This study investigates the role of SOCS proteins (SOCS1 and SOCS3) in insulin signaling and insulin resistance. The authors found that SOCS1 and SOCS3 target IRS1 and IRS2, two critical insulin receptor substrates, for ubiquitination and subsequent degradation through the elongin BC ubiquitin-ligase complex. This degradation is essential for the induction of insulin resistance and glucose intolerance. In cultured cells and mouse liver, SOCS1 and SOCS3 reduced IRS1 and IRS2 levels, leading to decreased insulin sensitivity. Adenoviral expression of wild-type SOCS1 in mouse liver resulted in significant reductions in hepatic IRS1 and IRS2 levels and glucose intolerance, while expression of mutant SOCS1 lacking the elongin BC binding site did not affect IRS protein levels or glucose metabolism. These findings suggest that SOCS-mediated degradation of IRS proteins is a key mechanism of inflammation-induced insulin resistance and provide a potential therapeutic target for treating insulin resistance syndromes and diabetes.This study investigates the role of SOCS proteins (SOCS1 and SOCS3) in insulin signaling and insulin resistance. The authors found that SOCS1 and SOCS3 target IRS1 and IRS2, two critical insulin receptor substrates, for ubiquitination and subsequent degradation through the elongin BC ubiquitin-ligase complex. This degradation is essential for the induction of insulin resistance and glucose intolerance. In cultured cells and mouse liver, SOCS1 and SOCS3 reduced IRS1 and IRS2 levels, leading to decreased insulin sensitivity. Adenoviral expression of wild-type SOCS1 in mouse liver resulted in significant reductions in hepatic IRS1 and IRS2 levels and glucose intolerance, while expression of mutant SOCS1 lacking the elongin BC binding site did not affect IRS protein levels or glucose metabolism. These findings suggest that SOCS-mediated degradation of IRS proteins is a key mechanism of inflammation-induced insulin resistance and provide a potential therapeutic target for treating insulin resistance syndromes and diabetes.