Insulin resistance disrupts cell integrity, mitochondrial function, and inflammatory signaling in lymphatic endothelium.
Insulin resistance disrupts cell integrity, mitochondrial function, and inflammatory signaling in lymphatic endothelium.
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DOI：
10.1111/micc.12492
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Muthuchamy M
中科院分区：
文献类型：
--
作者：
Lee Y;Chakraborty S;Meininger CJ;Muthuchamy M
Lymphatic vessel dysfunction and increased lymph leakage have been directly associated with several metabolic diseases. However, the underlying cellular mechanisms causing lymphatic dysfunction have not been determined. Aberrant insulin signaling affects the metabolic function of cells, and consequently impairs tissue function. We hypothesized that insulin resistance in lymphatic endothelial cells (LECs) decreases eNOS activity, disrupts barrier integrity increases permeability, and activates mitochondrial dysfunction and pro-inflammatory signaling pathways. LECs were treated with insulin and/or glucose to determine the mechanisms leading to insulin resistance. Acute insulin treatment increased eNOS phosphorylation and NO production in LECs via activation of the PI3K/Akt signaling pathway. Prolonged hyperglycemia and hyperinsulinemia induced insulin resistance in LECs. Insulin resistant LECs produced less NO due to a decrease in eNOS phosphorylation and showed a significant decrease in impedance across an LEC monolayer that was associated with disruption in the adherence junctional proteins. Additionally, insulin resistance in LECs impaired mitochondrial function by decreasing basal-, maximal-, and ATP-linked-oxygen consumption rates and activated NF-κB nuclear translocation coupled with increased pro-inflammatory signaling. Our data provide the first evidence that insulin resistance disrupts endothelial barrier integrity, decreases eNOS phosphorylation and mitochondrial function, and activates inflammation in LECs.
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