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. 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 wild-type (WT) mice were fed high-fat diet (HFD) for 3 wks, 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 wks of HFD, MCK-IL10 mice developed comparable obesity to WT littermates, but remained insulin sensitive in skeletal muscle. This was mostly due to significant increases in glucose metabolism, IRS-1 and Akt activity in muscle. HFD increased macrophage-specific CD68 and F4/80 levels in WT muscle that was associated with marked increases in TNF-α, IL-6 and CCR2 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.