The intracellular IL-6 signal transduction pathways. Modified from Kamimura et al. (7). The formation of the hexameric IL-6/IL-6Rα/gp130 complex initiates signal transduction by activating JAK kinases. Phosphorylated tyrosine residues (P) in gp130 are recognized by SHP-2 and STAT molecules, leading to generation of the two major gp130 signaling pathways: the Y759-derived SHP-2/ERK mitogen-activated protein kinase (MAPK) cascade (right) and the YXXQ-mediated STAT pathway (left). GAB, Grb-associated binder; PI3K, phosphatidylinositol 3-kinase.
Model of IL-6 actions of potential relevance for the pathogenesis of type 1 and type 2 diabetes. IL-6 is produced by many inflammatory cells, adipose tissue, working muscle, and even the β-cell. Expression is determined by genetic variation, intrauterine environment, age, and sex steroids. IL-6 induces insulin resistance in adipose tissue and liver and may synergize with proinflammatory cytokines to produce β-cell damage. IL-6 also regulates energy expenditure probably by the effect on brown adipose tissue via effects on the CNS. EE, energy expenditure; IA, immune activation; IR, insulin resistance; SC, synergy with proinflammatory cytokines.
* The reports were ranked based on the number of investigated individuals and thus the power of the study: 1 = low, 2 = intermediate, or 3 = high power. Only studies evaluating insulin resistance using minimal model measures or the euglycemic-hyperinsulinemic clamp were included, since studies using less precise determinations of insulin resistance may be flawed. Studies investigating obesity alone contain no comments. Not all genetic variants investigated are commented on if considered noninformative in the context or no association was established.
Does IL-6 play a role in β-cell destruction and apoptosis?
For an impact of IL-6 on β-cells (ref. no.)
Against an impact of IL-6 on β-cells (ref. no.)
IL-6 alone is not cytotoxic to rat and human islets/β-cells (31–35).
IL-6 potentiates IL-1–induced NO synthesis in rat islets (34).
IL-6 does not potentiate cytokine-induced NO synthesis in human islets (33).
IL-6 and dexamethasone induces Reg gene expression in RIN-m5F cells (36).
IL-6 protects mouse pancreatic islets and β-cells from inflammatory cytokine-induced cell death and functional impairment both in vitro and in vivo (37).
In vivo human autopsies
The HIP/PAP is expressed in islets of a new-onset type 1 diabetic patient and is released from healthy cadaveric human islets upon IL-6 treatment. HIP/PAP acts as a T-cell autoantigen in NOD mice (38).
IL-6 islet expression does not correlate with insulitis/β-cell destruction in humans (35).
IL-6 islet expression correlates with insulitis/β-cell destruction in NOD mice (35), and islet IL-6 expression is higher in NOD females than in males (39).
Il6-Tg under the control of the insulin promoter
β-Cell–specific overexpression of Il6 promotes islet inflammation in the NOD mouse (40) and in a non–diabetes-prone mouse strain (41).
IL-6 delays overt diabetes development in NOD mice (40) and the nondiabetic strain does not develop diabetes (41).
Il6-Tg non–diabetes-prone mice do not develop autoimmune diabetes (8).
Double Il6-Il6Rα-Tg non–diabetes-prone mice do not develop autoimmune diabetes (42).
NA, not available. →, unchanged; ↑, increased; ↓, decreased.
In vitro effects of IL-6 on insulin resistance in adipocyte cell lines
Effect of IL-6 on insulin sensitivity (ref. no.)
Negative effect on insulin sensitivity
Short-term IL-6 treatment enhances glucose transport, and the effect is additive to insulin-stimulated glucose transport (59).*
IL-6 decreases IRS-1 protein expression and insulin-stimulated tyrosine phosphorylation and reduces insulin-stimulated glucose transport (60).*
IL-6 decreases protein expression of the IR-β subunit and IRS-1 and inhibits insulin-induced activation of IR-β, protein kinase B, and ERK-1/2. It further suppresses insulin-induced lipogenesis and glucose transport by reducing expression of GLUT4 (61).*†
IL-6 decreases adiponectin gene expression and secretion in a dose- and time-dependent manner (63).*
Investigated cell lines:
* 3T3-L1 adipocytes,
† 3T3-F442A adipocytes. Protein kinase B is also known as Akt. IR, insulin receptor.
IL-6 as an insulin resistance–inducing agent in skeletal muscle
Result (ref. no.)
Indicates IL-6 induction of insulin resistance
In vivo rodent
Five-day continuous subcutaneous infusion of hIL-6 (sixfold elevation of IL-6 ∼ levels reached in obesity) does not suppress skeletal muscle insulin receptor signal transduction in mice at rest (71).
Two-hour IL-6 challenge reduces insulin-stimulated glucose uptake in skeletal muscle in mice and is associated with defects in insulin-stimulated IRS-1–associated PI3K activity, increased levels of fatty acyl-CoA, and increased tyrosine phosphorylation of STAT3 in skeletal muscle (52).
In vivo human
Three-hour IL-6 (high- and low-dose) administration does not affect muscle glucose uptake at rest (70).
SOCS-3 expression in human skeletal muscle is not related to insulin resistance in the presence of elevated IL-6 (65).
PI3K, phosphatidylinositol 3-kinase.
Studies of IL-6 on insulin signaling in hepatocytes
Result (ref. no.)
IL-6 induces insulin resistance
IL-6 inhibits insulin-stimulated glycogen deposition in primary rat hepatocytes through decreased glucose incorporation into glycogen and increased glycogen degradation (72).
Mouse hepatocytes and HepG2 cells
Acute 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).
Acute 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).
Acute 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).
Sixfold 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).
Short-term IL-6 pretreatment blunts insulin’s ability to suppress hepatic glucose production and insulin-stimulated IRS-2–associated PI3K activity in liver (52).