Huang Chaojuan, Zhang Yuyang, Li Mingxu, Gong Qiuju, Yu Siqi, Li Zhiwei, Ren Mengmeng, Zhou Xia, Zhu Xiaoqun, Sun Zhongwu
Department of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
Front Endocrinol (Lausanne). 2025 Jan 15;15:1443301. doi: 10.3389/fendo.2024.1443301. eCollection 2024.
Insulin 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.
The 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.
This study identified genetically determined elevated level of proinsulin increased reaction time (beta=0.03, 95% confidence interval [95%CI]=0.01 to 0.05, =0.005), while decreasing the surface area of rostral middle frontal (beta=-49.28, 95%CI=-86.30 to -12.27, =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.
Briefly, our study noticed that elevated level of insulin resistance adversely affected cognition, with a partial mediation effect through alterations in brain cortical structure.
胰岛素抵抗与认知密切相关；然而，它们之间的因果关系仍存在争议。我们的研究旨在确立胰岛素抵抗与认知之间的因果关系及方向，同时量化脑皮质结构在这种关联中的中介作用。
分别从MAGIC、ENIGMA和英国生物银行数据集中获取胰岛素抵抗（空腹胰岛素、稳态模型评估β细胞功能和稳态模型评估胰岛素抵抗、胰岛素原）、脑皮质结构和认知表型（视觉记忆、反应时间）的公开可用数据源。我们首先进行了双向两样本孟德尔随机化（MR）分析，以检验胰岛素抵抗对认知表型的易感性。此外，我们应用两步MR来评估皮质表面积和厚度在从胰岛素抵抗到认知障碍途径中的中介作用。采用主要的逆方差加权法，并进行稳健的敏感性分析，以探索和验证我们的发现。还进行了反向MR分析，以评估认知对胰岛素抵抗和脑皮质结构的因果效应。
本研究发现，基因决定的胰岛素原水平升高会增加反应时间（β=0.03，95%置信区间[95%CI]=0.01至0.05，P=0.005），同时减少额中回前部的表面积（β=-49.28，95%CI=-86.30至-12.27，P=0.009）。额中回前部的表面积介导了胰岛素原对反应时间总效应的20.97%（95%CI=1.44%至40.49%）。未观察到异质性、多效性或反向因果关系的证据。
简而言之，我们的研究发现胰岛素抵抗水平升高对认知有不利影响，并通过脑皮质结构的改变产生部分中介作用。
