Three muscle biopsies were performed in 53 overt type 2 diabetics over a period of approximately 2 years. At baseline, 21 (40%) had an increased capillary basement membrane width in muscle. Thirty-five patients received glipizide and 18 received placebo. In the patients receiving placebo, the mean of the muscle capillary basement membrane width increased from 158.7 +/- 11.5 nm (SEM) to 170.9 +/- 14.7 nm (P = NS), but in those receiving glipizide the value decreased from 192.9 +/- 13.2 nm to 161.0 +/- 10.2 nm (P = 0.02). Plasma glucose and glycosylated hemoglobin A1 decreased significantly (P less than 0.001) after 2 years in patients receiving glipizide. In 15, mean glycosylated hemoglobin A1 reached a normal range, and mean basement membrane width decreased to a level close to that found in subjects without diabetes (P = NS). These findings are consistent with the hypothesis that effective response to oral medication can decrease the basement membrane thickening, suggesting that diabetic microangiopathy is not necessarily progressive.