To evaluate the effect of pioglitazone on insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM) patients, a double-blind placebo-controlled trial was carried out with 30 NIDDM patients. Twenty-one subjects, three on diet alone and 18 on sulfonylurea (SU), orally received 30 mg pioglitazone once daily for 12 weeks. Nine subjects, one on diet alone and eight on SU, received a matching placebo once daily for 12 weeks. Euglycemic (5.2 mmol/l) hyperinsulinemic (1200 pmol/l) clamp combined with an oral glucose load (OGL) was performed before and after 3-month treatment with pioglitazone or placebo to determine insulin-stimulated glucose disposal and splanchnic glucose uptake (SGU). No significant differences existed in the patients' characteristics, including age and body mass index, between the two study groups. The pioglitazone treatment increased the mean glucose infusion rate (GIR) prior to OGL from 8.2 +/- 2.2 to 9.2 +/- 2.0 mg/kg.min (mean +/- SD, P = 0.003) and increased the SGU rate from 28.5 +/- 19.4 to 59.4 +/- 27.1% (P = 0.010). The placebo treatment produced no significant changes in either GIR or SGU after treatment. A significant difference (P = 0.042) was observed in change of SGU between the pioglitazone and placebo treatment groups. In conclusion, the results indicate that pioglitazone is effective for ameliorating insulin resistance in NIDDM by enhancing SGU as well as peripheral glucose uptake.