Salidroside alleviates ethanol exposure-exacerbated hepatic insulin resistance in diabetic mice

Long-term excessive ethanol consumption is known to accelerate the progression of diabetes mellitus (DM). Our previous study indicated that salidroside (SAL) improves hepatic insulin resistance in DM mice. However, the underlying mechanisms of ethanol on this process and whether SAL can exert a therapeutic effect are not fully understood. The aim of this study is to investigate the effect of SAL on ethanol-exacerbated hepatic insulin resistance and its underlying mechanisms in DM conditions. Primary mouse hepatocytes were isolated and cultured to establish an insulin sensitivity impaired model. The effects of ethanol exposure at different concentrations or for different durations on intracellular lipid accumulation, the insulin signaling pathway of Akt/glycogen synthase kinase 3β (GSK3β), and the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome signaling were observed. An NLRP3 inhibitor was used to determine whether the effects of ethanol were dependent on the overactivation of the NLRP3 inflammasome signaling and to investigate the intervention effects of SAL. A DM model was established by feeding a high-fat diet combined with streptozotocin injection to observe the effects of ethanol exposure on blood glucose and body weight, biochemical and histopathological indicators, as well as the Akt/GSK3β and NLRP3 inflammasome signaling in liver tissue. In vitro, ethanol exposure exacerbated lipid accumulation and insulin sensitivity impairment in hepatocytes in a concentration- and time-dependent manner. This effect was dependent on the overactivation of the NLRP3 inflammasome, and co-incubation with SAL could effectively improve the above phenomena. In vivo, ethanol exposure also exacerbated liver insulin resistance, and SAL treatment could improve this condition. SAL has an ameliorative effect on the ethanol-exacerbated liver insulin resistance in diabetic mice.