Rosiglitazone promotes PPARγ-dependent and -independent alterations in gene expression in mouse islets.

The glitazone class of insulin-sensitizing agents act, in part, by the activation of peroxisome proliferator-activated receptor (PPAR)-γ in adipocytes. However, it is unclear whether the expression of PPARγ in the islets is essential for their potential β-cell-sparing properties. To investigate the in vivo effects of rosiglitazone on β-cell biology, we used an inducible, pancreatic and duodenal homeobox-1 enhancer element-driven, Cre recombinase to knockout PPARγ expression specifically in adult β-cells (PPARgKO). Subjecting the PPARgKO mice to a chow diet led to virtually undetectable changes in glucose or insulin sensitivity, which was paralleled by minimal changes in islet gene expression. Similarly, challenging the mutant mice with a high-fat diet and treatment with rosiglitazone did not alter insulin sensitivity, glucose-stimulated insulin secretion, islet size, or proliferation in the knockout mice despite PPARγ-dependent and -independent changes in islet gene expression. These data suggest that PPARγ expression in the β-cells is unlikely to be directly essential for normal β-cell function or the insulin-sensitizing actions of rosiglitazone.