymes involved in synthesis and degradation of kidney glycoproteins, respectively) in the kidney and serum, 24-hr proteinuria, and light microscopy studies of the kidney were performed. Glipizide-treated mice improved their OGTT. There was no difference in body weight; however, a 16% decrease (P less than 0.05) in kidney weight was observed in glipizide-treated mice. Both enzymes were significantly increased in the kidneys of mice treated with glipizide. No difference in serum enzymes was found between the two groups of mice. About 58% of the saline-treated mice had moderate glomerulosclerosis. By contrast, only 27% of glipizide-treated mice had moderate glomerulosclerosis. Also, a significant decrease in proteinuria was found in glipizide-treated mice. These data suggest that glipizide improves glucose metabolism, decreases kidney size, prevents kidney glycoprotein and mesangial matrix accumulation, and reduces proteinuria in type II diabetic KK mice. This indicates that good glycemic control prevents further progression of established diabetic nephropathy in animals.