Carbon tetrachloride (CCl4 ), a potent hepatotoxin, is linked to the histopathological outcomes of inflammatory or oxidative stress, and cell death. However, further study of additional dysmetabolism induced by CCl 4 toxicant has not yet been investigated. In current study, chronical and acute exposures of CCl 4 in mice were used to unmask the biological molecular mechanism responsible for insulin-dependent metabolic disorder. In experimental methods, a number of biochemical assays were used in assessment of biological impacts on insulin-produced pancreas and insulin-responsive hepatocyte after long- and short-term exposures of CCl 4 toxicant, respectively. As a result, data from oral glucose tolerance test showed that CCl 4 exposures induced glucose tolerance and disrupted blood insulin and glucagon levels time-dependently. Meanwhile, biochemical and histocytological analyses further indicated that CCl 4 exposures significantly resulted in liver cell damage, induced abnormal changes of hepatic and skeletal glycogen synthesis. In addition, acute CCl 4 -exposed mice showed reduced functional proteins of glucose transporter 2 (GLUT2), insulin receptor β, insulin receptor substrate 1, glycogen synthase kinase 3β (GSK3β), p-AKT Ser473 associated with AKT signaling pathway in liver cells, whereas acute CCl 4 exposure downregulated the endogenous expressions of the insulin and glucagon hormonal proteins in the pancreas. Taken together, the current findings highlight that CCl 4 impaired insulin-dependent glucose homeostasis through modulating hepatocellular AKT signaling pathway in acute CCl 4 exposure and GLUT2/GSK3β pathway in chronic CCl 4 -exposed liver cells.