Abstract
Pancreatic β-cell failure is a critical event in the onset of both main types of diabetes mellitus but underlying mechanisms are not fully understood. β-cells have low anti-oxidant capacity, making them more susceptible to oxidative stress. In type 1 diabetes (T1D), reactive oxygen species (ROS) are associated with pro-inflammatory conditions at the onset of the disease. Here, we investigated the effects of hydrogen peroxide-induced oxidative stress on human β-cells. We show that primary human β-cell function is decreased. This reduced function is associated with an ER stress response and the shuttling of FOXO1 to the nucleus. Furthermore, oxidative stress leads to loss of β-cell maturity genes MAFA and PDX1, and to a concomitant increase in progenitor marker expression of SOX9 and HES1. Overall, we propose that oxidative stress-induced β-cell failure may result from partial dedifferentiation. Targeting antioxidant mechanisms may preserve functional β-cell mass in early stages of development of T1D.
Highlights
Type 1 diabetes (T1D) is a chronic autoimmune disease caused by T cell-mediated destruction of pancreatic insulin-producing b-cells [1,2,3]
We validated the effect of H2O2 in human islets by showing a shuttling of the transcription factor FOXO1 from its normal cytoplasmic localization to the nucleus upon H2O2 treatment (Figure 1A), a known adaptation response to oxidative stress [30]
Our study demonstrates that oxidative stress leads to loss of bcell function that is associated with a stress response and evidence of dedifferentiation, as indicated by the loss of b-cell maturity markers and the upregulation of endocrine progenitor markers
Summary
Type 1 diabetes (T1D) is a chronic autoimmune disease caused by T cell-mediated destruction of pancreatic insulin-producing b-cells [1,2,3]. Autoimmune recognition of b-cell antigens leads to decreased b-cell mass and the subsequent decline of insulin-mediated regulation of glucose levels in the blood eventually results in chronic hyperglycemia and T1D. Oxidative stress has been implicated in the onset of b-cell failure in T1D [4,5,6]. Oxidative stress occurs when reactive oxygen species (ROS) levels overcome antioxidant defenses. B-cells have been shown to be sensitive to oxidative stress when compared to other islet cell types, as they display low levels of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, and catalase [8,9,10] ROS, a byproduct of mitochondrial metabolism, act as signaling molecules for glucose-stimulated insulin secretion in b-cells. b-cells have been shown to be sensitive to oxidative stress when compared to other islet cell types, as they display low levels of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, and catalase [8,9,10]
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