AIMS/HYPOTHESIS It is well established that physical activity, abdominal ectopic fat and glycaemic regulation are related but the underlying structure of these relationships is unclear. The previously proposed twin-cycle hypothesis (TC) provides a mechanistic basis for impairment in glycaemic control through the interactions of substrate availability, substrate metabolism and abdominal ectopic fat accumulation. Here, we hypothesise that the effect of physical activity in glucose regulation is mediated by the twin-cycle. We aimed to examine this notion in the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) Consortium cohorts comprised of participants with normal or impaired glucose regulation (cohort 1: N ≤ 920) or with recently diagnosed type 2 diabetes (cohort 2: N ≤ 435). METHODS We defined a structural equation model that describes the TC and fitted this within the IMI DIRECT dataset. A second model, twin-cycle plus physical activity (TC-PA), to assess the extent to which the effects of physical activity in glycaemic regulation are mediated by components in the twin-cycle, was also fitted. Beta cell function, insulin sensitivity and glycaemic control were modelled from frequently sampled 75 g OGTTs (fsOGTTs) and mixed-meal tolerance tests (MMTTs) in participants without and with diabetes, respectively. Abdominal fat distribution was assessed using MRI, and physical activity through wrist-worn triaxial accelerometry. Results are presented as standardised beta coefficients, SE and p values, respectively. RESULTS The TC and TC-PA models showed better fit than null models (TC: χ2 = 242, p = 0.004 and χ2 = 63, p = 0.001 in cohort 1 and 2, respectively; TC-PA: χ2 = 180, p = 0.041 and χ2 = 60, p = 0.008 in cohort 1 and 2, respectively). The association of physical activity with glycaemic control was primarily mediated by variables in the liver fat cycle. CONCLUSIONS/INTERPRETATION These analyses partially support the mechanisms proposed in the twin-cycle model and highlight mechanistic pathways through which insulin sensitivity and liver fat mediate the association between physical activity and glycaemic control.

中文翻译：

---

IMI DIRECT研究表明，体育活动在2型糖尿病发作之前和之后在代谢稳态中的作用。

目的/假设众所周知，体育活动，腹部异位脂肪和血糖调节有关，但这些关系的潜在结构尚不清楚。先前提出的双周期假说（TC）通过底物可利用性，底物代谢和腹部异位脂肪蓄积的相互作用为血糖控制受损提供了机械基础。在这里，我们假设身体活动在葡萄糖调节中的作用是由双周期介导的。我们旨在在“创新药物倡议患者分层糖尿病研究（IMI DIRECT）联盟”队列中研究这一概念，该队列由葡萄糖调节正常或受损（队列1：N≤920）或最近被诊断为2型糖尿病（队列2）的参与者组成。 N≤435）。方法我们定义了描述TC的结构方程模型，并将其拟合到IMI DIRECT数据集中。还安装了第二个模型，即双周期加体力活动（TC-PA），以评估双环中的成分介导体力活动对血糖调节的影响程度。β细胞功能，胰岛素敏感性和血糖控制分别从无糖尿病和有糖尿病的受试者中频繁采样的75 g OGTT（fsOGTT）和混合餐耐受测试（MMTT）建模。使用MRI评估腹部脂肪分布，并通过腕戴式三轴加速度计评估身体活动。结果分别表示为标准化的beta系数，SE和p值。结果TC和TC-PA模型显示出比空模型更好的拟合度（TC：χ2= 242，p = 0.004和χ2= 63，p = 0。队列1和2中的001；TC-PA：在群组1和2中，χ2= 180，p = 0.041，χ2= 60，p = 0.008）。体育活动与血糖控制的相关性主要是由肝脏脂肪循环中的变量介导的。结论/解释这些分析部分地支持了双周期模型中提出的机制，并强调了胰岛素敏感性和肝脂肪介导体育活动与血糖控制之间联系的机制途径。