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CELLULAR AND MOLECULAR
12,14-prostaglandin J2 Close KATP Channels and Induce Insulin Secretion
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (K.S., H.S., S.O., M.M.); Department of Physiology, Nippon Dental University School of Dentistry at Tokyo, Tokyo, Japan (M.I., S.M.); and Department of Geriatric Medicine, Akita University School of Medicine, Akita, Japan (M.K.)
It is known that peroxisome proliferator-activated receptor-
(PPAR-) ligands stimulate acute-phase insulin secretion with a rapid Ca2+ influx into pancreatic 
-cells, but the precise mechanisms are not clear. The effects of PPAR-
ligands on pancreatic -cells also remain unclear. We investigated the effects of PPAR- ligands (fenofibrate and fenofibric acid), a PPAR- ligand (troglitazone), and an endogenous ligand of PPAR- [15-deoxy-
12,14-prostaglandin J2 (15-deoxy-12,14-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-12,14-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-12,14-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-12,14-PGJ2 ( 5 x 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-12,14-PGJ2 ( 10-5 mol/l) increased insulin secretion from HIT-T15 when applied for 10 min. Our data suggest that PPAR- and - ligands interact directly with the -cell membrane and stimulate insulin secretion.
Address correspondence to: Dr. Kenju Shimomura, Department of Medicine and Molecular Science, Gunma University School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511 Japan. E-mail: kenju.shimomura{at}physiol.ox.ac.uk
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