TY - JOUR

T1 - The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes

T2 - an IMI DIRECT study

AU - Koivula, Robert W

AU - Atabaki-Pasdar, Naeimeh

AU - Giordano, Giuseppe N

AU - White, Tom

AU - Adamski, Jerzy

AU - Bell, Jimmy D

AU - Beulens, Joline

AU - Brage, Søren

AU - Brunak, Søren

AU - De Masi, Federico

AU - Dermitzakis, Emmanouil T

AU - Forgie, Ian M

AU - Frost, Gary

AU - Hansen, Torben

AU - Hansen, Tue H

AU - Hattersley, Andrew

AU - Kokkola, Tarja

AU - Kurbasic, Azra

AU - Laakso, Markku

AU - Mari, Andrea

AU - McDonald, Timothy J

AU - Pedersen, Oluf

AU - Rutters, Femke

AU - Schwenk, Jochen M

AU - Teare, Harriet J A

AU - Thomas, E Louise

AU - Vinuela, Ana

AU - Mahajan, Anubha

AU - McCarthy, Mark I

AU - Ruetten, Hartmut

AU - Walker, Mark

AU - Pearson, Ewan

AU - Pavo, Imre

AU - Franks, Paul W

AU - IMI-DIRECT consortium

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

U2 - 10.1007/s00125-019-05083-6

DO - 10.1007/s00125-019-05083-6

M3 - Journal article

C2 - 32002573

VL - 63

SP - 744

EP - 756

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 4

ER -