Department of Clinical Sciences, Lund University, Genetic and Molecular Epidemiology, CRC, Skåne University Hospital Malmö, Building 91, Level 12, Jan Waldenströms gata 35, SE-205 02, Malmö, Sweden.
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Diabetologia. 2020 Apr;63(4):744-756. doi: 10.1007/s00125-019-05083-6. Epub 2020 Jan 30.
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).
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.
The TC and TC-PA models showed better fit than null models (TC: χ = 242, p = 0.004 and χ = 63, p = 0.001 in cohort 1 and 2, respectively; TC-PA: χ = 180, p = 0.041 and χ = 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.
目的/假设：体力活动、腹部异位脂肪和血糖调节之间的关系已得到充分证实，但这些关系的潜在结构尚不清楚。先前提出的双循环假说（TC）通过底物可用性、底物代谢和腹部异位脂肪积累的相互作用，为血糖控制受损提供了一种机制基础。在这里，我们假设体力活动对葡萄糖调节的影响是由双循环介导的。我们旨在在包含正常或受损葡萄糖调节（队列 1：N≤920）或最近诊断为 2 型糖尿病（队列 2：N≤435）的参与者的创新药物倡议糖尿病患者分层研究（IMI DIRECT）联盟队列中检验这一观点。
我们定义了一个描述 TC 的结构方程模型，并将其拟合到 IMI DIRECT 数据集内。还拟合了第二个模型，即双循环加体力活动（TC-PA），以评估体力活动对血糖调节的影响在多大程度上是由双循环中的成分介导的。在没有和有糖尿病的参与者中，分别从频繁采样 75g OGTT（fsOGTT）和混合餐耐量试验（MMTT）中对β细胞功能、胰岛素敏感性和血糖控制进行建模。使用 MRI 评估腹部脂肪分布，使用腕戴三轴加速度计评估体力活动。结果分别以标准化β系数、SE 和 p 值表示。
TC 和 TC-PA 模型的拟合度优于零模型（队列 1 和 2 中的 TC：χ=242，p=0.004 和 χ=63，p=0.001；TC-PA：χ=180，p=0.041 和 χ=60，p=0.008）。体力活动与血糖控制的相关性主要由肝脂肪循环中的变量介导。
结论/解释：这些分析部分支持双循环模型中提出的机制，并强调了胰岛素敏感性和肝脂肪通过哪些机制途径介导体力活动与血糖控制之间的关联。
