An MG53-IRS1-interaction disruptor ameliorates insulin resistance

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

doi:10.1038/s12276-018-0099-9

Jun Sub Park, Bo Woon Choi + Show 8 more

Open Access

https://doi.org/10.1038/s12276-018-0099-9

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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.

Highlights

Introduction Type2 diabetes mellitus (T2DM) is a metabolic disorder caused by insulin resistance in the liver, fat, and muscle
Using a bimolecular luminescence complementation (BiLC) system, we found a small chemical called Mitsugumin 53 (MG53)-insulin receptor substrate-1 (IRS-1) interaction disruptor-1 (MID-1)
MID-1 interferes with the binding of MG53 to IRS-1, increases IRS-1 levels, and improves insulin signaling in C2C12 myotubes[21]

Summary

Introduction

Introduction Type2 diabetes mellitus (T2DM) is a metabolic disorder caused by insulin resistance in the liver, fat, and muscle. The genetic disruption of MG53 increases IRS1 levels, improves insulin signaling in mouse skeletal muscle and ameliorates insulin resistance in diet-induced obese (DIO) mice[7, 9]. MID-1 interferes with the binding of MG53 to IRS-1, increases IRS-1 levels, and improves insulin signaling in C2C12 myotubes[21]. Oral administration of MID-00935 improved insulin signaling in skeletal muscle and ameliorated insulin resistance in DIO mice.

Results

Conclusion