Considering that IRS-2 plays an important role in hepatic nutrient homeostasis, we have investigated the expression of GK and GK activity and also GKRP expression in the liver, using two experimental models of insulin receptor substrate-2 deficiency in mice: IRS-2 deficient mice that develop type 2 diabetes at 10–12 weeks of age and IRS-2 deficient mice in which Irs-2 was specifically reintroduced into pancreatic β-cells [RIP-Irs-2/IRS-2(−/−)] to restore pancreatic β-cell compensation. Here, IRS2 is linked to type 2 diabetes mellitus.