PMID- 22643931
OWN - NLM
STAT- MEDLINE
DCOM- 20121121
LR  - 20211021
IS  - 1432-0428 (Electronic)
IS  - 0012-186X (Linking)
VI  - 55
IP  - 8
DP  - 2012 Aug
TI  - 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.
PG  - 2226-37
LID - 10.1007/s00125-012-2581-6 [doi]
AB  - 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.
FAU - Roma, L P
AU  - Roma LP
AD  - Universite catholique de Louvain, Institut de recherche experimentale et 
      clinique, Pole d'endocrinologie, diabete et nutrition, Avenue Hippocrate 55, 
      B1.55.06, 1200, Brussels, Belgium.
FAU - Pascal, S M
AU  - Pascal SM
FAU - Duprez, J
AU  - Duprez J
FAU - Jonas, J-C
AU  - Jonas JC
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120529
PL  - Germany
TA  - Diabetologia
JT  - Diabetologia
JID - 0006777
RN  - 0 (Insulin)
RN  - 0 (Metalloporphyrins)
RN  - 0 (RNA, Messenger)
RN  - 0 (manganese(III)-tetrakis(4-benzoic acid)porphyrin)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Cells, Cultured
MH  - Glutathione/pharmacology
MH  - Green Fluorescent Proteins/pharmacology
MH  - Insulin/*biosynthesis/metabolism
MH  - Insulin Secretion
MH  - Insulin-Secreting Cells/*metabolism
MH  - Luminescent Measurements/methods
MH  - Male
MH  - Metalloporphyrins/*pharmacology
MH  - Mitochondria/metabolism
MH  - Oxidative Stress/*drug effects
MH  - Pancreas, Exocrine/*metabolism
MH  - RNA, Messenger
MH  - Rats
MH  - Rats, Wistar
EDAT- 2012/05/31 06:00
MHDA- 2012/12/10 06:00
CRDT- 2012/05/31 06:00
PHST- 2011/11/25 00:00 [received]
PHST- 2012/04/19 00:00 [accepted]
PHST- 2012/05/31 06:00 [entrez]
PHST- 2012/05/31 06:00 [pubmed]
PHST- 2012/12/10 06:00 [medline]
AID - 10.1007/s00125-012-2581-6 [doi]
PST - ppublish
SO  - Diabetologia. 2012 Aug;55(8):2226-37. doi: 10.1007/s00125-012-2581-6. Epub 2012 
      May 29.