Aims: Thioredoxin-interacting protein (TXNIP) is a crucial molecular promoter of oxidative stress and has been identified to be associated with cellular senescence. It is an important mediator of β cell insulin secretion and has effects on β cell mass. However, its role in β cell senescence is unclear. The present study was designed to investigate the effects and mechanisms of TXNIP on the senescence and aging- and diet-related dysfunction of β cells. Methods: Human pancreatic paraffin tissues and serum samples from different ages were collected to detect TXNIP expression. TXNIP-/- and C57BL/6J mice were fed either a normal chow diet (NCD) or a high-fat diet (HFD) until 5, 11, 14, or 20 months. The recapitulation experiment was conducted with TXNIP protein injection. MIN6 cells were transfected with LV-TXNIP and LV-siTXNIP. The biochemical indexes, ageing-related markers, cell cycle proteins, and pathways were examined both in vivo and in vitro. Results: TXNIP expression showed an age-related increase in β cells and serum samples from humans. TXNIP significantly impaired glucose metabolism and insulin secretion in an age-dependent manner. TXNIP aggravated age-related and obesity-induced structural failure, oxidative stress, decreased proliferation, increased apoptosis in β cells, and induced the cell cycle arrest. TXNIP interacted with p38 mitogen-activated protein kinase (p38MAPK) and modulated the p16/p21-CDK-Rb axis to accelerate β cell senescence. Innovation and Conclusions: The present study demonstrated that TXNIP may exacerbate pancreatic β cell senescence and age-related dysfunction by inducing cell cycle arrest through the p38-p16/p21-CDK-Rb pathway, in natural and pathological states. Antioxid. Redox Signal. 38, 480-495.
Keywords: TXNIP; cell cycle; cellular senescence; p38MAPK; β cell.