Hepatic Insulin Clearance: Mechanism and Physiology

Upon its secretion from pancreatic β-cells, insulin reaches the liver through the portal circulation to exert its action and eventually undergo clearance in the hepatocytes. In addition to insulin secretion, hepatic insulin clearance regulates the homeostatic level of insulin that is required to reach peripheral insulin target tissues to elicit proper insulin action. Receptor-mediated insulin uptake followed by its degradation constitutes the basic mechanism of insulin clearance. Upon its phosphorylation by the insulin receptor tyrosine kinase, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) takes part in the insulin-insulin receptor complex to increase the rate of its endocytosis and targeting to the degradation pathways. This review summarizes how this process is regulated and how it is associated with insulin-degrading enzyme in the liver. It also discusses the physiological implications of impaired hepatic insulin clearance: Whereas reduced insulin clearance cooperates with increased insulin secretion to compensate for insulin resistance, it can also cause hepatic insulin resistance. Because chronic hyperinsulinemia stimulates hepatic de novo lipogenesis, impaired insulin clearance also causes hepatic steatosis. Thus impaired insulin clearance can underlie the link between hepatic insulin resistance and hepatic steatosis. Delineating these regulatory pathways should lead to building more effective therapeutic strategies against metabolic syndrome.
This work was supported by grants from the National Institutes of Health (R01-DK-054254, R01-DK-083850, and R01-HL-112248) to S.M.N., and from Ministerio de Economía, Industria y Competitividad (SAF2014-58702-C2-2-R and SAF2016-77871-C2-2-R) to G.P. The work was also supported by the EFSD European Research Programme on New Targets for Type 2 Diabetes supported by an educational research grant from MSD to G.P.