RT Journal Article
SR Electronic
T1 Fenofibrate, Troglitazone, and 15-Deoxy-Δ12,14-prostaglandin J2 Close KATP Channels and Induce Insulin Secretion
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1273
OP 1280
DO 10.1124/jpet.104.067249
VO 310
IS 3
A1 Kenju Shimomura
A1 Hiroyuki Shimizu
A1 Mizuho Ikeda
A1 Shuichi Okada
A1 Masafumi Kakei
A1 Shigeji Matsumoto
A1 Masatomo Mori
YR 2004
UL http://jpet.aspetjournals.org/content/310/3/1273.abstract
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