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

Abstract

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.

Effects of Exercises on IL-6 and GLUT4 Expression in Diabetic Rats

“…The exercise-mediated increase of IL-6 and GLUT4 expression, along with the associated decrease in blood glucose and insulin levels, suggests the importance of aerobic exercises in insulin clearance and glucose homeostasis. In support of this theory, Kurauti et al [24] revealed that exercise training increased the expression of IL-6 and its secretion from skeletal muscle, as well as the expression and activity of insulin-degrading enzyme. Studies have also shown that exercise training and muscle contractions increase IL-6 secretion into the bloodstream and modulate glucose homeostasis [28].…”

“…Some studies have demonstrated that IL-6 increases insulin secretion, possibly by increasing the activity of the phospholipase C-inositol triphosphate-dependent pathway and also by increasing glucagon-like peptide 1 secretion from L cells and pancreatic alpha cells [22,23]. More recently, Kurauti et al [24] reported that IL-6 knockout mice displayed lower insulin clearance in the liver and skeletal muscle owing to the decreased expression and activity of insulin-degrading enzyme. These findings indicate that IL-6 is a critical factor for the maintenance of normal carbohydrate and lipid metabolism and prevention of diabetes development.…”

The immune-opioid axis in prediabetes: prediction of prediabetes with insulin resistance by plasma interleukin-10 and Endomorphin-2 to kappa-opioid receptors ratio

“…Positive correlations between IL-6 and IDE activity and between IL-6 and IDE protein expression are observed. Our outcomes denote the novel role of IL-6 on insulin metabolism, suggesting new potential therapeutic strategies and focusing on insulin degradation, for the treatment and/or prevention of diseases linked to hyperinsulinemia, such as obesity and T2DM [32].…”

O efeito benéfico do exercício físico contra a destruição de células &#223 em modelo murino de DM1.

“…A ausência do hormônio insulina proveniente da perda das células β leva ao quadro de hiperglicemia e hipoinsulinemia, e consequente alteração no metabolismo e utilização da glicose (1), [11][12][13]. O DM1 representa de 10 a 15% dos casos de Diabetes mellitus e sua incidência vem crescendo mundialmente (1).…”

“…Tem sido reportada em vários trabalhos uma função endócrina para o músculo esquelético (10) onde durante o exercício físico imunomoduladores são produzidos, como a interleucina 6 (IL-6), uma citocina pleiotrópica importante do sistema imunológico (11). A IL-6 quando secretada durante o exercício físico via contração muscular, estimula a secreção de outras citocinas anti-inflamatórias como IL-1Ra (antagonista do receptor da interleucina-1) e a IL-10 (interleucina-10) e inibe a produção de citocinas pro-inflamatórias como TNFα (12,13).…”