Interleukin-10 prevents diet-induced insulin resistance by attenuating macrophage and cytokine response in skeletal muscle

Eun Gyoung Hong, Jin Ko Hwi, You Ree Cho, Hyo Jeong Kim, Zhexi Ma, Tim Y. Yu, Randall H. Friedline, Evelyn Kurt-Jones, Robert Finberg, Matthew A. Fischer, Erica L. Granger, Christopher C. Norbury, Stephen D. Hauschka, William M. Philbrick, Chun Geun Lee, Jack A. Elias, Jason K. Kim

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228 Scopus citations

Abstract

OBJECTIVE - Insulin resistance is a major characteristic of type 2 diabetes and is causally associated with obesity. Inflammation plays an important role in obesity-associated insulin resistance, but the underlying mechanism remains unclear. Interleukin (IL)-10 is an anti-inflammatory cytokine with lower circulating levels in obese subjects, and acute treatment with IL-10 prevents lipid-induced insulin resistance. We examined the role of IL-10 in glucose homeostasis using transgenic mice with muscle-specific overexpression of IL-10 (MCK-IL10). RESEARCH DESIGN AND METHODS - MCK-IL10 and wildtype mice were fed a high-fat diet (HFD) for 3 weeks, and insulin sensitivity was determined using hyperinsulinemic-euglycemic clamps in conscious mice. Biochemical and molecular analyses were performed in muscle to assess glucose metabolism, insulin signaling, and inflammatory responses. RESULTS - MCK-IL10 mice developed with no obvious anomaly and showed increased whole-body insulin sensitivity. After 3 weeks of HFD, MCK-IL10 mice developed comparable obesity to wild-type littermates but remained insulin sensitive in skeletal muscle. This was mostly due to significant increases in glucose metabolism, insulin receptor substrate-1, and Akt activity in muscle. HFD increased macrophage-specific CD68 and F4/80 levels in wild-type muscle that was associated with marked increases in tumor necrosis factor-α, IL-6, and C-C motif chemokine receptor-2 levels. In contrast, MCK-IL10 mice were protected from diet-induced inflammatory response in muscle. CONCLUSIONS - These results demonstrate that IL-10 increases insulin sensitivity and protects skeletal muscle from obesity-associated macrophage infiltration, increases in inflammatory cytokines, and their deleterious effects on insulin signaling and glucose metabolism. Our findings provide novel insights into the role of anti-inflammatory cytokine in the treatment of type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)2525-2535
Number of pages11
JournalDiabetes
Volume58
Issue number11
DOIs
StatePublished - Nov 2009

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Hong, E. G., Hwi, J. K., Cho, Y. R., Kim, H. J., Ma, Z., Yu, T. Y., Friedline, R. H., Kurt-Jones, E., Finberg, R., Fischer, M. A., Granger, E. L., Norbury, C. C., Hauschka, S. D., Philbrick, W. M., Lee, C. G., Elias, J. A., & Kim, J. K. (2009). Interleukin-10 prevents diet-induced insulin resistance by attenuating macrophage and cytokine response in skeletal muscle. Diabetes, 58(11), 2525-2535. https://doi.org/10.2337/db08-1261