Abstract
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.
Footnotes
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doi:10.1124/jpet.104.067249.
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ABBREVIATIONS: KATP, ATP-sensitive potassium; PPAR, peroxisome proliferator-activated receptor; 15-deoxy-Δ12,14-PGJ2, 15-deoxy-Δ12,14-prostaglandin J2; FBS, fetal bovine serum; PG, prostaglandin.
- Received February 23, 2004.
- Accepted June 15, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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