Insulin in the Brain: Its Pathophysiological Implications for States Related with Central Insulin Resistance, Type 2 Diabetes and Alzheimer’s Disease

Abstract

Although the brain has been considered an insulin-insensitive organ, recent reports on the location of insulin and its receptors in the brain have introduced new ways of considering this hormone responsible for several functions. The origin of insulin in the brain has been explained from peripheral or central sources, or both. Regardless of whether insulin is of peripheral origin or produced in the brain, this hormone may act through its own receptors present in the brain. The molecular events through which insulin functions in the brain are the same as those operating in the periphery. However, certain insulin actions are different in the central nervous system, such as hormone-induced glucose uptake due to a low insulin-sensitive GLUT-4 activity, and because of the predominant presence of GLUT-1 and GLUT-3. In addition, insulin in the brain contributes to the control of nutrient homeostasis, reproduction, cognition, and memory, as well as to neurotrophic, neuromodulatory, and neuroprotective effects. Alterations of these functional activities may contribute to the manifestation of several clinical entities, such as central insulin resistance, type 2 diabetes mellitus (T2DM), and Alzheimer’s disease (AD). A close association between T2DM and AD has been reported, to the extent that AD is twice more frequent in diabetic patients, and some authors have proposed the name “type 3 diabetes” for this association. There are links between AD and T2DM through mitochondrial alterations and oxidative stress, altered energy and glucose metabolism, cholesterol modifications, dysfunctional protein O-GlcNAcylation, formation of amyloid plaques, altered Aβ metabolism, and tau hyperphosphorylation. Advances in the knowledge of preclinical AD and T2DM may be a major stimulus for the development of treatment for preventing the pathogenic events of these disorders, mainly those focused on reducing brain insulin resistance, which is seems to be a common ground for both pathological entities.

High‐fat diet protects the blood–brain barrier in an Alzheimer's disease mouse model

“…Insulin receptor (IR) has two isoforms expressed in the brain, A (IR‐a) and B (IR‐b). IR‐a is more prominent (Blazquez, Velazquez, Hurtado‐Carneiro, & Ruiz‐Albusac, 2014). When fed with HFD, IR‐a levels in Tg mice were found comparable to those of WT CTRL (Supporting Information Figure S4A).…”

Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer's brain

“…The well‐replicated finding of lower FDG‐PET standardized uptake value ratio (SUVr) in AD reflects lower FDG cellular uptake and, by extension, less glucose cellular uptake as FDG competes for the same facilitated transporters as endogenous glucose 45. Glucose is primarily delivered from the extracellular space into neurons via the insulin‐independent glucose transporter GLUT3, and the insulin‐dependent GLUT4,46, 47 though many other GLUTs contribute. AD is characterized by downregulation of neuronal GLUT3 and glial/endothelial GLUT1, which provides far fewer avenues for glucose uptake into either cell type and thus leads to a reduction in neuronal activity and metabolism 48, 49.…”

The Influence of Intranasal Insulin on Hypothalamic-Pituitary-Thyroid Axis in Normal and Diabetic Rats

“…It is commonly accepted that insulin injections are the best way to treat DM1. However, in recent years, intranasal administration of insulin (I-I) has also found an application in the treatment of patients with DM and Alzheimer's disease, bipolar disorders, and some other neurological disorders [19][20][21]. Along with the action on the CNS, I-I via the central mechanisms controls biochemical and physiological processes in the periphery [21][22][23].…”