Pioglitazone hydrochloride (AD-4833), one of the thiazolidinedione analogs, is a new anti-diabetic agent which improves peripheral insulin resistance in diabetic patients. We determined the direct effect of AD-4833 on insulin secretion in HIT-T 15 cells. The effects of AD-4833 (10(-7) M to 10(-5) M) on insulin secretion were examined in 3 and 7 mM glucose-containing F-12 K media. The addition of 10(-5) M AD-4833 significantly increased insulin secretion in both media, but its stimulatory effect was more potent in the medium containing 7 mM glucose. The addition of 10(-5) M AD-4833 caused an immediate, significant increase in cytosolic free Ca2+ concentration ([Ca2+]i). Nifedipine at all concentrations from 10 to 1000 nM significantly attenuated insulin secretion by 10(-5) M AD-4833. In addition, 10(-5) M AD-4833 failed to stimulate insulin secretion in the CA(2+)-free Kreb's-Ringer bicarbonate buffer. These data indicated that AD-4833 stimulates in vitro insulin secretion in HIT-T 15 cells, perhaps by inducing Ca2+ influx.