Acute nutrient regulation of the unfolded protein response and integrated stress response in cultured rat pancreatic islets
Inadequate chaperone function relative to client protein load in the endoplasmic reticulum triggers an adaptive unfolded protein response (UPR), including the integrated stress response (ISR), the latter being also activated by other types of stresses. It is well established that pancreatic beta cells, which synthesise and secrete insulin upon nutrient stimulation, are markedly affected by pathological disruption or excessive activation of the UPR. However, whether and how physiological nutrient stimulation affects the beta cell UPR has been little investigated.
Materials and methods
We compared the effects of increasing glucose concentrations and of endoplasmic reticulum Ca2+ emptying with thapsigargin on the UPR (X-box binding protein [Xbp1] mRNA splicing and XBP1/activating transcription factor [ATF] 6-target gene expression) and ISR (eukaryotic translation initiation factor 2A phosphorylation, ATF4 protein levels and target gene expression) in isolated rat islets.
Thapsigargin strongly increased both UPR and ISR. In comparison, glucose moderately increased the UPR between 5 and 30 mmol/l, but exerted complex effects on the ISR as follows: (1) marked reduction between 2 and 10 mmol/l; (2) moderate increase parallel to the UPR between 10 and 30 mmol/l. These glucose effects occurred within 2 h, were mimicked by other metabolic substrates, but were independent of changes in Ca2+ influx or insulin secretion. Remarkably, attenuating the glucose stimulation of protein synthesis with a low concentration of cycloheximide prevented UPR activation but not ISR reduction by high glucose.
Nutrient stimulation acutely activates rat islet UPR in a manner dependent on protein synthesis, while exerting complex effects on the ISR. These effects may contribute to nutrient-induced maintenance of the beta cell phenotype.
- Acute nutrient regulation of the unfolded protein response and integrated stress response in cultured rat pancreatic islets
Volume 50, Issue 7 , pp 1442-1452
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- Beta cell
- Endoplasmic reticulum stress
- Gene expression
- Integrated stress response
- Nutrient stimulation
- Pancreatic islet
- Protein synthesis
- Succinic acid
- Unfolded protein response
- Industry Sectors
- Author Affiliations
- 1. Unit of Endocrinology and Metabolism, Faculty of Medicine, Université Catholique de Louvain, Avenue Hippocrate, 55 (UCL 55.30), 1200, Brussels, Belgium
- 2. Service of Pathology, Faculty of Medicine, Université Catholique de Louvain, Brussels, Belgium
- 3. Gene Expression Unit, Department of Molecular Cell Biology, Katholiek Universiteit Leuven, Leuven, Belgium