An MG53-IRS1-interaction disruptor ameliorates insulin resistance

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. A promising drug candidate for type II diabetes targets a protein interaction involved in insulin resistance. In healthy individuals, the insulin receptor substrate 1 (IRS-1) protein stimulates glucose uptake, particularly in skeletal muscles. In patients with diabetes, the interaction of IRS-1 with another protein, MG53, interferes with insulin signaling and causes insulin resistance, resulting in excess glucose in the blood. Drugs for treating diabetes aim to lower glucose levels, but no existing drugs directly target glucose levels in skeletal muscles. Now, Bong-Woo Kim and Young-Gyu Ko at Korea University in Seoul, South Korea, and co-workers have designed a drug that specifically inhibits the IRS-1-MG53 interaction. Oral administration of the drug showed promise in trials on diet-induced obese mice, increasing IRS-1 levels in skeletal muscles, lowering fasting glucose levels and improving insulin sensitivity.