Brain insulin resistance in type 2 diabetes and Alzheimer disease

Concepts and conundrums

Steven E. Arnold, Zoe Arvanitakis, Shannon L. Macauley-Rambach, Aaron M. Koenig, Hoau Yan Wang, Rexford S Ahima, Suzanne Craft, Sam Gandy, Christoph Buettner, Luke E. Stoeckel, David M. Holtzman, David M. Nathan

Research output: Contribution to journalReview article

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.

Original languageEnglish (US)
Pages (from-to)168-181
Number of pages14
JournalNature Reviews Neurology
Volume14
Issue number3
DOIs
StatePublished - Mar 1 2018

Fingerprint

Type 2 Diabetes Mellitus
Dementia
Insulin Resistance
Alzheimer Disease
Brain
Neuroglia
Comorbidity
Obesity
Insulin
Neurons
Cognitive Dysfunction

ASJC Scopus subject areas

  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Arnold, S. E., Arvanitakis, Z., Macauley-Rambach, S. L., Koenig, A. M., Wang, H. Y., Ahima, R. S., ... Nathan, D. M. (2018). Brain insulin resistance in type 2 diabetes and Alzheimer disease: Concepts and conundrums. Nature Reviews Neurology, 14(3), 168-181. https://doi.org/10.1038/nrneurol.2017.185

Brain insulin resistance in type 2 diabetes and Alzheimer disease : Concepts and conundrums. / Arnold, Steven E.; Arvanitakis, Zoe; Macauley-Rambach, Shannon L.; Koenig, Aaron M.; Wang, Hoau Yan; Ahima, Rexford S; Craft, Suzanne; Gandy, Sam; Buettner, Christoph; Stoeckel, Luke E.; Holtzman, David M.; Nathan, David M.

In: Nature Reviews Neurology, Vol. 14, No. 3, 01.03.2018, p. 168-181.

Research output: Contribution to journalReview article

Arnold, SE, Arvanitakis, Z, Macauley-Rambach, SL, Koenig, AM, Wang, HY, Ahima, RS, Craft, S, Gandy, S, Buettner, C, Stoeckel, LE, Holtzman, DM & Nathan, DM 2018, 'Brain insulin resistance in type 2 diabetes and Alzheimer disease: Concepts and conundrums', Nature Reviews Neurology, vol. 14, no. 3, pp. 168-181. https://doi.org/10.1038/nrneurol.2017.185
Arnold, Steven E. ; Arvanitakis, Zoe ; Macauley-Rambach, Shannon L. ; Koenig, Aaron M. ; Wang, Hoau Yan ; Ahima, Rexford S ; Craft, Suzanne ; Gandy, Sam ; Buettner, Christoph ; Stoeckel, Luke E. ; Holtzman, David M. ; Nathan, David M. / Brain insulin resistance in type 2 diabetes and Alzheimer disease : Concepts and conundrums. In: Nature Reviews Neurology. 2018 ; Vol. 14, No. 3. pp. 168-181.
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