Mitochondrial oxidative stress contributes differently to rat pancreatic islet cell apoptosis and insulin secretory defects after prolonged culture in a low non-stimulating glucose concentration

Aims/hypothesis Pancreatic beta cells chronically exposed to low glucose concentrations show signs of oxidative stress, loss of glucose-stimulated insulin secretion (GSIS) and increased apoptosis. Our aim was to confirm the role of mitochondrial oxidative stress in rat islet cell apoptosis under the...

Full description

Saved in:
Bibliographic Details
Published in:Diabetologia 2012-08, Vol.55 (8), p.2226-2237
Main Authors: Roma, L. P., Pascal, S. M., Duprez, J., Jonas, J.-C.
Format: Article
Language:English
Subjects:
Adenoviruses
Animals
Apoptosis
Apoptosis - drug effects
Biological and medical sciences
Cells, Cultured
Diabetes. Impaired glucose tolerance
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Etiopathogenesis. Screening. Investigations. Target tissue resistance
Genes
Glucose
Glutathione - pharmacology
Green Fluorescent Proteins - pharmacology
Human Physiology
Insulin - biosynthesis
Insulin - metabolism
Insulin resistance
Insulin Secretion
Insulin-Secreting Cells - metabolism
Internal Medicine
Kinases
Luminescent Measurements - methods
Male
Medical sciences
Medicine
Medicine & Public Health
Metabolic Diseases
Metabolism
Metalloporphyrins - pharmacology
Mitochondria - metabolism
Oxidation
Oxidative stress
Oxidative Stress - drug effects
Pancreas, Exocrine - metabolism
Proteins
Rats
Rats, Wistar
RNA, Messenger
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Aims/hypothesis Pancreatic beta cells chronically exposed to low glucose concentrations show signs of oxidative stress, loss of glucose-stimulated insulin secretion (GSIS) and increased apoptosis. Our aim was to confirm the role of mitochondrial oxidative stress in rat islet cell apoptosis under these culture conditions and to evaluate whether its reduction similarly improves survival and GSIS. Methods Apoptosis, oxidative stress-response gene mRNA expression and glucose-induced stimulation of mitochondrial metabolism, intracellular Ca 2+ concentration and insulin secretion were measured in male Wistar rat islets cultured for 1 week in RPMI medium containing 5–10 mmol/l glucose with or without manganese(III)tetrakis(4-benzoic acid)porphyrin (MnTBAP) or N -acetyl- l- cysteine (NAC). Oxidative stress was measured in islet cell clusters cultured under similar conditions using cytosolic and mitochondrial redox-sensitive green fluorescent protein (roGFP1/mt-roGFP1). Results Prolonged culture in 5 vs 10 mmol/l glucose increased mt-roGFP1 (but not roGFP1) oxidation followed by beta cell apoptosis and loss of GSIS resulting from reduced insulin content, mitochondrial metabolism, Ca 2+ influx and Ca 2+ -induced secretion. Tolbutamide-induced, but not high K + -induced, Ca 2+ influx was also suppressed. Under these conditions, MnTBAP, but not NAC, triggered parallel ∼50–70% reductions in mt-roGFP1 oxidation and beta cell apoptosis, but failed to protect against the loss of GSIS despite significant improvement in glucose-induced and tolbutamide-induced Ca 2+ influx. Conclusions/interpretation Mitochondrial oxidative stress contributes differently to rat pancreatic islet cell apoptosis and insulin secretory defects during culture in a low glucose concentration. Thus, targeting beta cell survival may not be sufficient to restore insulin secretion when beta cells suffer from prolonged mitochondrial oxidative stress, e.g. in the context of reduced glucose metabolism.
ISSN:0012-186X
1432-0428
DOI:10.1007/s00125-012-2581-6