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

Koivula, Robert W. LU ; Atabaki-Pasdar, Naeimeh LU orcid ; Giordano, Giuseppe N. LU ; White, Tom ; Adamski, Jerzy ; Bell, Jimmy D. ; Beulens, Joline ; Brage, Søren ; Brunak, Søren and De Masi, Federico , et al. (2020) In Diabetologia 63(4). p.744-756
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... (More)

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.

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organization
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type
Contribution to journal
publication status
published
subject
keywords
Beta cell function, Ectopic fat, Glycaemic control, Insulin sensitivity, Physical activity, Prediabetes, Structural equation modelling, Type 2 diabetes
in
Diabetologia
volume
63
issue
4
pages
13 pages
publisher
Springer
external identifiers
  • scopus:85078864179
  • pmid:32002573
ISSN
0012-186X
DOI
10.1007/s00125-019-05083-6
language
English
LU publication?
yes
id
8fb95319-a8c1-4a81-8732-e6a05499a74f
date added to LUP
2020-02-10 13:54:58
date last changed
2024-03-04 12:56:31
@article{8fb95319-a8c1-4a81-8732-e6a05499a74f,
  abstract     = {{<p>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: χ<sup>2</sup> = 242, p = 0.004 and χ<sup>2</sup> = 63, p = 0.001 in cohort 1 and 2, respectively; TC-PA: χ<sup>2</sup> = 180, p = 0.041 and χ<sup>2</sup> = 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.</p>}},
  author       = {{Koivula, Robert W. and Atabaki-Pasdar, Naeimeh and Giordano, Giuseppe N. and White, Tom and Adamski, Jerzy and Bell, Jimmy D. and Beulens, Joline and Brage, Søren and Brunak, Søren and De Masi, Federico and Dermitzakis, Emmanouil T. and Forgie, Ian M. and Frost, Gary and Hansen, Torben and Hansen, Tue H. and Hattersley, Andrew and Kokkola, Tarja and Kurbasic, Azra and Laakso, Markku and Mari, Andrea and McDonald, Timothy J. and Pedersen, Oluf and Rutters, Femke and Schwenk, Jochen M. and Teare, Harriet J.A. and Thomas, E. Louise and Vinuela, Ana and Mahajan, Anubha and McCarthy, Mark I. and Ruetten, Hartmut and Walker, Mark and Pearson, Ewan and Pavo, Imre and Franks, Paul W.}},
  issn         = {{0012-186X}},
  keywords     = {{Beta cell function; Ectopic fat; Glycaemic control; Insulin sensitivity; Physical activity; Prediabetes; Structural equation modelling; Type 2 diabetes}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{744--756}},
  publisher    = {{Springer}},
  series       = {{Diabetologia}},
  title        = {{The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes : an IMI DIRECT study}},
  url          = {{http://dx.doi.org/10.1007/s00125-019-05083-6}},
  doi          = {{10.1007/s00125-019-05083-6}},
  volume       = {{63}},
  year         = {{2020}},
}