The invention discloses a mouse model with the IRTKS gene in the liver specifically eliminated as well as construction and applications of the mouse model. Through homologous recombination, a 2.245-kb frt-neo-frt-loxp-Flox-loxp sequence replaces a sequence containing exon2 in the mouse IRTKS gene, and thus the chimeric mouse with IRTKS<flox/+> is obtained; by utilizing the Cre recombinase, the obtained chimeric mouse mates with the mouse Alb-Cre with specific expression of Cre of the liver, and finally, the mouse model with IRTKS gene in the liver specifically eliminated is obtained. The mouse model with the IRTKS gene eliminated constructed by adopting the method provided the invention can be used for researching diabetes mellitus; through the body weight, fasting blood-glucose, sugar tolerance and clinicopathologic analysis, the result shows that the features conform to the human diabetes mellitus morbidity features, and thus a good animal model is provided for researching the diabetes mellitus morbidity mechanism and evaluating and screening treatment medicines.