Mechanisms of Insulin Resistance at the Crossroad of Obesity with Associated Metabolic Abnormalities and Cognitive Dysfunction


Obesity mediates most of its direct medical sequelae through the development of insulin resistance (IR). The cellular effects of insulin occur through two main postreceptor pathways that are the phosphatidylinositol 3-kinase (PI3-K) and the mitogen-activated protein kinase (MAP-K) pathways. Obesity-related IR implicates the PI3-K pathway that confers the metabolic effects of insulin. Numerous and complex pathogenic pathways link obesity with the development of IR, including chronic inflammation, mitochondrial dysfunction (with the associated production of reactive oxygen species and endoplasmic reticulum stress), gut microbiota dysbiosis and adipose extracellular matrix remodelling. IR itself plays a key role in the development of metabolic dysfunction, including hypertension, dyslipidaemia and dysglycaemia. Furthermore, IR promotes weight gain related to secondary hyperinsulinaemia, with a resulting vicious cycle of worsening IR and its metabolic sequelae. Ultimately, IR underlies obesity-related conditions such as type 2 diabetes mellitus (T2D) and polycystic ovary syndrome (PCOS). IR also underlies many obesity-related malignancies, through the effects of compensatory hyperinsulinaemia on the relatively intact MAP-K insulin pathway, which controls cellular growth processes and mitoses. Furthermore, the emergent data over recent decades support an important role of obesity- and T2D-related central IR in the development of cognitive dysfunction, including effects on hippocampal synaptic plasticity. Importantly, IR is largely reversible through the optimisation of lifestyle factors that include regular engagement in physical activity with the avoidance of sedentariness, improved diet including increased fibre intake and sleep sufficiency. IR lies at the key crossroad between obesity and both metabolic and cognitive dysfunction. Given the importance of IR in the pathogenesis of many 21st century chronic diseases and its eminent reversibility, it is important that we all embrace and facilitate optimised lifestyles to improve the future health and wellbeing of the populace.

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Divisions: College of Health & Life Sciences > Aston Medical School
Additional Information: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// 4.0/).
Uncontrolled Keywords: Cognitive dysfunction,Insulin resistance,Metabolic dysfunction,Obesity,Catalysis,Molecular Biology,Spectroscopy,Computer Science Applications,Physical and Theoretical Chemistry,Organic Chemistry,Inorganic Chemistry
Publication ISSN: 1422-0067
Last Modified: 14 May 2024 07:20
Date Deposited: 11 Jan 2021 08:44
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Related URLs: https://www.mdp ... 2-0067/22/2/546 (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Review article
Published Date: 2021-01-07
Accepted Date: 2021-01-06
Authors: Barber, Thomas M.
Kyrou, Ioannis (ORCID Profile 0000-0002-6997-3439)
Randeva, Harpal S.
Weickert, Martin O.



Version: Published Version

License: Creative Commons Attribution

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