Dual role of interleukin-6 in regulating insulin sensitivity in murine skeletal muscle.
OBJECTIVE
Cytokines are elevated in various insulin-resistant states, including type 2 diabetes and obesity, although the contribution of interleukin-6 (IL-6) in the induction of these diseases is controversial.


METHODS
We analyzed the impact of IL-6 on insulin action in murine primary myocytes, skeletal muscle cell lines, and mice (wild type and protein-tyrosine phosphatase 1B [PTP1B] deficient).


RESULTS
IL-6 per se increased glucose uptake by activating serine/threonine protein kinase 11 (LKB1)/AMP-activated protein kinase/protein kinase B substrate of 160 kDa (AS160) pathway. A dual effect on insulin action was observed when myotubes and mice were exposed to this cytokine: additive with short-term insulin (increased glucose uptake and systemic insulin sensitivity) but chronic exposure produced insulin resistance (impaired GLUT4 translocation to plasma membrane and defects in insulin signaling at the insulin receptor substrate 1 [IRS-1] level). Three mechanisms seem to operate in IL-6-induced insulin resistance: activation of c-Jun NH(2)-terminal kinase 1/2 (JNK1/2), accumulation of suppressor of cytokine signaling 3 (socs3) mRNA, and an increase in PTP1B activity. Accordingly, silencing JNK1/2 with either small interfering RNA or chemical inhibitors impaired phosphorylation of IRS-1 (Ser307), restored insulin signaling, and normalized insulin-induced glucose uptake in myotubes. When using a pharmacological approach, liver X receptor agonists overcome IL-6-induced insulin resistance by producing downregulation of socs3 and ptp1b gene expression. Finally, the lack of PTP1B confers protection against IL-6-induced insulin resistance in skeletal muscle in vitro and in vivo, in agreement with the protection against the IL-6 hyperglycemic effect observed on glucose and insulin tolerance tests in adult male mice.


CONCLUSIONS
These findings indicate the important role of IL-6 in the pathogenesis of insulin resistance and further implicate PTP1B as a potential therapeutic target in the treatment of type 2 diabetes.
Nieto-Vazquez
Iria
I
Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University, Madrid, Spain.
Fernández-Veledo
Sonia
S
de Alvaro
Cristina
C
Lorenzo
Margarita
M
D000263:Adenylate Kinase / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001692:Biological Transport / Q000187:drug effects; D005121:Extremities; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D015850:Interleukin-6 / Q000502:physiology*; D051379:Mice; D032342:Muscle Cells / Q000187:drug effects / Q000502:physiology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology*; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D016133:Polymerase Chain Reaction; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics
D051275:Glucose Transporter Type 4; D007328:Insulin; D015850:Interleukin-6; D034741:RNA, Small Interfering; C495693:Slc2a4 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D000263:Adenylate Kinase; D005947:Glucose
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