Role for inducible cAMP early repressor in promoting pancreatic beta cell dysfunction evoked by oxidative stress in human and rat islets

Abstract

Aims/hypothesisPro-atherogenic and pro-oxidant, oxidised LDL trigger adverse effects on pancreatic beta cells, possibly contributing to diabetes progression. Because oxidised LDL diminish the expression of genes regulated by the inducible cAMP early repressor (ICER), we investigated the involvement of this transcription factor and of oxidative stress in beta cell failure elicited by oxidised LDL.MethodsIsolated human and rat islets, and insulin-secreting cells were cultured with human native or oxidised LDL or with hydrogen peroxide. The expression of genes was determined by quantitative real-time PCR and western blotting. Insulin secretion was monitored by EIA kit. Cell apoptosis was determined by scoring cells displaying pycnotic nuclei.ResultsExposure of beta cell lines and islets to oxidised LDL, but not to native LDL raised the abundance of ICER. Induction of this repressor by the modified LDL compromised the expression of important beta cell genes, including insulin and anti-apoptotic islet brain 1, as well as of genes coding for key components of the secretory machinery. This led to hampering of insulin production and secretion, and of cell survival. Silencing of this transcription factor by RNA interference restored the expression of its target genes and alleviated beta cell dysfunction and death triggered by oxidised LDL. Induction of ICER was stimulated by oxidative stress, whereas antioxidant treatment with N-acetylcysteine or HDL prevented the rise of ICER elicited by oxidised LDL and restored beta cell functions.Conclusions/interpretationInduction of ICER links oxidative stress to beta cell failure caused by oxidised LDL and can be effectively abrogated by antioxidant treatment.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-011-2165-x) contains supplementary material, which is available to authorised users.

Hyperglycemia downregulates Connexin36 in pancreatic islets via the upregulation of ICER-1/ICER-1γ

“…However, little is known about the ICER-1 target genes responsible for the pro-apoptotic impact of this repressor. Together with our previous research (Allagnat et al 2008, Favre et al 2011, Haefliger et al 2013, the present study has identified Cx36 has a relevant ICER-1/ICER-1g target. Given the requirement of a proper Cx36 signaling in insulin secretion and b-cell survival (Meda 2012), our data strongly suggest that Cx36 contributes to the deleterious sequence of events triggered by ICER-1/ICER-1g, which presumably leads to glucose desensitization and b-cell failure in the pre-diabetic stage.…”

“…Previous studies have documented the deleterious impact of prolonged ICER-1/ICER-1g overexpression on b-cell function and survival (Inada et al 2004, Abderrahmani et al 2006, Allagnat et al 2008, Favre et al 2011. However, little is known about the ICER-1 target genes responsible for the pro-apoptotic impact of this repressor.…”

“…Quantitative PCR was performed using the SYBR Premix ExTaq (Takara Bio Europe/SAS, Saint-Germain-en-Laye, France) in a Lightcycler Instrument (Roche Diagnostics . CREM-1/ICER-1/ICER-1g western blotting was performed on nuclear extracts using the rabbit polyclonal anti-CREM-1 sc440 (Santa Cruz Biotechnology, Inc. Heidelberg, Germany, 1:2000) as described previously (Allagnat et al 2008, Favre et al 2011, Haefliger et al 2013. After incubation at room temperature (1 h) with a convenient secondary antibody conjugated to HRP (Fluka Chemie, Sigma-Aldrich Chemie GmbH, Buchs, Switzerland, diluted 1:20 000), membranes were revealed by enhanced chemiluminescence (ECL, Amersham Biosciences, GE Healthcare Europe GmbH, Glattbrugg, Switzerland).…”

Association of a polymorphism in the 3' untranslated region of the <i>OLR1</i> gene with milk fat and protein in dairy cows

“…On the other hand, there is increasing evidence that Ox-LDL induces beta cell dysfunction and reduction of insulin production (Maziere et al 2004, Abderrahmani et al 2007, Favre et al 2011. Considering the role of insulin in stimulating protein synthesis in mammary gland (Mackle et al 2000, Molento et al 2002, Menzies et al 2009, Appuhamy et al 2011, it can be hypothesized that Ox-LDL may decrease protein synthesis by reducing insulin production in beta cells and its signalling in mammary cells.…”

Mitochondria and Antioxidants: The Active Players in Islet Oxidative Stress

“…LDL oxidation level, which is relevant to pathology of T2D, significantly changes the expression of genes involved in the production and secretion of insulin and in cell survival mechanisms. This effect was offset by NAC (Favre et al 2011). NAC counteracts the damaging effect of human amylin (hA), a small fibrillogenic protein, which accumulates in beta-cells in most subjects with T2D (Konarkowska et al 2005).…”