The objective of this study was to clarify the influence of pioglitazone (Pio) on proinsulin (PI) in patients with type 2 diabetes mellitus. The subjects were 55 patients with type 2 diabetes. Among them, 18, 18, and 19 patients were respectively treated with Pio alone (group P), gliclazide (Gli) alone (group G), or Pio plus Gli (group PG) for 12 weeks. Fasting blood samples were obtained before and after treatment and were used to measure fasting plasma glucose (FPG), HbA1C, immunoreactive insulin (IRI), and PI. The levels of FPG, HbA1C, and IRI showed a significant decrease after treatment with Pio in groups P and PG. Treatment with Pio also caused PI to decrease significantly (group P: from 24.7 +/- 12.9 (mean +/- SD) to 14.0 +/- 6.2 pmol/L, p < 0.01, group PG: from 24.3 +/- 11.3 to 14.4 +/- 6.5 pmol/L, p < 0.01). In group G, treatment with Gli caused FPG and HbA1C to decrease significantly, but PI showed no change (21.5 +/- 12.3 to 21.6 +/- 10.4 pmol/L, p = n.s.). In patients with type 2 diabetes, treatment with Pio achieved an improvement of glycemic control and reduced the load on the pancreatic beta cells.