Genetically predicted brain cortical structure mediates the causality between insulin resistance and cognitive impairment
BackgroundInsulin resistance is tightly related to cognition; however, the causal association between them remains a matter of debate. Our investigation aims to establish the causal relationship and direction between insulin resistance and cognition, while also quantifying the mediating role of brai...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2024.1443301/full |
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| author | Chaojuan Huang Yuyang Zhang Mingxu Li Qiuju Gong Siqi Yu Zhiwei Li Mengmeng Ren Xia Zhou Xiaoqun Zhu Zhongwu Sun |
| author_facet | Chaojuan Huang Yuyang Zhang Mingxu Li Qiuju Gong Siqi Yu Zhiwei Li Mengmeng Ren Xia Zhou Xiaoqun Zhu Zhongwu Sun |
| author_sort | Chaojuan Huang |
| collection | DOAJ |
| description | BackgroundInsulin resistance is tightly related to cognition; however, the causal association between them remains a matter of debate. Our investigation aims to establish the causal relationship and direction between insulin resistance and cognition, while also quantifying the mediating role of brain cortical structure in this association.MethodsThe publicly available data sources for insulin resistance (fasting insulin, homeostasis model assessment beta-cell function and homeostasis model assessment insulin resistance, proinsulin), brain cortical structure, and cognitive phenotypes (visual memory, reaction time) were obtained from the MAGIC, ENIGMA, and UK Biobank datasets, respectively. We first conducted a bidirectional two-sample Mendelian randomization (MR) analysis to examine the susceptibility of insulin resistance on cognitive phenotypes. Additionally, we applied a two-step MR to assess the mediating role of cortical surficial area and thickness in the pathway from insulin resistance to cognitive impairment. The primary Inverse-variance weighted, accompanied by robust sensitivity analysis, was implemented to explore and verify our findings. The reverse MR analysis was also performed to evaluate the causal effect of cognition on insulin resistance and brain cortical structure.ResultsThis study identified genetically determined elevated level of proinsulin increased reaction time (beta=0.03, 95% confidence interval [95%CI]=0.01 to 0.05, p=0.005), while decreasing the surface area of rostral middle frontal (beta=-49.28, 95%CI=-86.30 to -12.27, p=0.009). The surface area of the rostral middle frontal mediated 20.97% (95%CI=1.44% to 40.49%) of the total effect of proinsulin on reaction time. No evidence of heterogeneity, pleiotropy, or reverse causality was observed.ConclusionsBriefly, our study noticed that elevated level of insulin resistance adversely affected cognition, with a partial mediation effect through alterations in brain cortical structure. |
| format | Article |
| id | doaj-art-e2d4f8ba758842a281bd1bfcd0d84dd0 |
| institution | Kabale University |
| issn | 1664-2392 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Endocrinology |
| spelling | doaj-art-e2d4f8ba758842a281bd1bfcd0d84dd02025-01-15T05:10:26ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922025-01-011510.3389/fendo.2024.14433011443301Genetically predicted brain cortical structure mediates the causality between insulin resistance and cognitive impairmentChaojuan Huang0Yuyang Zhang1Mingxu Li2Qiuju Gong3Siqi Yu4Zhiwei Li5Mengmeng Ren6Xia Zhou7Xiaoqun Zhu8Zhongwu Sun9Department of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, ChinaDepartment of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, ChinaDepartment of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, ChinaDepartment of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, ChinaDepartment of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, ChinaDepartment of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, ChinaDepartment of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, ChinaDepartment of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, ChinaDepartment of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, ChinaDepartment of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, ChinaBackgroundInsulin resistance is tightly related to cognition; however, the causal association between them remains a matter of debate. Our investigation aims to establish the causal relationship and direction between insulin resistance and cognition, while also quantifying the mediating role of brain cortical structure in this association.MethodsThe publicly available data sources for insulin resistance (fasting insulin, homeostasis model assessment beta-cell function and homeostasis model assessment insulin resistance, proinsulin), brain cortical structure, and cognitive phenotypes (visual memory, reaction time) were obtained from the MAGIC, ENIGMA, and UK Biobank datasets, respectively. We first conducted a bidirectional two-sample Mendelian randomization (MR) analysis to examine the susceptibility of insulin resistance on cognitive phenotypes. Additionally, we applied a two-step MR to assess the mediating role of cortical surficial area and thickness in the pathway from insulin resistance to cognitive impairment. The primary Inverse-variance weighted, accompanied by robust sensitivity analysis, was implemented to explore and verify our findings. The reverse MR analysis was also performed to evaluate the causal effect of cognition on insulin resistance and brain cortical structure.ResultsThis study identified genetically determined elevated level of proinsulin increased reaction time (beta=0.03, 95% confidence interval [95%CI]=0.01 to 0.05, p=0.005), while decreasing the surface area of rostral middle frontal (beta=-49.28, 95%CI=-86.30 to -12.27, p=0.009). The surface area of the rostral middle frontal mediated 20.97% (95%CI=1.44% to 40.49%) of the total effect of proinsulin on reaction time. No evidence of heterogeneity, pleiotropy, or reverse causality was observed.ConclusionsBriefly, our study noticed that elevated level of insulin resistance adversely affected cognition, with a partial mediation effect through alterations in brain cortical structure.https://www.frontiersin.org/articles/10.3389/fendo.2024.1443301/fullbrain cortical structurecognitioninsulin resistancemediationMendelian randomization |
| spellingShingle | Chaojuan Huang Yuyang Zhang Mingxu Li Qiuju Gong Siqi Yu Zhiwei Li Mengmeng Ren Xia Zhou Xiaoqun Zhu Zhongwu Sun Genetically predicted brain cortical structure mediates the causality between insulin resistance and cognitive impairment Frontiers in Endocrinology brain cortical structure cognition insulin resistance mediation Mendelian randomization |
| title | Genetically predicted brain cortical structure mediates the causality between insulin resistance and cognitive impairment |
| title_full | Genetically predicted brain cortical structure mediates the causality between insulin resistance and cognitive impairment |
| title_fullStr | Genetically predicted brain cortical structure mediates the causality between insulin resistance and cognitive impairment |
| title_full_unstemmed | Genetically predicted brain cortical structure mediates the causality between insulin resistance and cognitive impairment |
| title_short | Genetically predicted brain cortical structure mediates the causality between insulin resistance and cognitive impairment |
| title_sort | genetically predicted brain cortical structure mediates the causality between insulin resistance and cognitive impairment |
| topic | brain cortical structure cognition insulin resistance mediation Mendelian randomization |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2024.1443301/full |
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