Metabolism: A Novel Shared Link between Diabetes Mellitus and Alzheimer’s Disease

Figure 1

Overview of the insulin signaling pathway and relevant mechanisms implicated in AD. (a) Tyrosine phosphorylation of insulin receptor substrates (IRS) allows the association of IRSs with the regulatory subunit of phosphoinositide 3-kinase (PI3K). The PI3K/AKT signaling pathway deactivates glycogen synthase kinase 3 (GSK-3), leading to the activation of glycogen synthase (GYS) and thus glycogen synthesis. In addition, the PI3K/AKT signaling pathway can affect protein synthesis/metabolism and clearance of Aβ by activating the mTOR pathway. (b) The insulin/insulin signaling pathway can promote glucose transportation by regulating GLUT, and high levels of glucose can lead to Aβ deposition. (c) Disordered glucose metabolism leads to ROS/RNS formation and decreased ATP production, which is the main manifestation of oxidative stress. Mitochondrial dysfunction can lead to impaired cellular energy production and reduction in insulin secretion and sensitivity. (d) Impaired insulin signaling pathway, Aβ deposition, and mitochondrial dysfunction promote each other to form a vicious circle.