Type 2 Diabetes Mellitus and Alzheimer's Disease: Role of Insulin Signalling and Therapeutic Implications

Abstract

In the last two decades, numerous in vitro studies demonstrated that insulin receptors and theirs downstream pathways are widely distributed throughout the brain. This evidence has proven that; at variance with previous believes; insulin/insulin-like-growth-factor (IGF) signalling plays a crucial role in the regulation of different central nervous system (CNS) tasks. The most important of these functions include: synaptic formation; neuronal plasticity; learning; memory; neuronal stem cell activation; neurite growth and repair. Therefore; dysfunction at different levels of insulin signalling and metabolism can contribute to the development of a number of brain disorders. Growing evidences demonstrate a close relationship between Type 2 Diabetes Mellitus (T2DM) and neurodegenerative disorders such as Alzheimer's disease. They, in fact, share many pathophysiological characteristics comprising impaired insulin sensitivity, amyloid β accumulation, tau hyper-phosphorylation, brain vasculopathy, inflammation and oxidative stress. In this article, we will review the clinical and experimental evidences linking insulin resistance, T2DM and neurodegeneration, with the objective to specifically focus on insulin signalling-related mechanisms. We will also evaluate the pharmacological strategies targeting T2DM as potential therapeutic tools in patients with cognitive impairment.

Keywords: Alzheimer’s disease; insulin receptor; insulin signalling; neurodegenerative disorders; type 2 diabetes mellitus.

Figure 1

Insulin signalling pathway. After insulin binding to the insulin receptor, autophosphorylation, which is essential for its activation, occurs. Then, the activated insulin receptor phosphorylates IRS proteins. IRSs activate PI3K, which catalyses the addition of a phosphate group to the membrane lipid PIP2, thereby converting it to PIP3. PTEN can convert PIP3 back to PIP2. Membrane-bound PIP3 recruits and activates PDK-1, which phosphorylates and activates Akt and atypical PKCs. Akt mediates most of insulin’s metabolic effects and in brain synaptic plasticity, neuronal homeostasis and memory. Abbreviations: IRS (insulin receptor substrate), PI3K (phosphatidylinositol 3 kinase), PIP2 (phosphatidylinositol 4,5-bisphosphate), PIP3 (phosphatidylinositol 3,4,5-trisphosphate), PTEN (phosphatase and tensin homolog), PDK-1 (phosphoinositide-dependent protein kinase-1), PKC (protein kinase c), Akt (protein kinase b), mTORC1 (mammalian target of rapamycin complex 1), GSK3β (glycogen synthase kinase 3β), FoxO (forkhead box O).

Figure 2

Contribution of T2DM and insulin resistance to neurodegeneration. Metabolic changes resulting from T2DM and insulin resistance can impact on the brain, resulting in synaptic dysfunction and promoting triggers/drivers of neurodegeneration: impaired neuronal insulin signalling, vascular damage, neuroinflammation, tau phosphorylation and Aβ accumulation.