Abstract
BackgroundType 2 diabetes mellitus (T2DM) is characterized by pancreatic β-cell failure, which arises from metabolic stress and results in β cell dedifferentiation, leading to β-cell death. Pathological activation of the renin–angiotensin system (RAS) contributes to increase cell stress, while RAS intervention reduces the onset of T2DM in high-risk populations and promotes insulin secretion in rodents. In this study, we investigated whether and how RAS induces β-cell dedifferentiation and the mechanism underlying this process.MethodsIn vitro, with the methods of quantitative real-time reverse transcriptase-PCR (qRT-PCR) and western blotting, we examined the change of cell identity-related gene expression, progenitor like gene expression, cellular function, and nuclear factor kappa b (NF-κb) signaling activity in β cell lines after exposure to angiotensin II (AngII) and disruption of RAS. In vivo, parallel studies were performed using db/db mice. Related protein expression was detected by Immunofluorescence analysis.ResultActivation of RAS induced dedifferentiation and impaired insulin secretion, eventually leading to β-cell failure. Mechanistically, Angll induced β-cell dedifferentiation via NF-κb signaling, while treatment with lrbesartan and sc-514 reversed the progenitor state of β cells.ConclusionThe present study found that RAS might induce β-cell dedifferentiation via angiotensin II receptor type 1 activation, which was promoted by NF-κb signaling. Therefore, blocking RAS or NF-kb signaling efficiently reversed the dedifferentiated status of β cells, suggesting a potential therapy for patients with type 2 diabetes.
Highlights
Type 2 diabetes mellitus (T2DM) is characterized by pancreatic β-cell failure, which arises from metabolic stress and results in β cell dedifferentiation, leading to β-cell death
renin–angiotensin system (RAS) inhibition reverses glucotoxicity-induced compromised β-cell identity To investigate the effect of RAS blockade on glucose-induced β-cell dysfunction, mouse pancreatic β-cell lines were exposed to increased concentrations of glucose in the presence or absence of Irbesartan (10 μmol/L) for 24 h (Additional file 1: Table S1). β-cell dysfunction was closely related to glucose levels, and exposure to a high glucose environment resulted in a sharp decrease in glucose-stimulated insulin secretion and the stimulatory index in β cells (Fig. 1a-d)
We found that a high glucose concentration triggered RAS signaling, which could be inhibited by Irbesartan, an angiotensin II type 1 receptor (AT1R) blocker
Summary
Type 2 diabetes mellitus (T2DM) is characterized by pancreatic β-cell failure, which arises from metabolic stress and results in β cell dedifferentiation, leading to β-cell death. Pathological activation of the renin–angiotensin system (RAS) contributes to increase cell stress, while RAS intervention reduces the onset of T2DM in high-risk populations and promotes insulin secretion in rodents. Pancreatic β-cell failure underlies the progressive development of type 2 diabetes, accompanied by the functional decline of β cells which commonly arises from metabolic stress and dedifferentiation (Swisa et al, 2017; Weir et al, 2013). Increasing evidence shows that the pathological stimulation of the renin–angiotensin system (RAS) is associated with type 2 diabetes and that RAS inhibitors, either Angiotensin (Ang) II type 1 receptor blockers (ARBs) or Angll-converting enzyme inhibitors (ACEi), delay new. It has been recognized recently that loss of the fully differentiated state is a potential mechanism underlying compromised β-cell function in type 2 diabetes (Spijker et al, 2015; Steven et al, 2016)
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