Insulin Resistance in Peripheral Tissues and the Brain: A Tale of Two Sites

Rhea, Elizabeth M.; Banks, William A.; Raber, Jacob

doi:10.3390/biomedicines10071582

Cited by 76Alzheimer's disease research and treatmentsAdipokines, Inflammation, and Metabolic DiseasesBarrier Structure and Function Studies

Insulin Resistance in Peripheral Tissues and the Brain: A Tale of Two Sites

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Rhea, Elizabeth M., Banks, William A., Raber, Jacob·2022·Biomedicines

DOI 10.3390/biomedicines10071582PMC PMC9312939

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Abstract

The concept of insulin resistance has been around since a few decades after the discovery of insulin itself. To allude to the classic Charles Dicken’s novel published 62 years before the discovery of insulin, in some ways, this is the best of times, as the concept of insulin resistance has expanded to include the brain, with the realization that insulin has a life beyond the regulation of glucose. In other ways, it is the worst of times as insulin resistance is implicated in devastating diseases, including diabetes mellitus, obesity, and Alzheimer’s disease (AD) that affect the brain. Peripheral insulin resistance affects nearly a quarter of the United States population in adults over age 20. More recently, it has been implicated in AD, with the degree of brain insulin resistance correlating with cognitive decline. This has led to the investigation of brain or central nervous system (CNS) insulin resistance and the question of the relation between CNS and peripheral insulin resistance. While both may involve dysregulated insulin signaling, the two conditions are not identical and not always interlinked. In this review, we compare and contrast the similarities and differences between peripheral and CNS insulin resistance. We also discuss how an apolipoprotein involved in insulin signaling and related to AD, apolipoprotein E (apoE), has distinct pools in the periphery and CNS and can indirectly affect each system. As these systems are both separated but also linked via the blood–brain barrier (BBB), we discuss the role of the BBB in mediating some of the connections between insulin resistance in the brain and in the peripheral tissues.

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Other factors such as genetic background, elevated circulating free fatty acids and impaired insulin transport across the blood-brain barrier have also been implicated in brain insulin resistance.
“although other factors, such as genetic background19, elevated circulating free fatty acids20 and impaired insulin transport across the blood–brain barrier21,22, have also been implicated.”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [21]

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Authors: Rhea, E. M., Banks, W. A., & Raber, J.
Affiliations: University of Washington (US)
Oregon Health & Science University (US)
Corresponding author: Raber, Jacob
ORCID: Rhea, Elizabeth M.
Banks, William A.
Raber, Jacob
Venue: Biomedicines
Publisher: MDPI AG
Published: 2022-07-02
Volume: 10
Issue: 7
Pages: 1582
ISSN: 2227-9059 (ISSN-L)
DOI: 10.3390/biomedicines10071582
PMC: PMC9312939
OpenAlex: W4283776315
Cited by: 76
References: 192
Citations by year: 2026: 18 · 2025: 21 · 2024: 19 · 2023: 15 · 2022: 3
FWCI: 1.99
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Biomedicines (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Institutes of Health (NIH) (RF1 AG059088, P30 AG066509, P30 DK017047-44)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords: insulin resistance, brain insulin resistance, peripheral insulin resistance, central nervous system, insulin signaling, apolipoprotein E, blood-brain barrier, Alzheimer's disease, cognitive decline, diabetes mellitus, obesity

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Insulin Resistance in Peripheral Tissues and the Brain: A Tale of Two Sites

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