Review

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

Published online:

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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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.

Author information

Affiliations

  1. Department of Neurology and the Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, Massachusetts 02129, USA.

    • Steven E. Arnold
    •  & Aaron M. Koenig
  2. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, 1750 W. Harrison Street, Suite 1000, Chicago, Illinois 60612, USA.

    • Zoe Arvanitakis
  3. Hope Center for Neurological Disorders, Department of Neurology, Campus Box 8111, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, Missouri 63110, USA.

    • Shannon L. Macauley-Rambach
    •  & David M. Holtzman
  4. Department of Physiology, Pharmacology and Neuroscience, City University of New York School of Medicine, 160 Convent Avenue, New York, New York 10031, USA.

    • Hoau-Yan Wang
  5. Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, 333 East Monument Street, Baltimore, Maryland 21205, USA.

    • Rexford S. Ahima
  6. Gerontology and Geriatric Medicine Center on Diabetes, Obesity, and Metabolism, Wake Forest School of Medicine, Wake Forest Baptist Medical Center, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.

    • Suzanne Craft
  7. Departments of Neurology and Psychiatry and the Mount Sinai Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1230, New York, New York 10029, USA.

    • Sam Gandy
  8. Diabetes, Obesity, and Metabolism Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA.

    • Christoph Buettner
  9. National Institute of Diabetes and Digestive and Kidney Diseases, 6707 Democracy Boulevard, Bethesda, Maryland 20817, USA. Diabetes Center and Clinical Research Center, Massachusetts General Hospital, Harvard Medical School, Bullfinch 55 Fruit Street, Boston, Massachusetts 02114, USA.

    • Luke E. Stoeckel
    •  & David M. Nathan

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Steven E. Arnold.