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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, Vol. 157, No. 5, 07.2009, p. 736-45.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Schinner, S, Krätzner, R, Baun, D, Dickel, C, Blume, R & Oetjen, E 2009, 'Inhibition of human insulin gene transcription by peroxisome proliferator-activated receptor gamma and thiazolidinedione oral antidiabetic drugs', BRIT J PHARMACOL, vol. 157, no. 5, pp. 736-45. https://doi.org/10.1111/j.1476-5381.2009.00208.x

APA

Schinner, S., Krätzner, R., Baun, D., Dickel, C., Blume, R., & Oetjen, E. (2009). Inhibition of human insulin gene transcription by peroxisome proliferator-activated receptor gamma and thiazolidinedione oral antidiabetic drugs. BRIT J PHARMACOL, 157(5), 736-45. https://doi.org/10.1111/j.1476-5381.2009.00208.x

Vancouver

Schinner S, Krätzner R, Baun D, Dickel C, Blume R, Oetjen E. Inhibition of human insulin gene transcription by peroxisome proliferator-activated receptor gamma and thiazolidinedione oral antidiabetic drugs. BRIT J PHARMACOL. 2009 Jul;157(5):736-45. https://doi.org/10.1111/j.1476-5381.2009.00208.x

Bibtex

@article{7999519c818841249ee3e696ec4dc6d1,
title = "Inhibition of human insulin gene transcription by peroxisome proliferator-activated receptor gamma and thiazolidinedione oral antidiabetic drugs",
abstract = "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.",
keywords = "Administration, Oral, Animals, Cell Line, Dose-Response Relationship, Drug, Down-Regulation, Eye Proteins, Genes, Reporter, Glucose, Homeodomain Proteins, Humans, Hypoglycemic Agents, Insulin, Insulin-Secreting Cells, Mice, Mice, Transgenic, PPAR gamma, Paired Box Transcription Factors, Promoter Regions, Genetic, Rats, Repressor Proteins, Thiazolidinediones, Transcription Initiation Site, Transcription, Genetic, Transcriptional Activation, Transfection",
author = "S Schinner and R Kr{\"a}tzner and D Baun and C Dickel and R Blume and E Oetjen",
year = "2009",
month = jul,
doi = "10.1111/j.1476-5381.2009.00208.x",
language = "English",
volume = "157",
pages = "736--45",
journal = "BRIT J PHARMACOL",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "5",

}

RIS

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 -