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1.
J Diabetes Investig ; 11(4): 823-833, 2020 Jul.
Article in English | MEDLINE | ID: mdl-31989791

ABSTRACT

AIMS/INTRODUCTION: Pancreatic ß-cells are sensitive to endoplasmic reticulum (ER) stress, which has a major role in the context of ß-cell death. Adrenomedullin (ADM) has been shown to exert a cytoprotective effect under various pathophysiological conditions. Several studies have suggested that thiazolidinediones have protective effects on ß-cells. During the course to elucidate the molecular mechanisms by which pioglitazone prevents ß-cell death, ADM emerged as a candidate. Here, we studied the regulation of ADM expression, including the effects of pioglitazone, and its role in pancreatic islets. MATERIALS AND METHODS: We analyzed ADM expression in islet cell lines treated with pioglitazone. The effects of ER stress on ADM and ADM receptor expressions were investigated by analyzing thapsigargin-treated MIN6 cells and islets isolated from Wfs1-/- and db/db mice. To study the anti-apoptotic effect of ADM, ER stress-exposed MIN6 cells were treated with ADM peptides or transfected with ADM expression plasmid. RESULTS: Pioglitazone increased the production and secretion of ADM in islets through peroxisome-proliferator activated receptor-γ-dependent mechanisms. Thapsigargin treatment increased expressions of both ADM and ADM receptor, composed of Ramp2, Ramp3 and Crlr, in MIN6 cells. ADM and ADM receptor expressions were also increased in isolated islets from Wfs1-/- and db/db mice. ADM peptides and ADM overexpression protected MIN6 cells from thapsigargin-induced apoptosis. CONCLUSIONS: ER stress stimulates ADM production and secretion in islets. ADM signaling might protect ß-cells from ER stress-induced apoptosis, and might be one of the self-protective mechanisms. ß-Cell protection by pioglitazone is partly through induction of ADM. ADM-based therapy could be a novel strategy for treating diabetes.


Subject(s)
Adrenomedullin/metabolism , Endoplasmic Reticulum Stress/drug effects , Insulin-Secreting Cells/physiology , Protective Agents/metabolism , Animals , Apoptosis/drug effects , Autocrine Communication/drug effects , Cell Line , Humans , Mice , PPAR gamma/metabolism , Paracrine Communication/drug effects , Pioglitazone/pharmacology , Receptors, Adrenomedullin/metabolism , Signal Transduction/drug effects , Thapsigargin/pharmacology
2.
EBioMedicine ; 18: 146-156, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28389215

ABSTRACT

In Wfs1-/-Ay/a islets, in association with endoplasmic reticulum (ER) stress, D-site-binding protein (Dbp) expression decreased and Nuclear Factor IL-3 (Nfil3)/E4 Promoter-binding protein 4 (E4bp4) expression increased, leading to reduced DBP transcriptional activity. Similar alterations were observed with chemically-induced ER stress. Transgenic mice expressing E4BP4 under the control of the mouse insulin I gene promoter (MIP), in which E4BP4 in ß-cells is expected to compete with DBP for D-box, displayed remarkable glucose intolerance with severely impaired insulin secretion. Basal ATP/ADP ratios in MIP-E4BP4 islets were elevated without the circadian oscillations observed in wild-type islets. Neither elevation of the ATP/ADP ratio nor an intracellular Ca2+ response was observed after glucose stimulation. RNA expressions of genes involved in insulin secretion gradually increase in wild-type islets early in the feeding period. In MIP-E4BP4 islets, however, these increases were not observed. Thus, molecular clock output DBP transcriptional activity, susceptible to ER stress, plays pivotal roles in ß-cell priming for insulin release by regulating ß-cell metabolism and gene expressions. Because ER stress is also involved in the ß-cell failure in more common Type-2 diabetes, understanding the currently identified ER stress-associated mechanisms warrants novel therapeutic and preventive strategies for both rare form and common diabetes.


Subject(s)
CLOCK Proteins/genetics , Endoplasmic Reticulum Stress , Animals , Basic-Leucine Zipper Transcription Factors/genetics , Basic-Leucine Zipper Transcription Factors/metabolism , CLOCK Proteins/metabolism , Calcium/analysis , Cell Line , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Glucose Tolerance Test , Humans , Insulin/genetics , Insulin/metabolism , Insulin Secretion , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/metabolism , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Transgenic , Microscopy, Electron , Promoter Regions, Genetic , Transcription Factors/genetics , Transcription Factors/metabolism , Transcription, Genetic
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