Insulin-induced cytokine production as potential contributor to hepatic insulin resistance

Overweight or obese patients try to compensate their insulin resistance by an enhanced production of insulin in pancreatic beta-cell. Since pancreatic hormones are released into the portal circulation, liver is exposed to very high concentrations of insulin over prolonged periods in these patients. There is evidence that insulin might enhance the inflammatory response to e.g. endotoxin in immune cells. Therefore, the hypothesis was tested that insulin per se might trigger the synthesis of pro-inflammatory cytokines in macrophages. These cytokines in turn might render hepatocytes insulin-resistant.

Human U937 cells were differentiated into macrophages and stimulated with 100 nM insulin for 24h. The induction of cytokine expression was determined by qPCR and Western blot. Primary cultures of rat hepatocytes were incubated with supernatants of insulin-treated U937 macrophages and the activation of the insulin receptor signal chain in these hepatocytes was recorded by qPCR of insulin-induced genes and Western blot of signal chain proteins.

Insulin induced the expression of IL-1β in U937 macrophages about 2.5-fold both on the mRNA and protein level. In contrast to the LPS-dependent IL-1β induction, the insulin-dependent IL-1β induction was not affected by polymyxin B. In U937 macrophages insulin induced the phosphorylation of IKKβ and IκB. The insulin-dependent IL-1β induction was abolished by the IKKβ inhibitor TPCA-1, indicating that insulin triggered the IL-1β formation by an activation of NFκB. Apart from IL-1β insulin induced the expression of OSM and IL-8. In hepatocytes that were incubated with supernatants of insulin-treated U937 macrophages the insulin-dependent glucokinase induction was reduced by 50%. This could be attributed to an inhibitory serine phosphorylation of the insulin receptor substrate either by an IL-1β-dependent activation of IKKβ or by an OSM-dependent activation of ERK1/2. In addition, an OSM-dependent STAT3 activation and SOCS3 induction was observed that might have contributed to the interruption of the insulin receptor signaling chain in hepatocytes.

An insulin-dependent activation of macrophages might thus contribute to the development of insulin resistance in the liver.

Corresponding author: Püschel, Gerhard P

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