An MG53-IRS1-interaction disruptor ameliorates insulin resistance

Jun Sub Park, Hyun Lee, Bo Woon Choi, Seonggu Ro, Doyoung Lee, Jeong Eun Na, Jeoung Ho Hong, Jae Seon Lee, Bong Woo Kim, Young Gyu Ko

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Mitsugumin 53 (MG53) is an E3 ligase that induces insulin receptor substrate-1 (IRS-1) ubiquitination and degradation in skeletal muscle. We previously demonstrated that the pharmaceutical disruption of the MG53-IRS-1 interaction improves insulin sensitivity by abrogating IRS-1 ubiquitination and increasing IRS-1 levels in C2C12 myotubes. Here, we developed a novel MG53-IRS-1 interaction disruptor (MID-00935) that ameliorates insulin resistance in diet-induced obese (DIO) mice. MID-00935 disrupted the molecular interaction of MG53 and IRS-1, abrogated MG53-induced IRS-1 ubiquitination and degradation and improved insulin signaling in C2C12 myotubes. Oral administration of MID-00935 increased insulin-induced IRS-1, Akt, and Erk phosphorylation via increasing IRS-1 levels in the skeletal muscle of DIO mice. In DIO mice, MID-00935 treatment lowered fasting blood glucose levels and improved glucose disposal in glucose and insulin tolerance tests. These results suggest that MID-00935 may be a potential muscle-targeting drug candidate for treating insulin resistance.

Original languageEnglish
Article number69
JournalExperimental and Molecular Medicine
Volume50
Issue number6
DOIs
Publication statusPublished - 2018 Jun 1

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

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    Park, J. S., Lee, H., Choi, B. W., Ro, S., Lee, D., Na, J. E., Hong, J. H., Lee, J. S., Kim, B. W., & Ko, Y. G. (2018). An MG53-IRS1-interaction disruptor ameliorates insulin resistance. Experimental and Molecular Medicine, 50(6), [69]. https://doi.org/10.1038/s12276-018-0099-9