Insulin exhibits short-term anti-inflammatory but long-term proinflammatory effects in vitro

Although insulin is indispensable for maintaining glucose homeostasis, it is still controversial whether or not a high concentration of insulin is deleterious. We examined the effect of insulin on the transcriptional activity of NF-κB, which mediates the expression of a variety of inflammation/coagulation-related genes using hepatocyte cell lines in vitro. We found that insulin (1 nM) alone caused minimal increase in NF-κB-mediated transcription. On the other hand, when cells were simultaneously treated with proinflammatory cytokines such as TNFα, the following dual effect of insulin was observed: short-term (6 h) suppressive, and long-term (36 h or later) stimulatory effects. The former effect was transient and appears to be mediated by the phosphatidylinositol 3 kinase (PI3K) signaling pathway. The latter effect, in contrast, was more pronounced, enhancing the TNFα-stimulated NF-κB-dependent transcription by more than sevenfold. This positive effect was NF-κB-specific, and was eliminated by mitogen-activated protein kinase (MAPK) inhibitors. Altogether, our data suggest that insulin has short-term anti-inflammatory but long-term proinflammatory effects. From a clinical standpoint, this implies that low basal and periodically high plasma insulin is beneficial, whereas a sustained rise in plasma insulin, as often seen in patients with obesity, may induce atherothrombotic disorders, because of the NF-κB-mediated overexpression of proinflammatory/procoagulant/antifibrinolytic proteins in the liver.