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Inhibition of human insulin gene transcription by peroxisome proliferator‐activated receptor γ and thiazolidinedione oral antidiabetic drugs
Author(s) -
Schinner S,
Krätzner R,
Baun D,
Dickel C,
Blume R,
Oetjen E
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00208.x
Subject(s) - rosiglitazone , thiazolidinedione , peroxisome proliferator activated receptor , transactivation , glucose homeostasis , insulin , endocrinology , medicine , reporter gene , biology , promoter , response element , transcription factor , chemistry , receptor , gene expression , insulin resistance , diabetes mellitus , gene , type 2 diabetes , biochemistry
Background and purpose: The transcription factor peroxisome proliferator‐activated receptor γ (PPARγ) is essential for glucose homeostasis. PPARγ ligands reducing insulin levels in vivo are used as drugs to treat type 2 diabetes mellitus. Genes regulated by PPARγ have been found in several tissues including insulin‐producing pancreatic islet β‐cells. However, the role of PPARγ at the insulin gene was unknown. Therefore, the effect of PPARγ and PPARγ ligands like rosiglitazone on insulin gene transcription was investigated. Experimental approach: Reporter gene assays were used in the β‐cell line HIT and in primary mature pancreatic islets of transgenic mice. Mapping studies and internal mutations were carried out to locate PPARγ‐responsive promoter regions. Key results: Rosiglitazone caused a PPARγ‐dependent inhibition of insulin gene transcription in a β‐cell line. This inhibition was concentration‐dependent and had an EC 50 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 PPARγ, 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 PPARγ/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 PPARγ target that may contribute to the action of thiazolidinediones in type 2 diabetes mellitus.