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)-gamma in adipocytes. However, it is unclear whether the expression of PPAR gamma in the islets is essential for their potential beta-cell-sparing properties. To investigate the in vivo effects of rosiglitazone on beta-cell biology, we used an inducible, pancreatic and duodenal homeobox-1 enhancer element-driven, Cre recombinase to knockout PPAR gamma expression specifically in adult beta-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 PPAR gamma-dependent and -independent changes in islet gene expression. These data suggest that PPAR gamma expression in the beta-cells is unlikely to be directly essential for normal beta-cell function or the insulin-sensitizing actions of rosiglitazone. (Endocrinology 153: 4593-4599, 2012)