---
title: "Metabolic Dysfunction, Neuroinflammation, and Mitochondrial Failure as Shared Drivers of Balance I"
id: "pubmed-42789205"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42789205"
content_type: "clinical_feed_article"
specialty: "Pharmacology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42789205/"
doi: "10.1007/s12035-026-06237-5"
published_at: "2026-09-25T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Metabolic Dysfunction, Neuroinflammation, and Mitochondrial Failure as Shared Drivers of Balance I
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42789205
- **Specialty:** [Pharmacology](https://medichelpline.com/clinical-feed/pharmacology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42789205/)
- **DOI:** [10.1007/s12035-026-06237-5](https://doi.org/10.1007%2Fs12035-026-06237-5)
- **Published At:** 2026-09-25T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- Balance impairment and postural instability are major contributors to falls and functional decline in aging, particularly in people with **Type 2 Diabetes Mellitus** (T2DM) and **Alzheimer’s Disease** (AD). - Traditional models attribute balance loss in T2DM mainly to peripheral neuropathy and in AD to cortical atrophy, but the reviewed evidence supports a convergent, central pathophysiology shared between both conditions. - The authors propose a self-reinforcing cycle in which systemic and cerebral **metabolic dysfunction** (including insulin resistance and glucotoxicity) drive activation of the **NLRP3 inflammasome** and chronic **neuroinflammation**, increasing proinflammatory cytokine release. - This inflammatory milieu exacerbates **mitochondrial dysfunction** and oxidative stress, compromising bioenergetics in high-energy motor circuits (e.g., striatum, basal ganglia) and contributing to peripheral effects such as sarcopenia and nerve demyelination. - The interplay of these pathways can explain both central and peripheral contributors to postural instability and bridges disease-specific silos between T2DM and AD. - Therapeutic strategies discussed include metabolic modulators such as **GLP-1 receptor agonists**, mitochondrial-targeted antioxidants, and multimodal rehabilitation, framed as potential precision-based interventions to reduce fall risk and preserve function. - The review synthesizes mechanistic links rather than presenting new clinical trial outcomes; where detailed quantitative results or trial specifics are required, the source indicates general therapeutic potential but does not report primary trial data. - Keywords emphasized by the authors include **Alzheimer’s Disease**, **Balance impairment**, **Mitochondrial Dysfunction**, **Neuroinflammation**, **Sarcopenia**, and **Type 2 Diabetes Mellitus**.
## Clinical Analysis & Structured Key Points
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Sodiq.fakorede@futo.edu.ng."), [Olubodun Michael Lateef](https://pubmed.ncbi.nlm.nih.gov/?term=Lateef+OM&cauthor_id=42789205)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42789205/#full-view-affiliation-2 "Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA."), [Augustine Lishilinimye Udefa](https://pubmed.ncbi.nlm.nih.gov/?term=Udefa+AL&cauthor_id=42789205)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42789205/#full-view-affiliation-3 "Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA.")[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42789205/#full-view-affiliation-4 "Department of Physiology, University of Calabar, Calabar, Cross River State, Nigeria."), [Abayomi Oyeyemi Ajagbe](https://pubmed.ncbi.nlm.nih.gov/?term=Ajagbe+AO&cauthor_id=42789205)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42789205/#full-view-affiliation-5 "Department of Anatomy, Nile University of Nigeria, Abuja, Nigeria."), [Sharmistha Roy](https://pubmed.ncbi.nlm.nih.gov/?term=Roy+S&cauthor_id=42789205)[ 6 ](https://pubmed.ncbi.nlm.nih.gov/42789205/#full-view-affiliation-6 "Department of Social and Behavioral Health, University of Nevada, Las Vegas, NV, USA."), [Priscilla Onaopemipo Akosile](https://pubmed.ncbi.nlm.nih.gov/?term=Akosile+PO&cauthor_id=42789205)[ 7 ](https://pubmed.ncbi.nlm.nih.gov/42789205/#full-view-affiliation-7 "Department of Population Health Sciences, University of Leicester, Leicester, UK."), [Taiwo Ayomide Awobona](https://pubmed.ncbi.nlm.nih.gov/?term=Awobona+TA&cauthor_id=42789205)[ 8 ](https://pubmed.ncbi.nlm.nih.gov/42789205/#full-view-affiliation-8 "Department of Nursing, University of Houston Downtown, Houston, TX, USA."), [Godson Emeka Anyanwu](https://pubmed.ncbi.nlm.nih.gov/?term=Anyanwu+GE&cauthor_id=42789205)[ 9 ](https://pubmed.ncbi.nlm.nih.gov/42789205/#full-view-affiliation-9 "Department of Anatomy, Kampala International University, Kampala, Uganda.") Affiliations Expand ### Affiliations * 1 Department of Prosthetics and Orthotics, Federal University of Technology, Owerri, Nigeria. Sodiq.fakorede@futo.edu.ng. * 2 Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA. * 3 Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA. * 4 Department of Physiology, University of Calabar, Calabar, Cross River State, Nigeria. * 5 Department of Anatomy, Nile University of Nigeria, Abuja, Nigeria. * 6 Department of Social and Behavioral Health, University of Nevada, Las Vegas, NV, USA. * 7 Department of Population Health Sciences, University of Leicester, Leicester, UK. * 8 Department of Nursing, University of Houston Downtown, Houston, TX, USA. * 9 Department of Anatomy, Kampala International University, Kampala, Uganda. * PMID: **42789205** * DOI: [ 10.1007/s12035-026-06237-5 ](https://doi.org/10.1007/s12035-026-06237-5) Item in Clipboard Review # The Interplay of Metabolic Dysfunction, Neuroinflammation, and Mitochondrial Dysfunction in Balance Impairment: Insights from Type 2 Diabetes Mellitus and Alzheimer's Disease Sodiq Fakorede et al. Mol Neurobiol. 2026. Show details Display options Display options Format Abstract PubMed PMID Mol Neurobiol Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Mol+Neurobiol%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Mol+Neurobiol%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42789205/) . 2026 Sep 25;63(1):922. doi: 10.1007/s12035-026-06237-5. ### Authors [Sodiq Fakorede](https://pubmed.ncbi.nlm.nih.gov/?term=Fakorede+S&cauthor_id=42789205)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42789205/#short-view-affiliation-1 "Department of Prosthetics and Orthotics, Federal University of Technology, Owerri, Nigeria. Sodiq.fakorede@futo.edu.ng."), [Olubodun Michael Lateef](https://pubmed.ncbi.nlm.nih.gov/?term=Lateef+OM&cauthor_id=42789205)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42789205/#short-view-affiliation-2 "Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA."), [Augustine Lishilinimye Udefa](https://pubmed.ncbi.nlm.nih.gov/?term=Udefa+AL&cauthor_id=42789205)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42789205/#short-view-affiliation-3 "Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA.")[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42789205/#short-view-affiliation-4 "Department of Physiology, University of Calabar, Calabar, Cross River State, Nigeria."), [Abayomi Oyeyemi Ajagbe](https://pubmed.ncbi.nlm.nih.gov/?term=Ajagbe+AO&cauthor_id=42789205)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42789205/#short-view-affiliation-5 "Department of Anatomy, Nile University of Nigeria, Abuja, Nigeria."), [Sharmistha Roy](https://pubmed.ncbi.nlm.nih.gov/?term=Roy+S&cauthor_id=42789205)[ 6 ](https://pubmed.ncbi.nlm.nih.gov/42789205/#short-view-affiliation-6 "Department of Social and Behavioral Health, University of Nevada, Las Vegas, NV, USA."), [Priscilla Onaopemipo Akosile](https://pubmed.ncbi.nlm.nih.gov/?term=Akosile+PO&cauthor_id=42789205)[ 7 ](https://pubmed.ncbi.nlm.nih.gov/42789205/#short-view-affiliation-7 "Department of Population Health Sciences, University of Leicester, Leicester, UK."), [Taiwo Ayomide Awobona](https://pubmed.ncbi.nlm.nih.gov/?term=Awobona+TA&cauthor_id=42789205)[ 8 ](https://pubmed.ncbi.nlm.nih.gov/42789205/#short-view-affiliation-8 "Department of Nursing, University of Houston Downtown, Houston, TX, USA."), [Godson Emeka Anyanwu](https://pubmed.ncbi.nlm.nih.gov/?term=Anyanwu+GE&cauthor_id=42789205)[ 9 ](https://pubmed.ncbi.nlm.nih.gov/42789205/#short-view-affiliation-9 "Department of Anatomy, Kampala International University, Kampala, Uganda.") ### Affiliations * 1 Department of Prosthetics and Orthotics, Federal University of Technology, Owerri, Nigeria. Sodiq.fakorede@futo.edu.ng. * 2 Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA. * 3 Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA. * 4 Department of Physiology, University of Calabar, Calabar, Cross River State, Nigeria. * 5 Department of Anatomy, Nile University of Nigeria, Abuja, Nigeria. * 6 Department of Social and Behavioral Health, University of Nevada, Las Vegas, NV, USA. * 7 Department of Population Health Sciences, University of Leicester, Leicester, UK. * 8 Department of Nursing, University of Houston Downtown, Houston, TX, USA. * 9 Department of Anatomy, Kampala International University, Kampala, Uganda. * PMID: **42789205** * DOI: [ 10.1007/s12035-026-06237-5 ](https://doi.org/10.1007/s12035-026-06237-5) Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID Linked Discoveries ## Abstract Balance impairment and postural instability represent critical challenges for the aging population, serving as primary precursors to falls and functional decline in individuals with Type 2 Diabetes Mellitus. While traditional clinical models have largely separated these conditions, attributing balance loss in T2DM to peripheral neuropathy and in AD to central cortical atrophy, mounting evidence suggests a convergence of multi-system impairments driven by a shared central pathophysiology. This narrative review proposes an integrative framework centered on a vicious, self-reinforcing cycle involving metabolic dysfunction, chronic neuroinflammation, and mitochondrial failure as the core mechanistic link driving balance impairment. We detail how systemic and cerebral insulin resistance, coupled with glucotoxicity, trigger the activation of the NLRP3 inflammasome and the subsequent release of pro-inflammatory cytokines. This inflammatory environment exacerbates mitochondrial bioenergetic failure and oxidative stress, selectively targeting high-energy motor circuits such as the striatum and basal ganglia while simultaneously contributing to musculoskeletal sarcopenia and peripheral nerve demyelination. By synthesizing the intricate interplay between these molecular pathways, this review moves beyond disease-specific silos to offer a novel perspective on the shared pathophysiology of postural instability. Furthermore, we explore the therapeutic potential of metabolic modulators, such as GLP-1 receptor agonists, and mitochondrial-targeted antioxidants, alongside multimodal rehabilitation strategies. Ultimately, this unified model provides a foundation for developing precision-based interventions to mitigate fall risk and preserve functional independence in vulnerable aging populations. **Keywords:** Alzheimer’s Disease; Balance impairment; Mitochondrial Dysfunction; Neuroinflammation; Sarcopenia; Type 2 Diabetes Mellitus. © 2026. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Declarations. Ethics Approval: Not applicable for this narrative review. Artificial Intelligence Use Disclosure: The authors used Claude AI (Anthropic) to assist with editing and grammar improvement during the preparation of this manuscript. All scientific content, interpretations, and conclusions are solely the work of the authors. Competing interests: The authors declare no competing interests. ## References 1. 1. Schwartz AV, Hillier TA, Sellmeyer DE et al (2002) Older women with diabetes have a higher risk of falls: a prospective study. Diabetes Care 25:1749–1754. - [DOI](https://doi.org/10.2337/diacare.25.10.1749) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/12351472/) 2. 1. Tilling LM, Darawil K, Britton M (2006) Falls as a complication of diabetes mellitus in older people. J Diabetes Complicat 20:158–162. - [DOI](https://doi.org/10.1016/j.jdiacomp.2005.06.004) 3. 1. Menz HB, Lord SR, St George R, Fitzpatrick RC (2004) Walking stability and sensorimotor function in older people with diabetic peripheral neuropathy. Arch Phys Med Rehabil 85:245–252. - [DOI](https://doi.org/10.1016/j.apmr.2003.06.015) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/14966709/) 4. 1. Vaz MM, Costa GC, Reis JG et al (2013) Postural control and functional strength in patients with type 2 diabetes mellitus with and without peripheral neuropathy. Arch Phys Med Rehabil 94:2465–2470. - [DOI](https://doi.org/10.1016/j.apmr.2013.06.007) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/23806609/) 5. 1. Puente-González AS, Sánchez-Sánchez MC, Fernández-Rodríguez EJ et al (2021) Effects of 6-month multimodal physical exercise program on bone mineral density, fall risk, balance, and gait in patients with Alzheimer’s disease: a controlled clinical trial. Brain Sci 11:63. - [DOI](https://doi.org/10.3390/brainsci11010063) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/33419016/) - [PMC](https://pmc.ncbi.nlm.nih.gov/articles/7825330/) Show all 137 references ## Publication types * Review Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Review%22%5Bpt%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Review) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42789205/) ## MeSH terms * Alzheimer Disease* / complications Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Alzheimer+Disease%2Fcomplications%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Alzheimer+Disease) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42789205/) * Alzheimer Disease* / metabolism Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Alzheimer+Disease%2Fmetabolism%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Alzheimer+Disease) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42789205/) * Alzheimer Disease* / pathology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Alzheimer+Disease%2Fpathology%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Alzheimer+Disease) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42789205/) * Alzheimer Disease* / physiopathology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Alzheimer+Disease%2Fphysiopathology%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Alzheimer+Disease) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42789205/) * Animals Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Animals%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Animals) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42789205/) * Diabetes Mellitus, Type 2* / complications Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Diabetes+Mellitus%2C+Type+2%2Fcomplications%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.g
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