Abstract
Dysfunction of β-cell is one of major characteristics in the pathogenesis of type 2 diabetes. The combination of obesity and type 2 diabetes, characterized as ‘diabesity’, is associated with elevated plasma free fatty acids (FFAs). Oxidative stress has been implicated in the pathogenesis of FFA-induced β-cell dysfunction. However, molecular mechanisms linking between reactive oxygen species (ROS) and FFA-induced β-cell dysfunction and apoptosis are less clear. In the present study, we test the hypothesis that NOX2-derived ROS may play a critical role in dysfunction and apoptosis of β-cells induced by FFA. Our results show that palmitate and oleate (0.5 mmol/L, 48 h) induced JNK activation and AKT inhibition which resulted in decreased phosphorylation of FOXO1 following nuclear localization and the nucleocytoplasmic translocation of PDX-1, leading to the reducing of insulin and ultimately dysfunction of pancreatic NIT-1 cells. We also found that palmitate and oleate stimulated apoptosis of NIT-1 cells through p38MAPK, p53 and NF-κB pathway. More interestingly, our data suggest that suppression of NOX2 may restore FFA-induced dysfunction and apoptosis of NIT-1 cells. Our findings provide a new insight of the NOX2 as a potential new therapeutic target for preservation of β-cell mass and function.
Highlights
Type 2 diabetes is a multifactorial disease including genetic and many other environmental factors
Increased reactive oxygen species (ROS) generation in NIT-1 cells treated with palmitate and oleate is mainly derived by NADPH oxidase 2 (NOX2)
The results indicate that transfection of siRNA-NOX2, but not control siRNA, significantly reduced ROS generation in NIT-1 cells treated with either palmitate or oleate (Fig. 1D), suggesting that NOX2 serves as the possible predominant source of ROS generation stimulated by palmitate and oleate
Summary
Type 2 diabetes is a multifactorial disease including genetic and many other environmental factors. Dysfunction of b-cell is one of major characteristics in the pathogenesis of type 2 diabetes [1]. The combination of obesity and type 2 diabetes, characterized as ‘diabesity’, is associated with excessive release of fatty acids from the expanded adipose tissue mass, leading to elevated plasma free fatty acids (FFAs) [2]. Dysfunction of b-cell is induced by several molecules including glucose, FFA, and certain cytokines such as TNF-a [3]. Elevated plasma FFA levels, which are often accompanied by obesity, may play a causal role in b-cell dysfunction. It is reported that acute FFA exposure stimulates insulin secretion, while prolonged FFA exposure decreases glucose-stimulated insulin secretion (GSIS) [4,5]. Molecular mechanisms linking FFA to b-cell dysfunction remain poorly understood
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