Oxidative Stress in Pancreatic Beta Cell Regeneration

Jingjing Wang, Hongjun Wang, Jingjing Wang, Hongjun Wang

Abstract

Pancreatic β cell neogenesis and proliferation during the neonatal period are critical for the generation of sufficient pancreatic β cell mass/reserve and have a profound impact on long-term protection against type 2 diabetes (T2D). Oxidative stress plays an important role in β cell neogenesis, proliferation, and survival under both physiological and pathophysiological conditions. Pancreatic β cells are extremely susceptible to oxidative stress due to a high endogenous production of reactive oxygen species (ROS) and a low expression of antioxidative enzymes. In this review, we summarize studies describing the critical roles and the mechanisms of how oxidative stress impacts β cell neogenesis and proliferation. In addition, the effects of antioxidant supplements on reduction of oxidative stress and increase of β cell proliferation are discussed. Exploring the roles and the potential therapeutic effects of antioxidants in the process of β cell regeneration would provide novel perspectives to preserve and/or expand pancreatic β cell mass for the treatment of T2D.

Figures

Figure 1
Figure 1
β cells are extremely susceptible to oxidative stress. Two major factors render β cells prone to the risk of oxidative stress: a high endogenous generation of ROS induced by stimuli including hyperglycemia, hyperlipidemia, hypoxia, ER stress, and low expressions of essential antioxidant enzymes such as SOD, catalase, and GPx. Percentages refer to the amount of mRNA expression in pancreatic islets versus liver tissue in rats.
Figure 2
Figure 2
Effects of oxidative stress in β cell neogenesis. (a) An overview of the ROS expression levels at distinct stages of β cell development in mouse embryo. The presence of ROS (E12.5–E17.5) largely overlaps with the Ngn3 expression period (E14–E18.5). (b) Schematic diagram of effects of ROS on β cell neogenesis. On the one hand, hypoxia as an important inducer of ROS activates HIF-1α which suppresses Ngn3 expression, which results in impaired β cell neogenesis. On the other hand, ROS directly upregulates Ngn3 and Pdx-1 in β cell development, and NADPH oxidase seems to be a crucial source of ROS in this process, leading to increased β cell neogenesis.
Figure 3
Figure 3
Oxidative stress plays critical roles in β cell cycle. On cell-cycle regulators, accumulated ROS in beta cells suppressed the expression of cyclins D1 and D2, as well as increased cell-cycle inhibitors such as p21 and p27, leading to decreased β cell proliferation rate. Meanwhile, ROS promoted nuclear the translocation/activation of FoxO1, which in turn prevents β cell replication through the inhibition of Pdx-1 and possibly other β cell-related gene transcriptions. Furthermore, ROS also directly downregulates transcription factors such as Pdx-1, MafA, Nkx6.1, and Ngn3 that are crucial in beta cell proliferation and differentiation.

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