Minireviews
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Apr 15, 2022; 13(4): 319-337
Published online Apr 15, 2022. doi: 10.4239/wjd.v13.i4.319
Cognitive disorder and dementia in type 2 diabetes mellitus
Genaro G Ortiz, Miguel Huerta, Héctor A González-Usigli, Erandis D Torres-Sánchez, Daniela LC Delgado-Lara, Fermín P Pacheco-Moisés, Mario A Mireles-Ramírez, Blanca MG Torres-Mendoza, Roxana I Moreno-Cih, Irma E Velázquez-Brizuela
Genaro G Ortiz, Daniela LC Delgado-Lara, Blanca MG Torres-Mendoza, Irma E Velázquez-Brizuela, Department of Philosophical and Methodological Disciplines, University Health Sciences Center, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico
Genaro G Ortiz, Héctor A González-Usigli, Mario A Mireles-Ramírez, Department of Neurology, Movement Disorders Clinic, Sub-Specialty Medical Unit, National Western Medical Center, Mexican Social Security Institute (IMSS), Guadalajara 44340, Jalisco, Mexico
Miguel Huerta, University Biomedical Research Center, University of Colima, Colima 28040, Mexico
Erandis D Torres-Sánchez, Department of Medical and Life Sciences, University Center of ‘La Ciénega’, University of Guadalajara, Ocotlán 47810, Jalisco, Mexico
Fermín P Pacheco-Moisés, Department of Chemistry, University Center of Exact Sciences and Engineering, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico
Blanca MG Torres-Mendoza, Division of Neurosciences, Western Biomedical Research Center, Mexican Social Security Institute (IMSS), Guadalajara 44340, Jalisco, Mexico
Roxana I Moreno-Cih, Gerontology Postgraduate Program, Public Health Department, University Health Sciences Center, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico
Author contributions: Ortiz GG contributed coordination and work writing; Huerta M contributed diabetes expert and reviewer, and amyline contribution; González-Usigli HA and Mireles-Ramírez MA contributed neurologists and clinical work reviewers and writing; Torres-Sánchez ED and Delgado-Lara DL updated analysis of references, and graphic art; Pacheco-Moisés FP, Torres-Mendoza BM and Moreno-Cih RI contributed basic concepts, and their writing; Velázquez-Brizuela IE and Ortiz GG contributed neuropsychology and dementia concepts and writing.
Conflict-of-interest statement: This work does not present any conflict of interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Genaro G Ortiz, MD, PhD, Professor, Senior Researcher, Department of Philosophical and Methodological Disciplines, University Health Sciences Center, University of Guadalajara, 800 Sierra Mojada St., Guadalajara 44340, Jalisco, Mexico. genarogabriel@yahoo.com
Received: May 12, 2021
Peer-review started: May 12, 2021
First decision: June 24, 2021
Revised: July 14, 2021
Accepted: March 17, 2022
Article in press: March 17, 2022
Published online: April 15, 2022
Processing time: 337 Days and 10.1 Hours
Abstract

Insulin, a key pleiotropic hormone, regulates metabolism through several signaling pathways in target tissues including skeletal muscle, liver, and brain. In the brain, insulin modulates learning and memory, and impaired insulin signaling is associated with metabolic dysregulation and neurodegenerative diseases. At the receptor level, in aging and Alzheimer’s disease (AD) models, the amount of insulin receptors and their functions are decreased. Clinical and animal model studies suggest that memory improvements are due to changes in insulin levels. Furthermore, diabetes mellitus (DM) and insulin resistance are associated with age-related cognitive decline, increased levels of β-amyloid peptide, phosphorylation of tau protein; oxidative stress, pro-inflammatory cytokine production, and dyslipidemia. Recent evidence shows that deleting brain insulin receptors leads to mild obesity and insulin resistance without influencing brain size and apoptosis development. Conversely, deleting insulin-like growth factor 1 receptor (IGF-1R) affects brain size and development, and contributes to behavior changes. Insulin is synthesized locally in the brain and is released from the neurons. Here, we reviewed proposed pathophysiological hypotheses to explain increased risk of dementia in the presence of DM. Regardless of the exact sequence of events leading to neurodegeneration, there is strong evidence that mitochondrial dysfunction plays a key role in AD and DM. A triple transgenic mouse model of AD showed mitochondrial dysfunction, oxidative stress, and loss of synaptic integrity. These alterations are comparable to those induced in wild-type mice treated with sucrose, which is consistent with the proposal that mitochondrial alterations are associated with DM and contribute to AD development. Alterations in insulin/IGF-1 signaling in DM could lead to mitochondrial dysfunction and low antioxidant capacity of the cell. Thus, insulin/IGF-1 signaling is important for increased neural processing and systemic metabolism, and could be a specific target for therapeutic strategies to decrease alterations associated with age-related cognitive decline.

Keywords: Alzheimer´s disease; Diabetes mellitus; Insulin; Vascular dementia; Cognitive decline

Core Tip: Cognitive disorders and dementia have multiple causes and clinical manifestations. Recently, defects in insulin signaling in the brain have been associated with cognitive disorders and dementia. In this regard, insulin signaling pathways in the brain regulate learning and memory, and modulate peripheral energy metabolism. In this review, the pathophysiological factors involved in cognitive disorders, dementia, and diabetes mellitus, and the link between these disorders, are presented in a summarized manner. Finally, we discuss the role of mitochondrial dysfunction in Alzheimer´s disease and diabetes mellitus.