The Common Pathophysiologic Mechanism in Type 2 Diabetes Mellitus and Alzheimer’s Disease: Role of Insulin Resistance

Abstract

Type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) are exceedingly heterogeneous and amyloidogenic degenerative diseases that are taking on epidemic proportions. In recent years, a pathophysiological link between both disorders is becoming more recognized. Also, a role for insulin signaling in the brain is becoming increasingly apparent. Accordingly, insulin resistance is now believed to contribute to AD pathology, in addition to being an important pathophysiological hallmark of T2DM. Here we discuss the effects of peripheral insulin resistance on the insulin pathway in the brain and conclude that brain insulin signaling may be compromised, thereby contributing to several aspects of AD pathology. Furthermore, in AD, impairment of the insulin/AKT signaling pathway has emerged as an important consequence of soluble amyloid-β (Aβ) neurotoxicity. As glycogen synthase kinase-3 (GSK-3) is an important effector of the insulin/AKT pathway, not only phosphorylation of microtubule associated protein tau is affected, but also synaptic plasticity and memory functions could be compromised. In this review, we discuss the pathophysiology of insulin resistance in both T2DM and AD, and aim to discriminate between associated consequences in the periphery and central nervous system. Based on the available experimental data at present, we hypothesize that insulin resistance as a common mechanism, may underlie co-morbid metabolic disorders as well as neurodegenerative disorders. In this context, drug targets aimed at rescuing insulin signaling may prove to be a constructive therapeutic strategy for both T2DM and AD.