Imbalanced Insulin Actions in Obesity and Type 2 Diabetes: Key Mouse Models of Insulin Signaling Pathway

Since the discovery of the tyrosine kinase activity of the insulin receptor (IR), researchers have been engaged in intensive efforts to resolve physiological functions of IR and itsmajor downstream targets, insulin receptor substrate 1 (Irs1) and Irs2. Studies conducted using systemic and tissue-specific gene-knockout mice of IR, Irs1, and Irs2 have revealed the physiological roles of these molecules in each tissue and interactions among multiple tissues. In obesity and type 2 diabetes, selective downregulation of Irs2 and its downstream actions to cause reduced insulin actions was associated with increased insulin actions through Irs1 in variety tissues. Thus, we propose the novel concept of 'organ- and pathway-specific imbalanced insulin action'' in obesity and type 2 diabetes, which includes and extends "selective insulin resistance.'' This Review focuses on recent progress in understanding insulin signaling and insulin resistance using key mouse models for elucidating pathophysiology of human obesity and type 2 diabetes.