Differential Effects of Interleukin-6 and -10 on Skeletal Muscle and Liver Insulin Action In Vivo

Differential Effects of Interleukin-6 and -10 on Skeletal Muscle and Liver Insulin Action In Vivo Hyo-Jeong Kim 1 , Takamasa Higashimori 1 , So-Young Park 1 , Hyejeong Choi 1 , Jianying Dong 1 , Yoon-Jung Kim 1 , Hye-Lim Noh 1 , You-Ree Cho 1 , Gary Cline 1 , Young-Bum Kim 2 and Jason K. Kim 1 1 Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut 2 Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts Address correspondence and reprint requests to Jason K. Kim, PhD, Yale University School of Medicine, Department of Internal Medicine, Section of Endocrinology and Metabolism, 300 Cedar St., The Anlyan Center, South 269C, P.O. Box 208020, New Haven, CT 06520-8020. E-mail: jason.k.kim{at}yale.edu Abstract 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. 2-[