Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo.
The circulating level of the inflammatory cytokine interleukin (IL)-6 is elevated in various insulin-resistant states including type 2 diabetes, obesity, cancer, and HIV-associated lipodystrophy. To determine the role of IL-6 in the development of insulin resistance, we examined the effects of IL-6 treatment on whole-body insulin action and glucose metabolism in vivo during hyperinsulinemic-euglycemic clamps in awake mice. Pretreatment of IL-6 blunted insulin's ability to suppress hepatic glucose production and insulin-stimulated insulin receptor substrate (IRS)-2-associated phosphatidylinositol (PI) 3-kinase activity in liver. Acute IL-6 treatment also reduced insulin-stimulated glucose uptake in skeletal muscle, and this was associated with defects in insulin-stimulated IRS-1-associated PI 3-kinase activity and increases in fatty acyl-CoA levels in skeletal muscle. In contrast, we found that co-treatment of IL-10, a predominantly anti-inflammatory cytokine, prevented IL-6-induced defects in hepatic insulin action and signaling activity. Additionally, IL-10 co-treatment protected skeletal muscle from IL-6 and lipid-induced defects in insulin action and signaling activity, and these effects were associated with decreases in intramuscular fatty acyl-CoA levels. This is the first study to demonstrate that inflammatory cytokines IL-6 and IL-10 alter hepatic and skeletal muscle insulin action in vivo, and the mechanism may involve cytokine-induced alteration in intracellular fat contents. These findings implicate an important role of inflammatory cytokines in the pathogenesis of insulin resistance.
Kim
Hyo-Jeong
HJ
Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut 06520-8020, USA.
Higashimori
Takamasa
T
Park
So-Young
SY
Choi
Hyejeong
H
Dong
Jianying
J
Kim
Yoon-Jung
YJ
Noh
Hye-Lim
HL
Cho
You-Ree
YR
Cline
Gary
G
Kim
Young-Bum
YB
Kim
Jason K
JK
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism; D007262:Infusions, Intravenous; D007328:Insulin / Q000502:physiology*; D016753:Interleukin-10 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D008055:Lipids / Q000008:administration & dosage; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*
D001786:Blood Glucose; D007328:Insulin; D015850:Interleukin-6; D008055:Lipids; D016753:Interleukin-10