Manowsky Julia, Camargo Rodolfo Gonzalez, Kipp Anna P, Henkel Janin, Püschel Gerhard P
University of Potsdam, Institute of Nutritional Science, Nutritional Biochemistry, Nuthetal, Germany;
University of Potsdam, Institute of Nutritional Science, Nutritional Biochemistry, Nuthetal, Germany; Cancer Metabolism Research Group, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil; and.
Am J Physiol Endocrinol Metab. 2016 Jun 1;310(11):E938-46. doi: 10.1152/ajpendo.00427.2015. Epub 2016 Apr 19.
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 β-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-1β, IL-8, CCL2, and OSM. The insulin-elicited induction of IL-1β was independent of the presence of endotoxin and most likely mediated by an insulin-dependent activation of NF-κB. 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 IKKβ, 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.
超重和肥胖与高胰岛素血症、胰岛素抵抗及低度炎症相关。尽管一般认为高胰岛素血症是β细胞试图代偿胰岛素抵抗的结果，但有证据表明高胰岛素血症本身可能促使胰岛素抵抗的发展，并可能导致低度炎症。为验证这一假说，将U937巨噬细胞暴露于胰岛素。在这些细胞中，胰岛素诱导促炎细胞因子IL-1β、IL-8、CCL2和OSM的表达。胰岛素引发的IL-1β诱导与内毒素的存在无关，很可能是由胰岛素依赖的NF-κB激活介导的。胰岛素处理的U937巨噬细胞的上清液使大鼠原代肝细胞培养物产生胰岛素抵抗；它们使胰岛素依赖的葡萄糖激酶诱导减弱了50%。胰岛素处理的U937巨噬细胞上清液中所含的细胞因子激活了ERK1/2和IKKβ，导致胰岛素受体底物的抑制性丝氨酸磷酸化。此外，STAT3被激活且诱导了SOCS3，进一步导致肝细胞中胰岛素受体信号链的中断。这些结果表明，高胰岛素血症本身可能导致超重和肥胖患者中普遍存在的低度炎症，从而尤其在肝脏中促进胰岛素抵抗的发展，因为门静脉循环中的胰岛素浓度远高于所有其他组织。
