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

1
Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry CV2 2DX, UK
2
Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK
3
Aston Medical Research Institute, Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK
4
Centre for Sport, Exercise and Life Sciences, Faculty of Health & Life Sciences, Coventry University, Coventry CV1 5FB, UK
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(2), 546; https://doi.org/10.3390/ijms22020546
Received: 21 December 2020 / Revised: 4 January 2021 / Accepted: 6 January 2021 / Published: 7 January 2021
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. View Full-Text
Keywords: insulin resistance; obesity; metabolic dysfunction; cognitive dysfunction insulin resistance; obesity; metabolic dysfunction; cognitive dysfunction
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MDPI and ACS Style

Barber, T.M.; Kyrou, I.; Randeva, H.S.; Weickert, M.O. Mechanisms of Insulin Resistance at the Crossroad of Obesity with Associated Metabolic Abnormalities and Cognitive Dysfunction. Int. J. Mol. Sci. 2021, 22, 546. https://doi.org/10.3390/ijms22020546

AMA Style

Barber TM, Kyrou I, Randeva HS, Weickert MO. Mechanisms of Insulin Resistance at the Crossroad of Obesity with Associated Metabolic Abnormalities and Cognitive Dysfunction. International Journal of Molecular Sciences. 2021; 22(2):546. https://doi.org/10.3390/ijms22020546

Chicago/Turabian Style

Barber, Thomas M.; Kyrou, Ioannis; Randeva, Harpal S.; Weickert, Martin O. 2021. "Mechanisms of Insulin Resistance at the Crossroad of Obesity with Associated Metabolic Abnormalities and Cognitive Dysfunction" Int. J. Mol. Sci. 22, no. 2: 546. https://doi.org/10.3390/ijms22020546

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