INS and Glucose intolerance: In addition, it was shown that global knockout of IR leads to neonatal death and the development of glucose intolerance and diabetes [131]; restoration of functional IRs in the brain, liver and β-cells partially rescues these mice from neonatal death and prevents the development of diabetes, suggesting that insulin signaling in other tissues that are considered non-insulin target tissues, such as islet β-cells, is essential to β-cell compensation and glucose homeostasis [131].