TY  - JOUR
A1  - Manowsky, Julia
A1  - Camargo, Rodolfo Gonzalez
A1  - Kipp, Anna Patricia
A1  - Henkel, Janin
A1  - Püschel, Gerhard Paul
T1  - Insulin-induced cytokine production in macrophages causes insulin resistance in hepatocytes
JF  - American journal of physiology : Endocrinology and metabolism
N2  - Overweight and obesity are associated with hyperinsulinemia, insulin resistance, and a low-grade inflammation. Although hyperinsulinemia is generally thought to result from an attempt of the beta-cell to compensate for insulin resistance, there is evidence that hyperinsulinaemia itself may contribute to the development of insulin resistance and possibly the low-grade inflammation. To test this hypothesis, U937 macrophages were exposed to insulin. In these cells, insulin induced expression of the proinflammatory cytokines IL-1 beta, IL-8, CCL2, and OSM. The insulin-elicited induction of IL-1 beta was independent of the presence of endotoxin and most likely mediated by an insulin-dependent activation of NF-kappa B. Supernatants of the insulin-treated U937 macrophages rendered primary cultures of rat hepatocytes insulin resistant; they attenuated the insulin-dependent induction of glucokinase by 50%. The cytokines contained in the supernatants of insulin-treated U937 macrophages activated ERK1/2 and IKK beta, resulting in an inhibitory serine phosphorylation of the insulin receptor substrate. In addition, STAT3 was activated and SOCS3 induced, further contributing to the interruption of the insulin receptor signal chain in hepatocytes. These results indicate that hyperinsulinemia per se might contribute to the low-grade inflammation prevailing in overweight and obese patients and thereby promote the development of insulin resistance particularly in the liver, because the insulin concentration in the portal circulation is much higher than in all other tissues.
KW  - metabolic syndrome
KW  - type 2 diabetes
KW  - inflammation
KW  - macrophage
KW  - insulin
KW  - cytokines
Y1  - 2016
U6  - https://doi.org/10.1152/ajpendo.00427.2015
SN  - 0193-1849
SN  - 1522-1555
VL  - 310
SP  - E938
EP  - E946
PB  - American Chemical Society
CY  - Bethesda
ER  -