〔Abstract〕 Abstract Objective Pathological changes and inducible nitric oxide synthase ( iNOS), phosphorylated insulin receptor substrate 1 serine 307 (p-IRS1ser 307), phosphorylated protein kinase B serine 473 ( p-AKTser 473), glycogen synthase kinase-3 β(GSK-3 β), and gluconeogenic synthase (GS) proteins were observed in the liver of rats under the condition of chronic intermittent hypoxia-replicated oxygen in control . And to explore the role of iN- OS/IRS1 /AKT/GSK-3 βsignaling pathway in chronic intermittent hypoxia-induced insulin resistance . Methods Forty SD rats were randomly divided into a control group ( NC group) and an experimental group ( CIH group), with 20 rats in each group . The NC group was placed in a normoxic environment for 12 weeks , while the CIH group was first subjected to intermittent hypoxia for 8 weeks , and then resumed normoxic rearing until the 12th week . Fasting blood glucose (FBG) and fasting insulin (FINS) were measured at baseline , week 8 and week 12 , and liv- er tissues were taken for pathology and measurement of iNOS , p-IRS1ser 307 , p-AKTser 473 , GSK3 βand GS lev- els , to compare the differences between groups . Results At baseline , there was no significant difference in liver pathology between the two groups , and the observed indexes were not statistically significant ( P > 0. 05 ); at 8 weeks , compared with the NC group , liver pathology in the CIH group showed significant disorganization of hepatic blood sinusoids and hepatocyte cords , obvious hepatocyte edema , smaller nuclei , increased lymphocyte infiltration , and a small number of fat vacuoles , significantly higher levels of FBG , FINS , insulin resistance index ( HOMA- IR), iNOS mRNA , p-IRS1ser 307 protein , GSK-3 βprotein levels , and decreased p-AKTser 473 protein and GS protein levels , all of which were statistically significant (all P < 0. 05) . IRS1ser 307 protein , GSK-3 βprotein lev- els were increased , p-AKTser 473 protein and GS protein levels were decreased , and the differences were statisti- cally significant (all P < 0. 05); at 12 weeks , no lymphocyte infiltration was seen in the CIH group compared with that of the NC group and fat vacuoles significantly increased , and there was no improvement in the other pathological damage that had already occurred , and the levels of p-AKTser 473 protein significantly increased . AKTser 473 protein level significantly increased , p-IRS1ser 307 protein and GS protein levels were significantly reduced , all of which were statistically significant (all P < 0. 05), and the rest of the observational indexes were not statistically significant. Pearson′s correlation analysis showed that HOMA-IR of CIH group was significantly positively correlated with the lev- els of iNOS mRNA , p-IRS1ser 307 protein , and GSK-3βprotein at 8 weeks ( r = 0. 874 , 0. 817 , 0. 872;all P < 0. 05), and significantly negatively correlated with the levels of p-AKTser 473 protein and GS protein ( r = - 0. 886 , - 0. 879;all P < 0. 05) . Conclusion Chronic intermittent hypoxia can lead to hepatic pathological damage that can- not be reversed even by reoxygenation interventions and may mediate the development of insulin resistance by upregu- lating the IRS1/AKT/GSK-3βsignaling pathway through the upregulation of iNOS mRNA expression.