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Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums
Open accessAbstract
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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“in AD and amnestic mild cognitive impairment (aMCI) glucose metabolism is dramatically decreased”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“In AD and aMCI, however, brain insulin resistance is present6,7.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [7]
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“Glucose enters the brain from the vasculature through highly efficient glucose transporters and requires insulin for optimal cellular utilization7.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [7]
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“Yet glucose metabolism in AD and aMCI brains is significantly impaired5–7,9,38.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [7]
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“The brain is an energy-demanding organ and relies heavily on efficient ATP production via glycolysis, the TCA cycle and oxidative phosphorylation (Fig. 1)7.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [7]
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“In addition to mTOR activation, insulin resistance can also result in neuronal glucose deficiency, with consequent decreased glucose metabolism, impaired ATP production, and dysfunction and/or death7,42”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [7]
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“The possible action of Al in the pathogenesis of diabetes mellitus and the concurrence of neurological disorders associated with Alzheimer’s disease and other dementias (Arnold et al., 2018) point to the common cellular basis of the pathogenesis of both metabolic and cognitive disorders, which can arise from toxic actions of Al.”
From Aluminium toxicosis: a review of toxic actions and effects (2019) · cites this paper as Arnold et al., 2018
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“insulin resistance could affect neuronal function and Aβ accumulation in the brain, which contribute to neuroinflammation and synaptic dysfunction and finally lead to cognitive decline (Arnold et al., 2018).”
From AD-Like Neuropsychiatric Dysfunction in a Mice Model Induced by a Combination of High-Fat Diet and Intraperitoneal Injection of Streptozotocin (2024) · cites this paper as Arnold et al., 2018
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“Recent studies have suggested a potential link between AD and insulin resistance, which exhibits a decreased level of key insulin signaling proteins and an increased level of insulin resistance markers in the brains of AD mice (Craft et al., 1998; Arnold et al., 2018; Kshirsagar et al., 2021).”
From AD-Like Neuropsychiatric Dysfunction in a Mice Model Induced by a Combination of High-Fat Diet and Intraperitoneal Injection of Streptozotocin (2024) · cites this paper as Arnold et al., 2018
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In the citing paper
“Indeed, type 2 diabetes (T2DM), a key component of which is insulin resistance, is a significant risk factor for developing AD7.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [7]
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“These mTOR-mediated events may help explain the observation that type 2 diabetes (T2DM) is a significant risk factor for development of AD7,41.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [7]
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“Brain insulin resistance is common in AD7,38,41.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [7]
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In the citing paper
“Indeed, mitochondrial dysfunction and insulin resistance are intimately related7,38.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [7]
Experimental — accuracy not yet measuredIn the citing paper
“it might involve the down-regulation or failure of insulin receptors, as well as impairments of downstream signalling, and contribute to the emergence and/or persistence of metabolic dysregulation”
From Intranasal insulin (2021) · cites this paper as [90]
In the citing paper
“Insulin may moreover boost brain energy supply via effects on astrocytes 129 and other glia cells, including oligodentrocytes.90”
From Intranasal insulin (2021) · cites this paper as [90]
In the citing paper
“Respective organ deficits include reductions in hippocampal volume, 141 as well as ischaemic impairments and cortical hypometabolism.90”
From Intranasal insulin (2021) · cites this paper as [90]
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Citations
Cites
Hearing loss and cognitive decline in older adults
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Self-citationEnergy Metabolism in the Liver
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Biessels, G. J., Staekenborg, S., Brunner, E., Brayne, C., & Scheltens, P. (2006) · The Lancet Neurology · doi:10.1016/s1474-4422(05)70284-2 · Cited by 2,187
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Depression and Type 2 Diabetes Over the Lifespan
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Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis
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Craft, S. (2012) · Archives of Neurology · doi:10.1001/archneurol.2011.233 · Cited by 1,253
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Cryan, J. F., O'Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., Codagnone, M. G., Cussotto, S., Fulling, C., Golubeva, A. V., et al. (2019) · Physiological Reviews · doi:10.1152/physrev.00018.2018 · Cited by 5,286
Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging
Jomova, K., Raptova, R., Alomar, S. Y., Alwasel, S. H., Nepovimova, E., Kuca, K., & Valko, M. (2023) · Archives of Toxicology · doi:10.1007/s00204-023-03562-9 · Cited by 2,638
Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease
Butterfield, D. A., & Halliwell, B. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-019-0132-6 · Cited by 1,954
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de Cabo, R., & Mattson, M. P. (2019) · New England Journal of Medicine · doi:10.1056/nejmra1905136 · Cited by 1,605
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Metadata
- Authors
- Arnold, S. E., Arvanitakis, Z., Macauley-Rambach, S. L., Koenig, A. M., Wang, H.-Y., Ahima, R. S., Craft, S., Gandy, S., Buettner, C., Stoeckel, L. E., Holtzman, D. M., & Nathan, D. M.
- Affiliations
- Harvard University (US)
- Rush University Medical Center (US)
- City University of New York (US)
- Johns Hopkins University (US)
- Atrium Health Wake Forest Baptist (US)
- Icahn School of Medicine at Mount Sinai (US)
- Washington University in St. Louis (US)
- Corresponding author
- Arnold, Steven E.
- ORCID
- Venue
- Nature Reviews Neurology
- Published
- 2018-01-29
- Volume
- 14
- Issue
- 3
- Pages
- 168-181
- ISSN
- 1759-4758 (ISSN-L)
- 1759-4766
- PMC
- PMC6098968
- OpenAlex
- W2786962139
- Cited by
- 1,597
- References
- 285
- Citations by year
- 2026: 223 · 2025: 244 · 2024: 218 · 2023: 205 · 2022: 210 · 2021: 176 · 2020: 163 · 2019: 102 · 2018: 52
- FWCI
- 16.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Funders
- BrightFocus Foundation
- National Institutes of Health
- National Institute on Aging (R21AG051958)
- National Institute of Neurological Disorders and Stroke (R01NS084965)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- brain insulin resistance, type 2 diabetes, Alzheimer's disease, Alzheimer's disease and related dementias, insulin signaling, cognitive impairment, obesity, glia, neurons, neuropathology, comorbidities, aging
- MeSH terms
- Brain, Dementia, Diabetes Mellitus, Type 2, Humans, Insulin, Insulin Resistance
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