Broadening the definition of brain insulin resistance in aging and Alzheimer's disease

Hilaree N. Frazier, Adam O. Ghoweri, Katie L. Anderson, Ruei Lung Lin, Nada M. Porter, Olivier Thibault

Research output: Contribution to journalReview articlepeer-review

32 Scopus citations

Abstract

It has been >20 years since studies first revealed that the brain is insulin sensitive, highlighted by the expression of insulin receptors in neurons and glia, the presence of circulating brain insulin, and even localized insulin production. Following these discoveries, evidence of decreased brain insulin receptor number and function was reported in both clinical samples and animal models of aging and Alzheimer's disease, setting the stage for the hypothesis that neuronal insulin resistance may underlie memory loss in these conditions. The development of therapeutic insulin delivery to the brain using intranasal insulin administration has been shown to improve aspects of memory or learning in both humans and animal models. However, whether this approach functions by compensating for poorly signaling insulin receptors, for reduced insulin levels in the brain, or for reduced trafficking of insulin into the brain remains unclear. Direct measures of insulin's impact on cellular physiology and metabolism in the brain have been sparse in models of Alzheimer's disease, and even fewer studies have analyzed these processes in the aged brain. Nevertheless, recent evidence supports the role of brain insulin as a mediator of glucose metabolism through several means, including altering glucose transporters. Here, we provide a review of contemporary literature on brain insulin resistance, highlight the rationale for improving memory function using intranasal insulin, and describe initial results from experiments using a molecular approach to more directly measure the impact of insulin receptor activation and signaling on glucose uptake in neurons.

Original languageEnglish
Pages (from-to)79-87
Number of pages9
JournalExperimental Neurology
Volume313
DOIs
StatePublished - Mar 2019

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health [ R01AG033649 , T32DK007778 , T32AG057461 ]; the University of Kentucky College of Medicine [Fellowship for Excellence in Graduate Research awarded to H. N. Frazier]; and the University of Kentucky Department of Pharmacology and Nutritional Sciences [Department Reinvestment Fund Award].

Funding Information:
This work was supported by the National Institutes of Health [R01AG033649, T32DK007778, T32AG057461]; the University of Kentucky College of Medicine [Fellowship for Excellence in Graduate Research awarded to H. N. Frazier]; and the University of Kentucky Department of Pharmacology and Nutritional Sciences [Department Reinvestment Fund Award].

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

  • Afterhyperpolarization
  • Brain insulin resistance
  • Calcium
  • Glucose transporters
  • Insulin receptor
  • Insulin signaling
  • Intranasal insulin

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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