TABLE 7

Studies of IL-6 on insulin signaling in hepatocytes

SettingResult (ref. no.)IL-6 induces insulin resistance
In vitro
    Rat hepatocytesIL-6 inhibits insulin-stimulated glycogen deposition in primary rat hepatocytes through decreased glucose incorporation into glycogen and increased glycogen degradation (72).Yes
    Mouse hepatocytes and HepG2 cellsAcute IL-6 challenge inhibits insulin receptor signal transduction and insulin action in both mouse hepatocytes and HepG2 cells 1) by decreasing tyrosine phosphorylation of IRS-1, 2) by decreasing the association of the p85 subunit of PI3K with IRS-1, and 3) by inhibiting insulin activation of Akt. Further, IL-6 inhibits insulin-induced glycogen synthesis by 75% (73).Yes
    HepG2 cellsAcute short-term IL-6 induces SOCS-3 mRNA and protein expression and is paralleled by inhibition of insulin receptor signaling as described above. Further, SOCS-3 directly inhibits insulin receptor autophosphorylation (74).Yes
In vivo
    MouseAcute short-term IL-6 challenge increases hepatic SOCS-3 expression and associates with inhibition of hepatic insulin-dependent receptor autophosphorylation and IRS-1 tyrosine phosphorylation (74).Yes
    MouseSixfold 5-day chronic IL-6 challenge increases STAT3 phosphorylation; reduces hepatic insulin receptor autophosphorylation by 60% and tyrosine phosphorylation of IRS-1 and -2 by 60 and 40%, respectively; and decreases refeeding-dependent glucokinase mRNA induction by ∼40% (71).Yes
    MouseShort-term IL-6 pretreatment blunts insulin’s ability to suppress hepatic glucose production and insulin-stimulated IRS-2–associated PI3K activity in liver (52).Yes
  • PI3K, phosphatidylinositol 3-kinase.