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

Aims/hypothesis Pro-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...

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Bibliographic Details
Published in:Diabetologia 2011-09, Vol.54 (9), p.2337-2346
Main Authors: Favre, D., Niederhauser, G., Fahmi, D., Plaisance, V., Brajkovic, S., Beeler, N., Allagnat, F., Haefliger, J. A., Regazzi, R., Waeber, G., Abderrahmani, A.
Format: Article
Language:English
Subjects:
Acetylcysteine - pharmacology
Animals
Antioxidants
Antioxidants - pharmacology
Apoptosis
Apoptosis - drug effects
Biological and medical sciences
Cells, Cultured
Cholesterol
Cyclic AMP Response Element Modulator - drug effects
Cyclic AMP Response Element Modulator - genetics
Cyclic AMP Response Element Modulator - physiology
Diabetes
Diabetes. Impaired glucose tolerance
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Etiopathogenesis. Screening. Investigations. Target tissue resistance
High density lipoprotein
Human Physiology
Humans
Hydrogen Peroxide - pharmacology
Hyperglycemia
Hypotheses
Insulin
Insulin - metabolism
Insulin-Secreting Cells - cytology
Insulin-Secreting Cells - drug effects
Insulin-Secreting Cells - physiology
Internal Medicine
Islets of Langerhans - cytology
Islets of Langerhans - drug effects
Islets of Langerhans - physiopathology
Kinases
Lipoproteins, LDL - pharmacology
Male
Medical sciences
Medicine
Medicine & Public Health
Metabolic Diseases
Models, Animal
Oxidation
Oxidative stress
Oxidative Stress - drug effects
Oxidative Stress - physiology
Pathophysiology
Proteins
Rats
Rats, Sprague-Dawley
RNA, Small Interfering - pharmacology
Transcription factors
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Summary:Aims/hypothesis Pro-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. Methods Isolated 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. Results Exposure 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/interpretation Induction of ICER links oxidative stress to beta cell failure caused by oxidised LDL and can be effectively abrogated by antioxidant treatment.
ISSN:0012-186X
1432-0428
DOI:10.1007/s00125-011-2165-x