Hepatic insulin signaling and glycogen synthesis pathways

The hepatic insulin signaling and glycogen synthesis pathway is a fundamental metabolic circuit responsible for maintaining systemic glucose homeostasis (StatPearls: NBK534817). In the postprandial state, insulin binds to the hepatic insulin receptor (INSR), initiating a signal transduction cascade through insulin receptor substrates (IRS) and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway (UniProt: P06213). A key downstream effect is the inhibition of glycogen synthase kinase 3 (GSK3), which allows glycogen synthase (GYS2) to remain in its active, dephosphorylated state, facilitating the conversion of glucose into glycogen (UniProt: P54840). Impairment of this pathway leads to hepatic insulin resistance, a central feature of type 2 diabetes and metabolic syndrome, characterized by excessive glucose production and reduced storage (PMID: 21864752). Therapeutic strategies targeting this pathway include insulin mimetics and sensitizers that aim to restore the liver's ability to respond to hormonal cues and regulate blood sugar levels effectively.

Other names

Hepatic insulin signaling cascadeInsulin-mediated glycogenesisLiver insulin signaling pathway

Activation of the hepatic insulin receptor (INSR) triggers a phosphorylation cascade involving insulin receptor substrates (IRS) and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which inhibits glycogen synthase kinase 3 (GSK3), thereby activating glycogen synthase (GYS2) to promote hepatic glucose storage (PMID: 21864752).