Inhibition of human insulin gene transcription by peroxisome proliferator-activated receptor γ and thiazolidinedione oral antidiabetic drugs

Background and purpose: The transcription factor peroxisome proliferator-activated receptor gamma (PPAR gamma) is essential for glucose homeostasis. PPAR gamma ligands reducing insulin levels in vivo are used as drugs to treat type 2 diabetes mellitus. Genes regulated by PPAR gamma have been found in several tissues including insulin-producing pancreatic islet beta-cells. However, the role of PPAR gamma at the insulin gene was unknown. Therefore, the effect of PPAR gamma and PPAR gamma ligands like rosiglitazone on insulin gene transcription was investigated. Experimental approach: Reporter gene assays were used in the beta-cell line HIT and in primary mature pancreatic islets of transgenic mice. Mapping studies and internal mutations were carried out to locate PPAR gamma-responsive promoter regions. Key results: Rosiglitazone caused a PPAR gamma-dependent inhibition of insulin gene transcription in a beta-cell line. This inhibition was concentration-dependent and had an EC50 similar to that for the activation of a reporter gene under the control of multimerized PPAR binding sites. Also in normal primary pancreatic islets of transgenic mice, known to express high levels of PPAR gamma, rosiglitazone inhibited glucose-stimulated insulin gene transcription. Transactivation and mapping experiments suggest that, in contrast to the rat glucagon gene, the inhibition of the human insulin gene promoter by PPAR gamma/rosiglitazone does not depend on promoter-bound Pax6 and is attributable to the proximal insulin gene promoter region around the transcription start site from -56 to +18. Conclusions and implications: The human insulin gene represents a novel PPAR gamma target that may contribute to the action of thiazolidinediones in type 2 diabetes mellitus.