Interleukin-6 increases the expression and activity of insulin-degrading enzyme

Mirian A Kurauti,Luiz F Rezende,Sandra M Ferreira,Mara P T Chacon-Mikahil,Antonio C Boschero,Guilherme D Telles,Gustavo J Santos,Carlos H G Sponton,Everardo M Carneiro,José M Costa-Júnior,Cláudia R Cavaglieri

doi:10.1038/srep46750

Mirian A Kurauti, Luiz F Rezende + Show 9 more

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https://doi.org/10.1038/srep46750

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Impairment of the insulin-degrading enzyme (IDE) is associated with obesity and type 2 diabetes mellitus (T2DM). Here, we used 4-mo-old male C57BL/6 interleukin-6 (IL-6) knockout mice (KO) to investigate the role of this cytokine on IDE expression and activity. IL-6 KO mice displayed lower insulin clearance in the liver and skeletal muscle, compared with wild type (WT), due to reduced IDE expression and activity. We also observed that after 3-h incubation, IL-6, 50 and 100 ng ml−1, increased the expression of IDE in HEPG2 and C2C12 cells, respectively. In addition, during acute exercise, the inhibition of IL-6 prevented an increase in insulin clearance and IDE expression and activity, mainly in the skeletal muscle. Finally, IL-6 and IDE concentrations were significantly increased in plasma from humans, after an acute exercise, compared to pre-exercise values. Although the increase in plasma IDE activity was only marginal, a positive correlation between IL-6 and IDE activity, and between IL-6 and IDE protein expression, was observed. Our outcomes indicate a novel function of IL-6 on the insulin metabolism expanding the possibilities for new potential therapeutic strategies, focused on insulin degradation, for the treatment and/or prevention of diseases related to hyperinsulinemia, such as obesity and T2DM.

Highlights

Impairment of the insulin-degrading enzyme (IDE) is associated with obesity and type 2 diabetes mellitus (T2DM)
We found that, during acute endurance exercise, IL-6 mediated the increase of IDE expression and activity, mainly in the skeletal muscle, increasing insulin clearance, a phenomenon that may occur in humans
Impaired IDE expression and/or activity are closely related to diseases associated with hyperinsulinemia, such as obesity and T2DM12

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Impairment of the insulin-degrading enzyme (IDE) is associated with obesity and type 2 diabetes mellitus (T2DM). IL-6 KO mice displayed lower insulin clearance in the liver and skeletal muscle, compared with wild type (WT), due to reduced IDE expression and activity. During acute exercise, the inhibition of IL-6 prevented an increase in insulin clearance and IDE expression and activity, mainly in the skeletal muscle. Insulin is one of the most important hormones in glucose homeostasis, and its action depends on its secretion, the sensitivity of target tissues, and clearance. Insulin clearance occurs mainly in the liver, primarily by the action of insulin-degrading enzyme (IDE)[9]. Despite increasing insulin signaling, acute IDE inhibition impaired glucose tolerance in mice, casting a shadow on the usefulness of the IDE inhibition for the treatment of T2DM20. IDE knockout (KO) mice display chronic hyperinsulinemia[21] that, over time, induces a reduction of insulin receptor expression, leading to insulin www.nature.com/scientificreports/

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