Interleukin-10 prevents diet-induced insulin resistance by attenuating macrophage and cytokine response in skeletal muscle.
Interleukin-10 prevents diet-induced insulin resistance by attenuating macrophage and cytokine response in skeletal muscle.
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作者：
Hong EG;Ko HJ;Cho YR;Kim HJ;Ma Z;Yu TY;Friedline RH;Kurt-Jones E;Finberg R;Fischer MA;Granger EL;Norbury CC;Hauschka SD;Philbrick WM;Lee CG;Elias JA;Kim JK
胰岛素抵抗是 2 型糖尿病的一个主要特征，并且与肥胖有因果关系。炎症在肥胖相关的胰岛素抵抗中发挥着重要作用，但其潜在机制仍不清楚。白细胞介素 (IL)-10 是一种抗炎细胞因子，在肥胖受试者中循环水平较低，使用 IL-10 进行急性治疗可预防脂质诱导的胰岛素抵抗。我们使用肌肉特异性过度表达 IL-10 (MCK-IL10) 的转基因小鼠研究了 IL-10 在葡萄糖稳态中的作用。 MCK-IL10 和野生型小鼠被喂食高脂肪饮食 (HFD) 3 周，并使用高胰岛素-正常血糖钳在清醒的小鼠中测定胰岛素敏感性。对肌肉进行生化和分子分析，以评估葡萄糖代谢、胰岛素信号传导和炎症反应。 MCK-IL10小鼠发育没有明显异常，并且表现出全身胰岛素敏感性增加。 HFD 3周后，MCK-IL10小鼠出现与野生型同窝小鼠相当的肥胖，但骨骼肌仍保持胰岛素敏感性。这主要是由于肌肉中葡萄糖代谢、胰岛素受体底物 1 和 Akt 活性显着增加。 HFD 增加了野生型肌肉中巨噬细胞特异性 CD68 和 F4/80 的水平，这与肿瘤坏死因子-α、IL-6 和 C-C 基序趋化因子受体 2 水平的显着增加有关。相比之下，MCK-IL10 小鼠受到保护，免受饮食诱导的肌肉炎症反应。这些结果表明，IL-10 可以增加胰岛素敏感性，并保护骨骼肌免受肥胖相关巨噬细胞浸润、炎性细胞因子增加及其对胰岛素信号传导和葡萄糖代谢的有害影响。我们的研究结果为抗炎细胞因子在 2 型糖尿病治疗中的作用提供了新的见解。
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). MCK-IL10 and wild-type 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. 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. 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.
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影响因子：
7.7
作者：
Park, SY;Cho, YR;Kim, JK
通讯作者：
Kim, JK
肿瘤坏死因子-α的脂肪表达--在与肥胖相关的胰岛素抵抗中的直接作用
影响因子：
56.9
作者：
HOTAMISLIGIL, GS;SHARGILL, NS;SPIEGELMAN, BM
通讯作者：
SPIEGELMAN, BM
DOI：
10.1006/clin.1994.1068
发表时间：
1994-05-01
期刊：
CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY
影响因子：
--
作者：
PENNLINE, KJ;ROQUEGAFFNEY, E;MONAHAN, M
通讯作者：
MONAHAN, M
影响因子：
7.7
作者：
Griffin, ME;Marcucci, MJ;Shulman, GI
通讯作者：
Shulman, GI
DOI：
10.1073/pnas.121164498
发表时间：
2001-06-19
影响因子：
11.1
作者：
Kim, JK;Fillmore, JJ;Shulman, GI
通讯作者：
Shulman, GI