Activation of the tyrosine kinase of the insulin receptor by insulin binding initiates a cascade of signaling pathways that mediates the metabolic and growth-promoting effects of insulin. Insulin action is regulated by the amount of circulating insulin, which is, in turn, partially regulated by insulin clearance in liver. Receptor-mediated insulin endocytosis followed by degradation mediates insulin clearance. Earlier studies in transfected cells suggested that the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a substrate of the insulin receptor in liver, upregulates receptor-mediated insulin endocytosis and degradation in a phosphorylation-dependent manner. To test this hypothesis, a transgenic mouse, L-SACC1, overexpressing a dominant-negative phosphorylation-defective S503A CEACAM1 mutant in liver was established. The transgenic mouse demonstrated that CEACAM1 increases insulin clearance to maintain insulin sensitivity. Because insulin resistance is the hallmark of type 2 diabetes, understanding the mechanism of CEACAM1 regulation of insulin clearance and action might lead to novel therapeutic strategies against this disease.