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An MG53-IRS1-interaction disruptor ameliorates insulin resistance
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 in...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994830/ https://www.ncbi.nlm.nih.gov/pubmed/29884820 http://dx.doi.org/10.1038/s12276-018-0099-9 |
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author | 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 |
author_facet | 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 |
author_sort | Park, Jun Sub |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5994830 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-59948302018-06-19 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 Exp Mol Med Article 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. Nature Publishing Group UK 2018-06-06 /pmc/articles/PMC5994830/ /pubmed/29884820 http://dx.doi.org/10.1038/s12276-018-0099-9 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article 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 |
title | An MG53-IRS1-interaction disruptor ameliorates insulin resistance |
title_full | An MG53-IRS1-interaction disruptor ameliorates insulin resistance |
title_fullStr | An MG53-IRS1-interaction disruptor ameliorates insulin resistance |
title_full_unstemmed | An MG53-IRS1-interaction disruptor ameliorates insulin resistance |
title_short | An MG53-IRS1-interaction disruptor ameliorates insulin resistance |
title_sort | mg53-irs1-interaction disruptor ameliorates insulin resistance |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994830/ https://www.ncbi.nlm.nih.gov/pubmed/29884820 http://dx.doi.org/10.1038/s12276-018-0099-9 |
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