When CEACAM1 level is reduced by >50%, hepatic insulin clearance fails and chronic hyperinsulinemia develops, causing hepatic insulin resistance, at least in part by downregulating insulin receptors in the hepatocyte (32, 33) and triggering de novo lipogenesis by activating SREBP1c-mediated transcription of lipogenic genes (13), including acetyl-CoA carboxylase (ACC), a limiting enzyme in lipid biosynthesis. Here, INSR is linked to hyperinsulinism.