The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes: an IMI DIRECT study

Abstract

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.

Keywords: Beta cell function; Ectopic fat; Glycaemic control; Insulin sensitivity; Physical activity; Prediabetes; Structural equation modelling; Type 2 diabetes.

Fig. 1

TC structural equation model definition diagram, fit estimates and effect estimate diagrams from a hypothesised model for the role of physical activity and liver fat in glycaemic control. (a) Model definitions, with squares representing manifest nodes and arrows indicating regression coefficients pointing towards an outcome of a respective regression. (b) Model fit; density plot of model fit χ² from variable-randomised comparable structural equation models applied on respective dataset (10,000 iterations). Dashed vertical lines indicate TC model χ², solid lines and shaded areas indicate χ² of all null iterations. (c, d) Effect estimate diagrams of the defined model applied on cohort 1 (no diabetes/prediabetes, c) and cohort 2 (type 2 diabetes, d), where the arrow thickness is weighted by effect estimate magnitude, and colours red and blue indicate positive and negative estimates, respectively. All continuous variables are normally transformed and adjusted for age, sex, metformin treatment (cohort 2), study centre, total energy intake, and carbohydrate, fat and protein intake. See Text box for node and edge abbreviations

Fig. 2

TC-PA structural equation model definition diagram, fit estimates and effect estimate diagrams from a hypothesised model for the role of physical activity and liver fat in glycaemic control. (a) Model definitions, with squares representing manifest nodes and arrows indicating regression coefficients pointing towards an outcome of a respective regression. (b) Model fit; density plot of model fit χ² from variable-randomised comparable structural equation models applied on respective dataset (10,000 iterations). Dashed vertical lines indicate TC-PA model χ², solid lines and shaded areas indicate χ² of all null iterations. (c, d) Effect estimate diagrams of the defined model applied on cohort 1 (no diabetes/prediabetes, c) and cohort 2 (type 2 diabetes, d), where the arrow thickness is weighted by effect estimate magnitude, and colours red and blue indicate positive and negative estimates, respectively. All continuous variables are normally transformed and adjusted for: age, sex, metformin treatment (cohort 2), study centre, total energy intake, and carbohydrate, fat and protein intake. See Text box for node and edge abbreviations