REVIEW article
Front. Aging Neurosci.
Sec. Neuroinflammation and Neuropathy
Brain Insulin Resistance: A Key Pathological Hub Linking Metabolic and Neuropsychiatric Comorbidities
Shanwen Tang 1,2
Yifan Liao 1,2
Rensong Yue 1
1. Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
2. Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Abstract
Abstract: The high rate of comorbidity between metabolic diseases and neuropsychiatric disorders suggests a shared underlying pathogenic mechanism. However, the biological basis of this relationship remains unclear. This study aims to clarify the role of brain insulin resistance (BIR) in linking metabolic dysfunction to neuropsychiatric symptoms based on existing evidence. The analysis shows that BIR disrupts limbic system function through two primary molecular pathways: (1) impairment of the PI3K/Akt/mTOR pathway, which decreases the expression of synaptic plasticity-related proteins and causes deficits in long-term potentiation (LTP); (2) activation of the TLR4/MyD88 inflammatory axis, promoting pro-inflammatory cytokine release from glial cells. These changes result in characteristic neuropsychiatric phenotypes, including amygdala hyperactivity (emotional disorders), hippocampal atrophy (memory impairment), and decreased prefrontal cortex (PFC) function (executive dysfunction). This review highlights that interventions targeting BIR might simultaneously improve metabolic outcomes and neuropsychiatric symptoms, providing a theoretical foundation for trans-diagnostic treatment models. The findings support the view of BIR as a modifiable interface for metabolic- neuropsychiatric comorbidities and advocate for the development of a multidisciplinary collaborative framework to facilitate mechanism-based precision therapy.
Summary
Keywords
Alzheimer's disease, Anxiety Disorders, Brain insulin resistance (BIR), depressive disorders, Diabetes-associated cognitive decline
Received
30 September 2025
Accepted
12 February 2026
Copyright
© 2026 Tang, Liao and Yue. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Rensong Yue
Disclaimer
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