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Troglitazone (CS-045) Inhibits ß-Cell Proliferation Rate Following Stimulation of Insulin Secretion in HIT-T 15 Cells

The First Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Japan

Address all correspondence and requests for reprints to: Dr. Ken-Ichi Ohtani, M.D., First Department of Internal Medicine, Gunma University School of Medicine, 3–39-22 Showa-machi, Maebashi Gunma 371, Japan. E-mail: kohtani{at}sb.gunma-u.ac.jp

Thiazolidinedione analogs are new antidiabetic agents that attenuate peripheral insulin resistance in noninsulin-dependent diabetic patients; however, the effects of these agents on insulin secretion are not known. We determined the short-term and long-term effects of troglitazone (CS-045) on insulin secretion in a Syrian hamster clonal ß-cell line, HIT-T 15 cells. The direct effect of troglitazone (CS-045: 10^-6–10^-4 M) on insulin secretion was examined in F-12 K incubation medium containing 7 mM glucose. CS-045 significantly stimulated insulin secretion within 10 min at the concentration of 10^-4 M and dose dependently stimulated insulin secretion within 60 min at the concentration of 10^-6–10^-4 M. The addition of 10^-5 M CS-045 showed an immediate increase of cytoplasmic free Ca²⁺ concentrations ([Ca²⁺]_i). Removal of extracellular Ca²⁺ by the addition of 1.5 mM EGTA completely abolished the 10^-4 M CS-045-induced insulin secretion for 10-min. Long-term incubation (24 h) with 10^-4 M CS-045 significantly decreased ß-cell insulin content and inhibited insulin secretion. During a 5-day incubation, CS-045 showed a dose-dependent reduction of insulin secretion measured during the final 24 h. Long-term incubation with CS-045 over 3 days inhibited the ß-cell proliferation rate, assessed with [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) assay. CS-045 dose dependently increased the amount of DNA fragmentation measured by ELISA. The addition of nifedipine failed to attenuate the reduction of ß-cell proliferation rate and insulin secretion by CS-045, nifedipine antagonized an increase in the amount of DNA fragmentation caused by 10^-4 M CS-045. The present studies provide evidence that CS-045 inhibits ß-cell function following an acute stimulation of insulin secretion in HIT-T 15 cells. The immediate stimulation of insulin secretion by CS-045 may be mediated by an increase in Ca²⁺ influx from extracellular space. The induction of apoptosis may partially involves the reduction of ß-cell number by CS-045.

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