Acute and Long-term Effects of Peroxisome Proliferator-activated Receptor-γ Activation on the Function and Insulin Secretory Responsiveness of Clonal Beta-Cells.

Thiazolidinediones (TZDs) are used as antidiabetic therapy. The purpose of the present study was to examine whether the TZD rosiglitazone has direct actions on pancreatic beta- cells that contribute to its overall eff ects. Eff ects of acute and prolonged (48 h) exposure to rosiglitazone, as a model glitazone compound, were assessed in clonal pancreatic BRIN-BD11 beta-cells maintained in standard, glucotoxic and lipotoxic cultures. In acute 20-min incubations, rosiglitazone (0.2 – 100 μ M) did not alter basal or glucose-stimulated insulin secretion. However, rosiglitazone (6.25 μ M) enhanced (p < 0.001) the acute insulinotropic action of GLP-1. Prolonged exposure to 6.25 μ M rosiglitazone in standard media had no eff ect on cell viability or cellular insulin content, but slightly reduced the insulin secretory response to glucose and alanine (p < 0.05). Prolonged (48 h) exposure to glucotoxic or lipotoxic conditions reduced beta-cell viability (p < 0.05), cellular insulin content (p < 0.001 and p < 0.05, respectively), and insulin release in response to glucose and a range of secretagogues. The adverse eff ect of lipotoxicity on beta-cell viability was prevented by concomitant exposure to 6.25 μ M rosiglitazone. Culture with 6.25 μ M rosiglitazone further decreased acute insulin release under glucotoxic conditions. However, when insulin secretion was expressed as percentage cellular insulin content, rosiglitazone (6.25 μ M) significantly improved many of the adverse eff ects of gluco- and lipotoxic conditions on insulin secretory responsiveness. The results suggest that despite decrease in cellular insulin content TZDs exert direct benefi cial eff ects on beta-cell viability and function during gluco- or lipotoxicity. [ABSTRACT FROM AUTHOR]