title: Apoptosis rate and transcriptional response of pancreatic islets exposed to the PPAR gamma agonist Pioglitazone.
abstract: To explore the molecular pathways underlying thiazolidinediones effects on pancreatic islets in conditions mimicking normo- and hyperglycemia, apoptosis rate and transcriptional response to Pioglitazone at both physiological and supraphysiological glucose concentrations were evaluated. Adult rat islets were cultured at physiological (5.6 mM) and supraphysiological (23 mM) glucose concentrations in presence of 10 μM Pioglitazone or vehicle. RNA expression profiling was evaluated with the PancChip 13k cDNA microarray after 24-h, and expression results for some selected genes were validated by qRT-PCR. The effects of Pioglitazone were investigated regarding apoptosis rate after 24-, 48- and 72-h. At 5.6 mM glucose, 101 genes were modulated by Pioglitazone, while 1,235 genes were affected at 23 mM glucose. Gene networks related to lipid metabolism were identified as altered by Pioglitazone at both glucose concentrations. At 23 mM glucose, cell cycle and cell death pathways were significantly regulated as well. At 5.6 mM glucose, Pioglitazone elicited a transient reduction in islets apoptosis rate while at 23 mM, Bcl2 expression was reduced and apoptosis rate was increased by Pioglitazone. Our data demonstrate that the effect of Pioglitazone on gene expression profile and apoptosis rate depends on the glucose concentration. The modulation of genes related to cell death and the increased apoptosis rate observed at supraphysiological glucose concentration raise concerns about Pioglitazone's direct effects in conditions of hyperglycemia and reinforce the necessity of additional studies designed to evaluate TZDs effects on the preservation of β-cell function in situations where glucotoxicity might be more relevant than lipotoxicity.
authors.affiliation: Laboratory for Cellular and Molecular Endocrinology LIM-25, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455 #4305, 01246-903, São Paulo, Brazil.|Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, 752B CRB 415 Curie Blvd., 19104, Philadelphia, Pennsylvania, USA.
authors.forename: Rodrigo N
authors.initials: RN
authors.lastname: Lamounier
authors.affiliation: Laboratory for Cellular and Molecular Endocrinology LIM-25, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455 #4305, 01246-903, São Paulo, Brazil.|Laboratory Medicine, University of Santo Amaro, Sao Paulo, Brazil.
authors.forename: Cassio N
authors.initials: CN
authors.lastname: Coimbra
authors.affiliation: Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, 752B CRB 415 Curie Blvd., 19104, Philadelphia, Pennsylvania, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: White
authors.affiliation: Laboratory for Cellular and Molecular Endocrinology LIM-25, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455 #4305, 01246-903, São Paulo, Brazil.
authors.forename: Flavia L
authors.initials: FL
authors.lastname: Costal
authors.affiliation: Laboratory for Cellular and Molecular Endocrinology LIM-25, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455 #4305, 01246-903, São Paulo, Brazil.|Laboratory Medicine, University of Santo Amaro, Sao Paulo, Brazil.
authors.forename: Leonardo S
authors.initials: LS
authors.lastname: Oliveira
authors.affiliation: Postgraduate Program in Medicine, Universidade Nove de Julho - Uninove, Sao Paulo, Brazil.
authors.forename: Daniel
authors.initials: D
authors.lastname: Giannella-Neto
authors.affiliation: Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, 752B CRB 415 Curie Blvd., 19104, Philadelphia, Pennsylvania, USA.
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
authors.affiliation: Laboratory for Cellular and Molecular Endocrinology LIM-25, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455 #4305, 01246-903, São Paulo, Brazil.
authors.forename: Maria Lúcia
authors.initials: ML
authors.lastname: Corrêa-Giannella