Excessive ethanol exposure exacerbates pyroptosis of pancreatic β-cells via NLRP3/GSDMD activation in type 2 diabetic...

Chronic excessive ethanol intake is known to exacerbate the progression of type 2 diabetes mellitus (T2DM). The overactivation of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, which triggers gasdermin D (GSDMD)-mediated pyroptosis of pancreatic β-cells, is a crucial pathway in the deterioration of T2DM. However, the effects of ethanol on this process and the underlying mechanisms are not well understood. This study aimed to investigate the impact of ethanol exposure on pyroptosis of pancreatic β-cells and to determine whether it involves the NLRP3/GSDMD signaling pathway using high glucose (HG)-treated INS-1 cells and T2DM mice. In vitro, ethanol exposure induced a time- and concentration-dependent increase in pyroptotic bodies, excessive generation of reactive oxygen species (ROS), and overactivation of the NLRP3/GSDMD signaling in HG-treated INS-1 cells. However, inhibition of NLRP3 or caspase-1 significantly alleviated these adverse effects. In the T2DM mouse model, ethanol feeding worsened glucose and lipid metabolic disorders, decreased insulin sensitivity, and resulted in abnormal islet morphology and β-cell pyroptosis, along with overactivation of the NLRP3/GSDMD signaling pathway in pancreatic tissues. Importantly, these effects of ethanol were absent in Nlrp3^-/- mice. Our findings demonstrate that excessive ethanol exposure can exacerbate pyroptosis of pancreatic β-cells in T2DM mice by activating the NLRP3/GSDMD signaling pathway, thereby accelerating disease progression. This study provides new insights into the mechanisms underlying the harmful effects of ethanol on T2DM and highlights the potential therapeutic role of targeting the NLRP3/GSDMD pathway in ethanol-associated diabetes complications.