PT - JOURNAL ARTICLE AU - Kenju Shimomura AU - Hiroyuki Shimizu AU - Mizuho Ikeda AU - Shuichi Okada AU - Masafumi Kakei AU - Shigeji Matsumoto AU - Masatomo Mori TI - Fenofibrate, Troglitazone, and 15-Deoxy-Δ<sup>12,14</sup>-prostaglandin J<sub>2</sub> Close K<sub>ATP</sub> Channels and Induce Insulin Secretion AID - 10.1124/jpet.104.067249 DP - 2004 Sep 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1273--1280 VI - 310 IP - 3 4099 - http://jpet.aspetjournals.org/content/310/3/1273.short 4100 - http://jpet.aspetjournals.org/content/310/3/1273.full SO - J Pharmacol Exp Ther2004 Sep 01; 310 AB - It is known that peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands stimulate acute-phase insulin secretion with a rapid Ca2+ influx into pancreatic β-cells, but the precise mechanisms are not clear. The effects of PPAR-α ligands on pancreatic β-cells also remain unclear. We investigated the effects of PPAR-α ligands (fenofibrate and fenofibric acid), a PPAR-γ ligand (troglitazone), and an endogenous ligand of PPAR-γ [15-deoxy-Δ12,14-prostaglandin J2 (15-deoxy-Δ12,14-PGJ2)] on KATP channel activity in clonal hamster insulinoma cell line, HIT-T15 cells. As assessed by whole-cell patch clamp, fenofibrate, fenofibric acid, troglitazone, and 15-deoxy-Δ12,14-PGJ2 reduced the KATP channel currents, and inhibition continued after washout of these agents. The concentration-response curves of fenofibrate, fenofibric acid, troglitazone, and 15-deoxy-Δ12,14-PGJ2 showed half-maximal inhibition of KATP channel currents (IC50) at 3.26, 94, 2.1, and 7.3 μmol/l, respectively. Fenofibrate (≥ 10-6 mol/l), 15-deoxy-Δ12,14-PGJ2 (≥ 5 × 10-5 mol/l), and troglitazone (≥ 10-6 mol/l) inhibited [3H]glibenclamide binding, but fenofibric acid did not. In addition, fenofibrate (≥ 10-6 mol/l), fenofibric acid (10-4 mol/l), troglitazone (10-4 mol/l), and 15-deoxy-Δ12,14-PGJ2 (≥ 10-5 mol/l) increased insulin secretion from HIT-T15 when applied for 10 min. Our data suggest that PPAR-α and -γ ligands interact directly with the β-cell membrane and stimulate insulin secretion. The American Society for Pharmacology and Experimental Therapeutics