Affiliation:
1. Department of Biochemistry, Albert Szent‐Gyorgyi Medical School University of Szeged Szeged Hungary
2. Department of Medical Imaging, Division of Nuclear Medicine and Translational Imaging, Faculty of Medicine University of Debrecen Debrecen Hungary
3. Institute of Surgical Research, Albert Szent‐Gyorgyi Medical School University of Szeged Szeged Hungary
4. Laboratory of Functional Genomics, Biological Research Centre, Eotvos Lorand Research Network Szeged Hungary
5. Department of Oto‐ Rhino‐Laryngology and Head and Neck Surgery University of Szeged Szeged Hungary
Abstract
AbstractSkeletal muscle plays a major role in whole‐body glucose metabolism. Insulin resistance in skeletal muscle is characterized by decreased insulin‐stimulated glucose uptake resulting from impaired intracellular trafficking and decreased glucose transporter 4 (GLUT4) expression. In this study, we illustrated that tilorone, a low‐molecular‐weight antiviral agent, improves glucose uptake in vitro and in vivo. Tilorone increased bone morphogenetic protein (BMP) signaling in C2C12 myoblasts, the transcription of multiple BMPs (BMP2, BMP4, BMP7, and BMP14), Smad4 expression, and the phosphorylation of BMP‐mediated Smad1/5/8. The activation of Akt2/AS160 (TBC1D4) signaling, the critical regulator of GLUT4 translocation, was also increased, as well as the levels of GLUT4 and GLUT1, leading to enhanced uptake of the radioactively labeled glucose analog 18F‐fluoro‐2‐deoxyglucose (18FDG). However, this excess glucose content did not result in increased ATP formation by mitochondrial respiration; both basal and ATP‐linked respiration were diminished, thereby contributing to the induction of AMPK. In differentiated myotubes, AS160 phosphorylation and 18FDG uptake also increased. Moreover, tilorone administration further increased insulin‐stimulated phosphorylation of Akt2 and glucose uptake of myotubes indicating an insulin‐sensitizing effect. Importantly, during in vivo experiments, the systemic administration of tilorone resulted in increased 18FDG uptake of skeletal muscle, liver, and adipose tissue in C57BL/6 mice. Our results provide new perspectives for the treatment of type 2 diabetes, which has a limited number of treatments that regulate protein expression or translocation.
Subject
Cell Biology,Clinical Biochemistry,Physiology