Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Aging Cell. 2023 Sep;22(9):e13923. doi: 10.1111/acel.13923. Epub 2023 Jul 5.
The causal influence of sarcopenia on cardiometabolic disease and Alzheimer's disease and whether and to what extent insulin resistance plays a mediating role therein were unclear. We performed two-step, two-sample Mendelian randomization applying genetic instruments of sarcopenia-related traits based on GWASs from the UK Biobank (up to 461,026 European participants) to examine their causal associations with six cardiometabolic diseases and Alzheimer's disease extracted from large-scale European descent GWASs with adjustment for body fat percentage and physical activity, and to assess proportions of the causal effects mediated by insulin resistance. Genetic instruments of insulin resistance were derived from the GWASs by Meta-Analyses of Glucose and Insulin-related traits Consortium and Global Lipids Genetics Consortium. Each 1-SD lower grip strength, appendicular lean mass (ALM) and whole-body lean mass (WBLM), as well as lower walking pace, were causally associated with higher risks of diabetes (odds ratio [OR] range: 1.20 [95% confidence interval: 1.10-1.32] for ALM to 2.30 [1.14-4.68] for walking pace), nonalcoholic fatty liver disease ([NAFLD], 1.33 [1.08-1.64] for ALM to 2.30 [1.02-5.18] for grip strength), hypertension (1.12 [1.05-1.20] for ALM to 4.43 [2.68-7.33] for walking pace), coronary heart disease ([CHD], 1.20 [1.13-1.27] for ALM to 2.73 [1.84-4.05] for walking pace), myocardial infarction ([MI], 1.18 [1.11-1.25] for ALM to 2.47 [1.63-3.73] for walking pace), small vessel stroke (1.25 [1.15-1.37] for ALM to 1.29 [1.10-1.52] for WBLM), and Alzheimer's disease (1.10 [1.05-1.15] for ALM to 1.28 [1.19-1.38] for WBLM). These causal associations were largely independent of body fat percentage and physical activity. Insulin resistance mediated 16%-34% of the effect of grip strength and 7%-28% of the effect of ALM on diabetes, NAFLD, hypertension, CHD, and MI. The direct effect of WBLM on diabetes diminished toward null with adjustment for insulin resistance. We found no evidence that insulin resistance was on the causal pathways from walking pace to the studied disease outcomes. Causal findings from the inverse-variance weighted method were validated by sensitivity analyses. These findings support improving sarcopenia-related traits as precautions against major cardiometabolic diseases and Alzheimer's disease, with particular emphasis on insulin resistance as a target in the intervention of sarcopenia-related cardiometabolic risk.
肌肉减少症对心血管代谢疾病和阿尔茨海默病的因果影响，以及胰岛素抵抗在其中是否起到介导作用及其程度尚不清楚。我们应用基于英国生物库（多达 461,026 名欧洲参与者）的 GWAS 的肌肉减少症相关特征的遗传工具，进行了两步两样本孟德尔随机化分析，以检查它们与从大型欧洲血统 GWAS 中提取的六种心血管代谢疾病和阿尔茨海默病的因果关联，并调整了体脂肪百分比和身体活动，评估了胰岛素抵抗介导的因果效应的比例。胰岛素抵抗的遗传工具是通过 Meta 分析葡萄糖和胰岛素相关特征联盟和全球脂质遗传学联盟的 GWAS 得出的。每降低 1 个标准差的握力、四肢瘦体重 (ALM) 和全身瘦体重 (WBLM)，以及步行速度较慢，与糖尿病的风险增加有关（OR 范围：1.20 [95%置信区间：1.10-1.32] 至 2.30 [1.14-4.68] 至步行速度），非酒精性脂肪性肝病 ([NAFLD]，1.33 [1.08-1.64] 至握力为 2.30 [1.02-5.18]），高血压（1.12 [1.05-1.20] 至步行速度为 4.43 [2.68-7.33]），冠心病 ([CHD]，1.20 [1.13-1.27] 至步行速度为 2.73 [1.84-4.05]），心肌梗死 ([MI]，1.18 [1.11-1.25] 至步行速度为 2.47 [1.63-3.73]），小血管性卒中（1.25 [1.15-1.37] 至 WBLM 为 1.29 [1.10-1.52]），以及阿尔茨海默病（1.10 [1.05-1.15] 至 WBLM 为 1.28 [1.19-1.38]）。这些因果关联在很大程度上独立于体脂肪百分比和身体活动。握力和 ALM 对糖尿病、NAFLD、高血压、CHD 和 MI 的影响中，胰岛素抵抗分别介导了 16%-34%和 7%-28%。WBLM 对糖尿病的直接影响在调整胰岛素抵抗后趋于零。我们没有发现证据表明胰岛素抵抗是步行速度与所研究疾病结果之间的因果途径。反向方差加权法的因果发现通过敏感性分析得到了验证。这些发现支持改善与肌肉减少症相关的特征，以预防主要的心血管代谢疾病和阿尔茨海默病，特别强调将胰岛素抵抗作为肌肉减少症相关心血管代谢风险干预的目标。
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