Acetaminophen (APAP) hepatotoxicity is mediated by N-acetyl-p-benzoquinone imine (NAPQI), a highly toxic metabolite generated by cytochrome P450 2E1 (CYP2E1). Thus, pathological conditions increasing CYP2E1 activity can favour APAP-induced liver injury, which is characterized by massive hepatocellular necrosis and secondary sterile inflammation. In a recent work, Wang et al. showed that APAP-induced hepatotoxicity was exacerbated in a murine model of type 1 diabetes induced by the administration of streptozotocin (STZ). Higher hepatotoxicity was in particular associated with a stronger proinflammatory response of the resident macrophages. Although the authors carried out numerous investigations, they did not study hepatic CYP2E1, nor discussed the possible role of this enzyme in the exacerbation of APAP hepatotoxicity. However, numerous investigations reported hepatic CYP2E1 induction in STZ-treated rodents, which could be secondary to insulinopenia and ketosis. This commentary also discusses the role of insulin resistance in CYP2E1 induction observed in obesity and nonalcoholic fatty liver disease. Investigators studying APAP-induced liver injury in the context of insulinopenia or hyperinsulinemia are thus encouraged to consider CYP2E1 as a significant player in the observed phenotypic changes.