INTRODUCTION

Recently, Cai et al.¹ reported a correlation between elevated cardiorespiratory fitness and a reduced risk of developing type 2 diabetes; however, the causation of this association and the underlying biological mechanisms remain unclear. The study investigated the genetic determinants of cardiorespiratory fitness in a cohort of 450,000 individuals of European ancestry from the UK Biobank. The study leveraged the genetic overlap between fitness, measured through an exercise test, and resting heart rate. Through this approach, the research identified 160 genetic loci associated with fitness, and these findings were validated in an independent cohort, the Fenland study. Gene-based analyses prioritized candidate genes, such as calcium voltage-gated channel subunit alpha1 C, sodium voltage-gated channel alpha subunit 10, myosin heavy chain 11 and myosin heavy chain 6, which are enriched in biological processes related to cardiac muscle development and muscle contractility. Utilizing a Mendelian randomization framework, the study showed that higher genetically predicted fitness is causally associated with a lower risk of type 2 diabetes, independent of adiposity. Integration with proteomic data showed potential mediators of this relationship, including N-terminal pro B-type natriuretic peptide, hepatocyte growth factor-like protein and sex hormone-binding globulin. In summary, the research findings provide insights into the biological mechanisms underlying cardiorespiratory fitness, and underscore the importance of improving fitness for the prevention of diabetes.

中文翻译：

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解读心肺健康与 2 型糖尿病之间的因果关系

介绍

最近，蔡等人。¹报道了心肺健康水平提高与 2 型糖尿病风险降低之间的相关性；然而，这种关联的因果关系和潜在的生物学机制仍不清楚。该研究调查了来自英国生物银行的 450,000 名欧洲血统个体的心肺健康的遗传决定因素。该研究利用了通过运动测试测量的健康与静息心率之间的遗传重叠。通过这种方法，该研究确定了 160 个与健康相关的基因位点，这些发现在独立队列 Fenland 研究中得到了验证。基于基因的分析优先考虑候选基因，例如钙电压门控通道亚基 α1 C、钠电压门控通道 α 亚基 10、肌球蛋白重链 11 和肌球蛋白重链 6，这些基因富含与心肌发育和相关的生物过程。肌肉收缩力。该研究利用孟德尔随机化框架，表明较高的基因预测健康水平与较低的 2 型糖尿病风险存在因果关系，与肥胖无关。与蛋白质组数据的整合显示了这种关系的潜在介质，包括 N 端 B 型利钠肽原、肝细胞生长因子样蛋白和性激素结合球蛋白。总之，研究结果提供了对心肺健康潜在生物学机制的见解，并强调了改善健康对于预防糖尿病的重要性。