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Elevated hippocampal copper in cases of type 2 diabetes

BACKGROUND: Type-2 diabetes (T2D) is characterized by chronic hyperglycaemia and glucose-evoked organ damage, and displays systemic copper overload, elevated risk of impaired cognitive function, and epidemiological links to sporadic Alzheimer's disease (sAD). Contrastingly, sAD exhibits impaire...

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Autores principales: Philbert, Sasha A., Schönberger, Sarah J., Xu, Jingshu, Church, Stephanie J., Unwin, Richard D., Cooper, Garth J.S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9646855/
https://www.ncbi.nlm.nih.gov/pubmed/36335667
http://dx.doi.org/10.1016/j.ebiom.2022.104317
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author Philbert, Sasha A.
Schönberger, Sarah J.
Xu, Jingshu
Church, Stephanie J.
Unwin, Richard D.
Cooper, Garth J.S.
author_facet Philbert, Sasha A.
Schönberger, Sarah J.
Xu, Jingshu
Church, Stephanie J.
Unwin, Richard D.
Cooper, Garth J.S.
author_sort Philbert, Sasha A.
collection PubMed
description BACKGROUND: Type-2 diabetes (T2D) is characterized by chronic hyperglycaemia and glucose-evoked organ damage, and displays systemic copper overload, elevated risk of impaired cognitive function, and epidemiological links to sporadic Alzheimer's disease (sAD). Contrastingly, sAD exhibits impaired cerebral-glucose uptake, elevation of cerebral glucose but not blood glucose levels, and widespread cerebral-copper deficiency. We hypothesized that sAD-like brain-metal perturbations would occur in T2D. METHODS: We measured nine essential elements in an observational case–control study of T2D without dementia (6 cases and 6 controls) in four brain regions and compared the results with those from our study of brain metals in sAD (9 cases and 9 controls), which employed equivalent analytical methodology. We evaluated intergroup differences by supervised and unsupervised multivariate-statistical approaches to contrast between T2D cases and controls, and to compare them with cerebral-metal patterns in sAD. FINDINGS: Unexpectedly, we found that hippocampal-copper levels in T2D were markedly elevated compared with controls (P = 0.005 and 0.007 by Welch's t-test in two technical-replicate experiments), to levels similar to those in cases of untreated Wilson's disease (WD), wherein elevated cerebral copper causes neurodegeneration. By contrast, hippocampal-copper levels in sAD were markedly deficient. Multivariate analysis identified marked differences in patterns of essential metals between hippocampal datasets from cases of T2D and of sAD. INTERPRETATION: Elevated hippocampal copper could contribute to the pathogenesis of cerebral neurodegeneration and cognitive impairment in T2D, similar to known impacts of elevated brain copper in WD. Therapeutic approaches with copper-lowering agents similar to those currently employed in pharmacotherapy of WD, may also be applicable in patients with T2D and impaired cognitive function. Further studies will be required to replicate and extend these findings and to investigate their potential therapeutic implications. FUNDING: In Acknowledgments, includes Endocore Research Trust; Lee Trust; Oakley Mental Health Research Foundation; Ministry of Business, Innovation & Employment; The Universities of Auckland and Manchester, and others.
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spelling pubmed-96468552022-11-15 Elevated hippocampal copper in cases of type 2 diabetes Philbert, Sasha A. Schönberger, Sarah J. Xu, Jingshu Church, Stephanie J. Unwin, Richard D. Cooper, Garth J.S. eBioMedicine Articles BACKGROUND: Type-2 diabetes (T2D) is characterized by chronic hyperglycaemia and glucose-evoked organ damage, and displays systemic copper overload, elevated risk of impaired cognitive function, and epidemiological links to sporadic Alzheimer's disease (sAD). Contrastingly, sAD exhibits impaired cerebral-glucose uptake, elevation of cerebral glucose but not blood glucose levels, and widespread cerebral-copper deficiency. We hypothesized that sAD-like brain-metal perturbations would occur in T2D. METHODS: We measured nine essential elements in an observational case–control study of T2D without dementia (6 cases and 6 controls) in four brain regions and compared the results with those from our study of brain metals in sAD (9 cases and 9 controls), which employed equivalent analytical methodology. We evaluated intergroup differences by supervised and unsupervised multivariate-statistical approaches to contrast between T2D cases and controls, and to compare them with cerebral-metal patterns in sAD. FINDINGS: Unexpectedly, we found that hippocampal-copper levels in T2D were markedly elevated compared with controls (P = 0.005 and 0.007 by Welch's t-test in two technical-replicate experiments), to levels similar to those in cases of untreated Wilson's disease (WD), wherein elevated cerebral copper causes neurodegeneration. By contrast, hippocampal-copper levels in sAD were markedly deficient. Multivariate analysis identified marked differences in patterns of essential metals between hippocampal datasets from cases of T2D and of sAD. INTERPRETATION: Elevated hippocampal copper could contribute to the pathogenesis of cerebral neurodegeneration and cognitive impairment in T2D, similar to known impacts of elevated brain copper in WD. Therapeutic approaches with copper-lowering agents similar to those currently employed in pharmacotherapy of WD, may also be applicable in patients with T2D and impaired cognitive function. Further studies will be required to replicate and extend these findings and to investigate their potential therapeutic implications. FUNDING: In Acknowledgments, includes Endocore Research Trust; Lee Trust; Oakley Mental Health Research Foundation; Ministry of Business, Innovation & Employment; The Universities of Auckland and Manchester, and others. Elsevier 2022-11-03 /pmc/articles/PMC9646855/ /pubmed/36335667 http://dx.doi.org/10.1016/j.ebiom.2022.104317 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Articles
Philbert, Sasha A.
Schönberger, Sarah J.
Xu, Jingshu
Church, Stephanie J.
Unwin, Richard D.
Cooper, Garth J.S.
Elevated hippocampal copper in cases of type 2 diabetes
title Elevated hippocampal copper in cases of type 2 diabetes
title_full Elevated hippocampal copper in cases of type 2 diabetes
title_fullStr Elevated hippocampal copper in cases of type 2 diabetes
title_full_unstemmed Elevated hippocampal copper in cases of type 2 diabetes
title_short Elevated hippocampal copper in cases of type 2 diabetes
title_sort elevated hippocampal copper in cases of type 2 diabetes
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9646855/
https://www.ncbi.nlm.nih.gov/pubmed/36335667
http://dx.doi.org/10.1016/j.ebiom.2022.104317
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