Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums

Key Points

  • The molecular signalling pathways through which insulin exerts its actions in the body also mediate its roles in synaptic neurotransmission, neuronal and glial metabolism, and the neuroinflammatory response in the brain

  • The actions of insulin in the brains of healthy individuals include central modulation of body metabolism and enhancement or regulation of memory and other cognitive and emotional functions

  • Insulin resistance is a core feature of type 2 diabetes mellitus (T2DM) and contributes not only to the hyperglycaemia that defines diabetes mellitus but also to the hyperlipidaemia, inflammation, oxidative stress and atherosclerosis that accompany it

  • T2DM substantially increases risk of not only cerebrovascular disease and stroke but also neurodegenerative dementias of late life, especially Alzheimer disease (AD)

  • Brain insulin resistance can be defined as the failure of brain cells to respond to insulin as they normally would, resulting in impairments in synaptic, metabolic and immune response functions

  • T2DM is associated with brain insulin resistance, and studies suggest that brain insulin resistance is a feature of AD; however, whether the two conditions are mechanistically linked or represent unrelated occurrences in ageing is unclear

Abstract

Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus (T2DM), two of the most pressing epidemics of our time. Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear. Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs. Here, we review key observations and experimental data on insulin signalling in the brain, highlighting its actions in neurons and glia. In addition, we define the concept of 'brain insulin resistance' and review the growing, although still inconsistent, literature concerning cognitive impairment and neuropathological abnormalities in T2DM, obesity and insulin resistance. Lastly, we review evidence of intrinsic brain insulin resistance in ADRDs. By expanding our understanding of the overlapping mechanisms of these conditions, we hope to accelerate the rational development of preventive, disease-modifying and symptomatic treatments for cognitive dysfunction in T2DM and ADRDs alike.

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Figure 1: Canonical insulin signalling pathways.
Figure 2: Insulin effects in major cell types of the brain.

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Acknowledgements

The authors express appreciation to R. Corriveau and B. Trombetta for manuscript review and comments. Manuscript preparation was supported in part with topic-related funding from the US NIH, the BrightFocus Foundation and the Berkman Family Charitable Trust.

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All authors contributed substantially to the discussion of content and editing of the manuscript before submission. S.E.A., H.-Y.W. and R.S.A. researched data for the article and S.E.A., Z.A., S.G. C.B. and D.M.N. wrote the article.

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Correspondence to Steven E. Arnold.

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Arnold, S., Arvanitakis, Z., Macauley-Rambach, S. et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol 14, 168–181 (2018). https://doi.org/10.1038/nrneurol.2017.185

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