Systems-wide Experimental and Modeling Analysis of Insulin Signaling through Forkhead Box Protein O1 (FOXO1) in Human Adipocytes, Normally and in Type 2 Diabetes.

摘要: Insulin resistance is a major aspect of type 2 diabetes (T2D), which results from impaired insulin signaling in target cells. Signaling to regulate forkhead box protein O1 (FOXO1) may be the most important mechanism for control transcription. Despite this, little known about how regulates FOXO1 and contribute adipocytes, are critical cell development resistance. We report detailed mechanistic analysis human adipocytes obtained non-diabetic subjects patients with T2D. show that mainly phosphorylated through mTORC2-mediated phosphorylation kinase B at Ser473 this unperturbed also demonstrate cross-talk MAPK branch stimulate FOXO1. The cellular abundance consequently activity halved Interestingly, inhibition mTORC1 rapamycin reduces levels This suggests reduction concentration consequence attenuation mTORC1, defines much diabetic state adipocytes. integrate network-wide mathematical model dynamics based on compatible data explained by an mTORC1-to-insulin receptor substrate-1 (IRS1) feedback reduced abundances receptor, GLUT4, AS160, ribosomal S6, demonstrates mTORC1-to-IRS1 state.