Effect of lipopolysaccharide on inflammation and insulin action in human muscle.
Effect of lipopolysaccharide on inflammation and insulin action in human muscle.
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DOI：
10.1371/journal.pone.0063983
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Musi N
中科院分区：
文献类型：
--
作者：
Liang H;Hussey SE;Sanchez-Avila A;Tantiwong P;Musi N
越来越多的动物研究表明，循环中肠源性脂多糖(LPS)的慢性升高(即代谢性内毒素血症)可能在胰岛素抵抗的发病机制中发挥作用。然而，内毒素在人体肌肉中的作用尚不清楚。此外，阻断/下调Toll样受体(TLR4)是否能阻止内毒素对人肌肉细胞的胰岛素作用和葡萄糖代谢的影响尚不清楚。在目前的研究中，我们比较了胰岛素抵抗[肥胖型非糖尿病和肥胖2型糖尿病(T2 DM)]受试者和消瘦个体的血浆内毒素浓度。此外，我们利用原代人骨骼肌细胞培养系统来研究内毒素对葡萄糖代谢的影响，以及这些影响是否通过TLR4介导。肥胖组、非糖尿病组和T2 DM组的血浆内毒素和脂多糖结合蛋白(LBP)浓度显著升高。血浆内毒素(r = −0.46，P = 0.005)和脂蛋白(r = −0.49，P = 0.005)浓度与肌肉胰岛素敏感性(M)呈负相关。在人肌管中，内毒素使JNK磷酸化和MCP-1、IL-6基因表达增加。这种炎症反应导致胰岛素刺激的IRS-1、Akt和AS160的磷酸化减少，并损害了葡萄糖运输。用TAK-242药物阻断TLR4和沉默TLR4基因均能抑制内毒素引起的人肌肉细胞炎症反应和胰岛素抵抗。综上所述，这些发现表明肥胖和T2 DM患者血浆内毒素浓度的升高可能在胰岛素抵抗的发病机制中发挥作用，TLR4的拮抗剂可能改善这些人的胰岛素作用。
Accumulating evidence from animal studies suggest that chronic elevation of circulating intestinal-generated lipopolysaccharide (LPS) (i.e., metabolic endotoxemia) could play a role in the pathogenesis of insulin resistance. However, the effect of LPS in human muscle is unclear. Moreover, it is unknown whether blockade/down regulation of toll-like receptor (TLR)4 can prevent the effect of LPS on insulin action and glucose metabolism in human muscle cells. In the present study we compared plasma LPS concentration in insulin resistant [obese non-diabetic and obese type 2 diabetic (T2DM)] subjects versus lean individuals. In addition, we employed a primary human skeletal muscle cell culture system to investigate the effect of LPS on glucose metabolism and whether these effects are mediated via TLR4. Obese non-diabetic and T2DM subjects had significantly elevated plasma LPS and LPS binding protein (LBP) concentrations. Plasma LPS (r = −0.46, P = 0.005) and LBP (r = −0.49, P = 0.005) concentrations negatively correlated with muscle insulin sensitivity (M). In human myotubes, LPS increased JNK phosphorylation and MCP-1 and IL-6 gene expression. This inflammatory response led to reduced insulin-stimulated IRS-1, Akt and AS160 phosphorylation and impaired glucose transport. Both pharmacologic blockade of TLR4 with TAK-242, and TLR4 gene silencing, suppressed the inflammatory response and insulin resistance caused by LPS in human muscle cells. Taken together, these findings suggest that elevations in plasma LPS concentration found in obese and T2DM subjects could play a role in the pathogenesis of insulin resistance and that antagonists of TLR4 may improve insulin action in these individuals.
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影响因子：
7.7
作者：
Cani, Patrice D.;Amar, Jacques;Burcelin, Remy
通讯作者：
Burcelin, Remy
影响因子：
9.3
作者：
Al-Attas OS;Al-Daghri NM;Al-Rubeaan K;da Silva NF;Sabico SL;Kumar S;McTernan PG;Harte AL
通讯作者：
Harte AL
影响因子：
16.2
作者：
Ghanim H;Abuaysheh S;Sia CL;Korzeniewski K;Chaudhuri A;Fernandez-Real JM;Dandona P
通讯作者：
Dandona P
影响因子：
15.9
作者：
Lamping, N;Dettmer, R;Schumann, RR
通讯作者：
Schumann, RR
影响因子：
3.6
作者：
Matsunaga, Naoko;Tsuchimori, Noboru;Ii, Masayuki
通讯作者：
Ii, Masayuki