Abstract
BackgroundOxidative stress (OS), through excessive and/or chronic reactive oxygen species (ROS), is a mediator of diabetes-related damages in various tissues including pancreatic β-cells. Here, we have evaluated islet OS status and β-cell response to ROS using the GK/Par rat as a model of type 2 diabetes.Methodology/Principal FindingsLocalization 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 H2O2 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.ConclusionsThe GK/Par model illustrates the effectiveness of adaptive response to OS by β-cells to achieve self-tolerance. It remains to be determined to what extend such islet antioxidant defenses upregulation might contribute to GK/Par β-cell secretory dysfunction.
Highlights
Oxidative stress (OS) is a well-established mediator of hyperglycemic damage to a wide range of tissues, i.e., neurons, retinal cells and vascular endothelium [1]
Plasma atocopherol was higher in D7 and adult Goto–Kakizaki/Paris line (GK/Par) than agematched Wistar rats, indicating that the OS in GK/Par does not result from a-tocopherol deficiency
These data showed that signs of overall OS in GK/Par rat developed after diabetes onset
Summary
Oxidative stress (OS) is a well-established mediator of hyperglycemic damage to a wide range of tissues, i.e., neurons, retinal cells and vascular endothelium [1]. Because of their high aerobic glucose metabolism rates, pancreatic b-cells have so far been considered victims of this hyperglycemia-induced reactive oxygen species (ROS) scenario [2], even more than other cell types, as they were reported to express low levels of some classical ROS-scavenging enzyme systems [3,4]. Oxidative stress (OS), through excessive and/or chronic reactive oxygen species (ROS), is a mediator of diabetes-related damages in various tissues including pancreatic b-cells. We have evaluated islet OS status and b-cell response to ROS using the GK/Par rat as a model of type 2 diabetes
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