TXNIP exacerbates the senescence and ageing-related dysfunction of β-cells by inducing cell cycle arrest through p38-p16/p21-CDK-Rb pathway

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 ageing- 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 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 failures, oxidative stress, decreased proliferation, and 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.