Diabetic beta-cells can achieve self-protection against oxidative stress through an adaptive up-regulation of their antioxidant defenses.
BACKGROUND
Oxidative stress (OS), through excessive and/or chronic reactive oxygen species (ROS), is a mediator of diabetes-related damages in various tissues including pancreatic beta-cells. Here, we have evaluated islet OS status and beta-cell response to ROS using the GK/Par rat as a model of type 2 diabetes.


RESULTS
Localization of OS markers was performed on whole pancreases. Using islets isolated from 7-day-old or 2.5-month-old male GK/Par and Wistar control rats, 1) gene expression was analyzed by qRT-PCR; 2) insulin secretion rate was measured; 3) ROS accumulation and mitochondrial polarization were assessed by fluorescence methods; 4) antioxidant contents were quantified by HPLC. After diabetes onset, OS markers targeted mostly peri-islet vascular and inflammatory areas, and not islet cells. GK/Par islets revealed in fact protected against OS, because they maintained basal ROS accumulation similar or even lower than Wistar islets. Remarkably, GK/Par insulin secretion also exhibited strong resistance to the toxic effect of exogenous H(2)O(2) or endogenous ROS exposure. Such adaptation was associated to both high glutathione content and overexpression (mRNA and/or protein levels) of a large set of genes encoding antioxidant proteins as well as UCP2. Finally, we showed that such a phenotype was not innate but spontaneously acquired after diabetes onset, as the result of an adaptive response to the diabetic environment.


CONCLUSIONS
The GK/Par model illustrates the effectiveness of adaptive response to OS by beta-cells to achieve self-tolerance. It remains to be determined to what extend such islet antioxidant defenses upregulation might contribute to GK/Par beta-cell secretory dysfunction.
Lacraz
Grégory
G
Equipe B2PE (Biologie et Pathologie du Pancréas Endocrine), Unité BFA (Biologie Fonctionnelle et Adaptative), Université Paris-Diderot et CNRS EAC7059, Paris, France.
Figeac
Florence
F
Movassat
Jamileh
J
Kassis
Nadim
N
Coulaud
Josiane
J
Galinier
Anne
A
Leloup
Corinne
C
Bailbé
Danielle
D
Homo-Delarche
Françoise
F
Portha
Bernard
B
D000222:Adaptation, Physiological; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation
D007328:Insulin; D006861:Hydrogen Peroxide