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Type 2 diabetes mellitus (T2DM) and prostate cancer are closely linked, affecting overlapping age groups of predominantly male populations. Flutamide (FLU) is metabolized in the liver to hydroxyflutamide (OHF), exerting anti-androgenic effects and is mainly used for prostate cancer treatment. During its use, occasional adverse reactions such as elevated blood glucose and worsening conditions in T2DM patients have been observed, but the cause remains unknown. This study aims to investigate the effects and mechanisms of FLU on hepatic insulin resistance under T2DM conditions. In vitro, a primary mouse hepatocyte model of insulin sensitivity impairment induced by high glucose (HG) was established to observe the effects of FLU/OHF on cellular lipid accumulation, reactive oxygen species (ROS) production, NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) signaling, and insulin signaling. NLRP3 inhibitors, ROS scavengers, and hepatocytes from Nlrp3-knockout mice were used to explore the mechanisms of FLU. In vivo, a high-fat diet (HFD)/streptozotocin (STZ) induced-T2DM mouse model was established to observe the effects of FLU gavage on glucose and lipid metabolism, insulin sensitivity, and histopathology. The results showed that FLU exposure exacerbated lipid accumulation, ROS production, over-activation of NLRP3 signaling, and impaired insulin signaling in HG-treated hepatocytes. Inhibition of NLRP3, scavenging of ROS, or knockout of Nlrp3 eliminated the above effects of FLU/OHF. FLU exacerbated glucose and lipid metabolism disorders in HFD/STZ induced-T2DM mice, increased hepatic insulin resistance, and activated the hepatic NLRP3 signaling pathway. The results of this study suggest that FLU treatment is associated with exacerbated hepatic insulin resistance in mice with T2DM, an effect that may be mediated through ROS overproduction and activation of NLRP3 signaling.