Ganglioside GM1 contributes to extracellular/intracellular regulation of insulin resistance, impairment of insulin signaling and down-stream eNOS activation, in human aortic endothelial cells after short- or long-term exposure to TNFα

Abstract

Vascular insulin resistance induced by inflammatory cytokines leads to the initiation and development of vascular diseases. In humans, circulating TNFα levels are increased during aging, suggesting a correlation between vascular insulin resistance and plasma TNFα levels. Currently, the precise molecular mechanisms of vascular insulin resistance mediated by TNFα are not well characterized. We aimed at clarifying whether glycosphingolipids contribute to vascular insulin resistance after inflammatory stimulation. In this study, we examined vascular insulin resistance using human aortic endothelial cells after treatment with different concentrations of TNFα for different time intervals for mimicking in vivo acute or chronic inflammatory situations. We show that ganglioside GM1 levels on cell membranes change depending on time of exposure to TNFα and its concentration and that the GM1 expression is associated with specific extracellular/intracellular regulation of the insulin signaling cascade. Furthermore, we provide evidence that factors such as aging and senescence affect the regulation of insulin resistance. Our data suggest that GM1 is a key player in the induction of vascular insulin resistance after short- or long-term exposure to TNFα and is a good extracellular target for prevention and cure of vascular diseases.