Mechanisms and Targeted Control of Pancreatic Beta Cell Antioxidant Response

Abstract

Type 1 diabetes (T1D) is an autoimmune disorder characterized by the destruction of insulin-producing beta cells in the pancreas, leading to chronic hyperglycemia. The intricate interplay between genetic predispositions, environmental triggers, and immune dysregulation underpins the development of T1D. A commonality between the environmental triggers is their involvement in the generation of reactive oxygen species (ROS). ROS are a byproduct of many cellular reactions and at low levels acts as an important second messenger to regulate proliferation, inflammation, and cell survival. However, excessive ROS accumulation can lead to oxidative stress, which may contribute to the pathogenesis of T1D. Failure to resolve oxidative stress causes damage to DNA, protein, and organelles, and ultimately results in cell death. One of the primary mechanisms to mitigate oxidative stress is through the activation of the transcription factor, nuclear factor erythroid-related 2 factor 2 (NRF2). We hypothesized that rapid activation of the antioxidant response in response to extrinsic stress is essential for proper beta cell function. To investigate the role of the antioxidant response in beta cells, we generated a beta cell specific NRF2 knockout mouse model (NRF2Δβ). These mice do not develop overt diabetes. However, despite these observations, we observed a modest impairment in first-phase insulin secretion. Additionally, the beta cells in NRF2Δβ mice displayed evidence of DNA damage and early signs of apoptosis, which are hallmarks of oxidative stress. To understand the mechanism behind impaired insulin secretion, we investigated mitochondrial structure and function. We observed mitochondria with disrupted morphology. Surprisingly, the mitochondria did not exhibit impaired function. We then asked whether loss of beta cell NRF2 was associated with increased susceptibility to beta cell damage induced by the toxic glucose analog, streptozotocin. We did not observe exacerbated diabetes development in NRF2Δβ mice. Collectively, these data suggest activation of compensatory mechanisms to mitigate beta cell stress and restore homeostasis in the absence of NRF2. RNA sequencing revealed several possible mechanisms such as increased autophagy, upregulation of antioxidants through alternative pathways, increased proteolysis, and increased glycosylation. In summary, this data highlights the importance of redox homeostasis in preserving beta cell function which may play a critical role in preventing or delaying T1D.