title: Fenofibrate, troglitazone, and 15-deoxy-Delta12,14-prostaglandin J2 close KATP channels and induce insulin secretion.
abstract: It is known that peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands stimulate acute-phase insulin secretion with a rapid Ca2+ influx into pancreatic beta-cells, but the precise mechanisms are not clear. The effects of PPAR-alpha ligands on pancreatic beta-cells also remain unclear. We investigated the effects of PPAR-alpha ligands (fenofibrate and fenofibric acid), a PPAR-gamma ligand (troglitazone), and an endogenous ligand of PPAR-gamma [15-deoxy-Delta12,14-prostaglandin J2 (15-deoxy-Delta12,14-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-Delta12,14-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-Delta12,14-PGJ2 showed half-maximal inhibition of KATP channel currents (IC50) at 3.26, 94, 2.1, and 7.3 micromol/l, respectively. Fenofibrate (> or = 10(-6) mol/l), 15-deoxy-Delta12,14-PGJ2 (> or = 5 x 10(-5) mol/l), and troglitazone (> or = 10(-6) mol/l) inhibited [3H]glibenclamide binding, but fenofibric acid did not. In addition, fenofibrate (> or = 10(-6) mol/l), fenofibric acid (10(-4) mol/l), troglitazone (10(-4) mol/l), and 15-deoxy-Delta12,14-PGJ2 (> or = 10(-5) mol/l) increased insulin secretion from HIT-T15 when applied for 10 min. Our data suggest that PPAR-alpha and -gamma ligands interact directly with the beta-cell membrane and stimulate insulin secretion.
authors.affiliation: Department of Medicine and Molecular Science, Gunma University School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511 Japan. kenju.shimomura@physiol.ox.ac.uk
authors.forename: Kenju
authors.initials: K
authors.lastname: Shimomura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimizu
authors.forename: Mizuho
authors.initials: M
authors.lastname: Ikeda
authors.forename: Shuichi
authors.initials: S
authors.lastname: Okada
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kakei
authors.forename: Shigeji
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Masatomo
authors.initials: M
authors.lastname: Mori
mesh_terms: D000818:Animals; D002839:Chromans / Q000494:pharmacology*; D006224:Cricetinae; D011345:Fenofibrate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007155:Immunologic Factors / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism*; D015221:Potassium Channels; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*; D000077288:Troglitazone; D014407:Tumor Cells, Cultured
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002839:Chromans; D007155:Immunologic Factors; D007328:Insulin; D008565:Membrane Proteins; D015221:Potassium Channels; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; C117780:mitochondrial K(ATP) channel; C006012:fenofibric acid; D000077288:Troglitazone; D015230:Prostaglandin D2; D011345:Fenofibrate