Insulin Resistance and Gender Define a Cell Autonomous Supernetworkof Protein Phosphorylation

Abstract Many hormones and growth factors, including insulin, act through networks of protein phosphorylation. Insulin resistance is an important factor in the pathophysiology many metabolic disorders. The aim this study was to uncover cell autonomous determinants insulin action phosphorylation using induced pluripotent stem (iPSC)-derived myoblasts (iMyos) vitro. Here, we show that iMyos from non-diabetic individuals highest quintile impaired signaling, defective insulin-stimulated glucose uptake decreased glycogen synthase activity compared sensitive individuals, indicating these cells mirror vitro alterations seen vivo. Global phosphoproteomic analysis uncovered a large network proteins whose altered association with resistance, most outside canonical insulin-signaling cascade. More surprisingly, also observed striking differences signature derived male versus female subjects, involving multiple pathways regulating diverse cellular functions, DNA RNA processing, GTPase SUMOylation/ubiquitination. These findings provide new insights into mechanisms underlying population evidence major, previously unrecognized, supernetwork signaling males females must be considered understanding molecular basis sex-based normal physiology disease.