The role of interleukin-6 (IL-6) on the modulation of insulin-degrading enzyme (IDE) during the acute exercise

Author(s)

Mirian Ayumi Kurauti

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2017-06-02

Examining board members

Antonio Carlos Boschero; Andre Schwambach Vieira; Eduardo Rochete Ropelle; Camila Aparecida Machado De Oliveira; Helenir Medri de Souza

• Advisor: Antonio Carlos Boschero

Abstract

Hyperinsulinemia is often associated with pathological conditions such as obesity and type 2 diabetes mellitus. It depends on increase in insulin secretion and/or decrease in insulin clearance that occurs, mainly, in liver by insulin-degrading enzyme (IDE). It is known that physical exercise reduces insulinemia, at least in part, due to increase in insulin clearance and IDE expression, however, the mechanisms involved in this modulation remains unclear. During exercise, muscle contractions secrete several molecules, named myokines, and the most important, in terms of quantity, is the inteleukin-6 (IL-6). In this study we first investigated the role of IL-6 on the modulation of IDE expression and activity. Secondly, we assessed a possible role of this cytokine on the increase in insulin clearance and IDE expression, during an acute exercise. First, we used C57BL/6 wild type (WT) and IL-6 knockout (KO) mice, and to evaluate the glycemic homeostasis, we performed both glucose and insulin tolerance tests (ipGTT and ipITT, respectively). We also evaluated the insulin clearance, glucose stimulated insulin secretion in isolated pancreatic islets and IDE (gene and protein) expression and activity in the liver and gastrocnemius muscle. The KO mice displayed impairment of glucose tolerance, compared with WT, an effect probably due to a reduced insulin secretion by the islets from these mice. This assumption was based on the fact that we did not observed alteration in insulin sensitivity. In addition, it was observed a reduction of the insulin clearance, probably due to the lower IDE expression and activity, in the liver and gastrocnemius muscle from KO mice, compared with WT. In vitro experiments, using HEPG2 and C2C12 cells, were also performed. The increase in IDE expression was observed after 3-h incubation at 50 or 100 ng/ml IL-6, in the HEPG2 and C2C12 cells, respectively. After, WT mice were distributed into 3 different groups: control (CTL), exercised (EXE), and exercised treated with 2 mg/kg tocilizumab (EXE+TCZ), an IL-6 receptor antibody. The acute exercise was performed on a treadmill during 3-h at moderate intensity. In these groups, we also evaluated the same parameters cited above. Interestingly, the inhibition of IL-6, in the EXE+TCZ mice, abrogated the increase of insulin clearance and IDE expression and activity, mainly in the gastrocnemius muscle. Finally, we also collected plasma samples from humans, before and 3-h after an acute exercise (30 min cycling at 70% VO2peak). Three hours after the end of the acute exercise, we observed an increase in IL-6 and IDE plasma concentrations, which were positively correlated. Although the increase in plasma IDE activity was only marginal, a positive correlation between IL-6 and IDE activity was also observed. In summary, our outcomes demonstrated a function, not yet described, of IL-6 on glycemic control that consists of incrase in insulin clearance and IDE expression and activity. This function seems to be essential for the augmentation of insulin clearance during physical exercise, increasing the IDE expression and activity mainly in the skeletal muscle, an effect that likely also occurs in human (AU)

• FAPESP's process: 14/24719-7 - Effect of physical exercise on the expression of peroxisome proliferator activated receptor gamma (PPARgamma) and Insulin Degrading Enzyme (IDE) in mouse pancreatic islets
• Grantee: Mirian Ayumi Kurauti
• Support Opportunities: Scholarships in Brazil - Doctorate