Inhibition of human insulin gene transcription by peroxisome proliferator-activated receptor gamma and thiazolidinedione oral antidiabetic drugs
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Inhibition of human insulin gene transcription by peroxisome proliferator-activated receptor gamma and thiazolidinedione oral antidiabetic drugs. / Schinner, S; Krätzner, R; Baun, D; Dickel, C; Blume, R; Oetjen, E.
in: BRIT J PHARMACOL, Jahrgang 157, Nr. 5, 07.2009, S. 736-45.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Inhibition of human insulin gene transcription by peroxisome proliferator-activated receptor gamma and thiazolidinedione oral antidiabetic drugs
AU - Schinner, S
AU - Krätzner, R
AU - Baun, D
AU - Dickel, C
AU - Blume, R
AU - Oetjen, E
PY - 2009/7
Y1 - 2009/7
N2 - BACKGROUND AND PURPOSE: The transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for glucose homeostasis. PPARgamma ligands reducing insulin levels in vivo are used as drugs to treat type 2 diabetes mellitus. Genes regulated by PPARgamma have been found in several tissues including insulin-producing pancreatic islet beta-cells. However, the role of PPARgamma at the insulin gene was unknown. Therefore, the effect of PPARgamma and PPARgamma 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 PPARgamma-responsive promoter regions.KEY RESULTS: Rosiglitazone caused a PPARgamma-dependent inhibition of insulin gene transcription in a beta-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 PPARgamma, 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 PPARgamma/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 PPARgamma target that may contribute to the action of thiazolidinediones in type 2 diabetes mellitus.
AB - BACKGROUND AND PURPOSE: The transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for glucose homeostasis. PPARgamma ligands reducing insulin levels in vivo are used as drugs to treat type 2 diabetes mellitus. Genes regulated by PPARgamma have been found in several tissues including insulin-producing pancreatic islet beta-cells. However, the role of PPARgamma at the insulin gene was unknown. Therefore, the effect of PPARgamma and PPARgamma 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 PPARgamma-responsive promoter regions.KEY RESULTS: Rosiglitazone caused a PPARgamma-dependent inhibition of insulin gene transcription in a beta-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 PPARgamma, 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 PPARgamma/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 PPARgamma target that may contribute to the action of thiazolidinediones in type 2 diabetes mellitus.
KW - Administration, Oral
KW - Animals
KW - Cell Line
KW - Dose-Response Relationship, Drug
KW - Down-Regulation
KW - Eye Proteins
KW - Genes, Reporter
KW - Glucose
KW - Homeodomain Proteins
KW - Humans
KW - Hypoglycemic Agents
KW - Insulin
KW - Insulin-Secreting Cells
KW - Mice
KW - Mice, Transgenic
KW - PPAR gamma
KW - Paired Box Transcription Factors
KW - Promoter Regions, Genetic
KW - Rats
KW - Repressor Proteins
KW - Thiazolidinediones
KW - Transcription Initiation Site
KW - Transcription, Genetic
KW - Transcriptional Activation
KW - Transfection
U2 - 10.1111/j.1476-5381.2009.00208.x
DO - 10.1111/j.1476-5381.2009.00208.x
M3 - SCORING: Journal article
C2 - 19338578
VL - 157
SP - 736
EP - 745
JO - BRIT J PHARMACOL
JF - BRIT J PHARMACOL
SN - 0007-1188
IS - 5
ER -