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Figure 3. Hepatic insulin clearance and the clearance-resistance loop. (A) Hepatic insulin clearance. Portal delivery, receptor-mediated endocytosis, and consequences of impaired clearance. Under physiological conditions, insulin secreted in a biphasic, pulsatile pattern by pancreatic β-cells enters the portal venous system, establishing a portal-to-peripheral insulin gradient. Upon reaching the liver, 50%-80% of portal insulin is extracted during the first pass via receptor-mediated endocytosis in hepatocytes. Insulin binding to the INSR activates tyrosine kinase signaling, which phosphorylates CEACAM1; the phosphorylated CEACAM1-INSR-insulin complex is recruited to clathrin-coated pits via AP2 and internalized into acidified endosomes, where insulin is degraded by IDE, CTSD, and PDI, while the INSR is recycled to the plasma membrane. The residual ~50% of insulin reaches the peripheral circulation, where muscle, adipose tissue, brain, and erythrocytes contribute to disposal; the kidneys handle an additional 25%-40% through megalin-mediated reabsorption and IDE-dependent degradation in proximal tubule cells. Physiological hepatic clearance supports suppression of HGP, lipogenesis regulation, and glycogen synthesis. Conditions that impair hepatic clearance - including downregulation of CEACAM1, hepatic steatosis, obesity, and high-fat feeding - disrupt this axis and promote chronic hyperinsulinemia, peripheral insulin resistance, and MASLD. Subcutaneous insulin administration bypasses the portal route, abolishing the portal-to-peripheral gradient and resulting in relative hepatic under-insulinization alongside peripheral hyperinsulinemia; (B) The clearance-resistance loop. Pathological feedback between hepatic IR and impaired insulin clearance. Hepatic insulin resistance reduces INSR kinase activity and CEACAM1 phosphorylation, impairing receptor-mediated endocytosis and lowering hepatic insulin clearance. The resulting chronic hyperinsulinemia desensitizes and promotes INSR downregulation, further worsening hepatic insulin signaling and completing a self-reinforcing feedback cycle. Each node of this loop independently contributes to a common set of metabolic consequences (central panel). This clearance-resistance loop may represent an underappreciated and early driver of metabolic deterioration, operating independently of primary defects in β-cell secretory capacity. CEACAM1: Carcinoembryonic antigen-related cell adhesion molecule 1; INSR: insulin receptor; AP2: adaptor protein 2; IDE: insulin-degrading enzyme; CTSD: cathepsin D; PDI: protein disulfide isomerase; HGP: hepatic glucose production; MASLD: metabolic dysfunction-associated steatotic liver disease; IR: insulin resistance; T2D: type 2 diabetes.