Transient oxidative stress damages mitochondrial machinery inducing persistent beta-cell dysfunction.
Transient exposure of beta-cells to oxidative stress interrupts the transduction of signals normally coupling glucose metabolism to insulin secretion. We investigated putative persistence of effects induced by one transient oxidative stress (200 microm H(2)O(2), 10 min) on insulin secreting cells following recovery periods of days and weeks. Three days after oxidative stress INS-1E cells and rat islets exhibited persistent dysfunction. In particular, the secretory response to 15 mm glucose was reduced by 40% in INS-1E cells stressed 3 days before compared with naïve cells. Compared with non-stressed INS-1E cells, we observed reduced oxygen consumption (-43%) and impaired glucose-induced ATP generation (-46%). These parameters correlated with increased mitochondrial reactive oxygen species formation (+60%) accompanied with down-regulation of subunits of the respiratory chain and decreased expression of genes responsible for mitochondrial biogenesis (TFAM, -24%; PGC-1alpha, -67%). Three weeks after single oxidative stress, both mitochondrial respiration and secretory responses were recovered. Moreover, such recovered INS-1E cells exhibited partial resistance to a second transient oxidative stress and up-regulation of UCP2 (+78%) compared with naïve cells. In conclusion, one acute oxidative stress induces beta-cell dysfunction lasting over days, explained by persistent damages in mitochondrial components.
Li
Ning
N
Department of Cell Physiology, Faculty of Medicine, University of Geneva, rue Michel-Servet 1, CH-1211 Geneva 4, Switzerland.
Brun
Thierry
T
Cnop
Miriam
M
Cunha
Daniel A
DA
Eizirik
Decio L
DL
Maechler
Pierre
P
D000818:Animals; D045744:Cell Line, Tumor; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D007328:Insulin; D017382:Reactive Oxygen Species; D005947:Glucose