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

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

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Insulin Receptor Substrate Proteins
Insulin Resistance
Insulin
Obese Mice
Ubiquitination
Nutrition
Muscle
Skeletal Muscle Fibers
Diet
Skeletal Muscle
Glucose
Degradation
Phosphorylation
Ubiquitin-Protein Ligases
Molecular interactions
Drug Delivery Systems
Glucose Tolerance Test
Oral Administration
Blood Glucose
Fasting

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

An MG53-IRS1-interaction disruptor ameliorates insulin resistance. / Park, Jun Sub; Lee, Hyun; Choi, Bo Woon; Ro, Seonggu; Lee, Doyoung; Na, Jeong Eun; Hong, Jeoung Ho; Lee, Jae Seon; Kim, Bong Woo; Ko, Young-Gyu.

In: Experimental and Molecular Medicine, Vol. 50, No. 6, 69, 01.06.2018.

Research output: Contribution to journalArticle

Park, JS, Lee, H, Choi, BW, Ro, S, Lee, D, Na, JE, Hong, JH, Lee, JS, Kim, BW & Ko, Y-G 2018, 'An MG53-IRS1-interaction disruptor ameliorates insulin resistance', Experimental and Molecular Medicine, vol. 50, no. 6, 69. https://doi.org/10.1038/s12276-018-0099-9
Park, Jun Sub ; Lee, Hyun ; Choi, Bo Woon ; Ro, Seonggu ; Lee, Doyoung ; Na, Jeong Eun ; Hong, Jeoung Ho ; Lee, Jae Seon ; Kim, Bong Woo ; Ko, Young-Gyu. / An MG53-IRS1-interaction disruptor ameliorates insulin resistance. In: Experimental and Molecular Medicine. 2018 ; Vol. 50, No. 6.
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