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Insulin resistance disrupts cell integrity, mitochondrial function, and inflammatory signaling in lymphatic endothelium
Author(s) -
Lee Yang,
Chakraborty Sanjukta,
Meininger Cynthia J.,
Muthuchamy Mariappan
Publication year - 2018
Publication title -
microcirculation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.793
H-Index - 83
eISSN - 1549-8719
pISSN - 1073-9688
DOI - 10.1111/micc.12492
Subject(s) - insulin resistance , insulin receptor , protein kinase b , medicine , enos , insulin , endocrinology , phosphorylation , tyrosine phosphorylation , biology , microbiology and biotechnology , endothelial dysfunction , nitric oxide synthase , nitric oxide
Objective 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 LEC s decreases eNOS activity, disrupts barrier integrity increases permeability, and activates mitochondrial dysfunction and pro‐inflammatory signaling pathways. Methods LEC s were treated with insulin and/or glucose to determine the mechanisms leading to insulin resistance. Results Acute insulin treatment increased eNOS phosphorylation and NO production in LEC s via activation of the PI 3K/Akt signaling pathway. Prolonged hyperglycemia and hyperinsulinemia induced insulin resistance in LEC s. Insulin‐resistant LEC s 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 LEC s impaired mitochondrial function by decreasing basal‐, maximal‐, and ATP ‐linked OCRs and activated NF ‐κB nuclear translocation coupled with increased pro‐inflammatory signaling. Conclusion Our data provide the first evidence that insulin resistance disrupts endothelial barrier integrity, decreases eNOS phosphorylation and mitochondrial function, and activates inflammation in LEC s.