@article{959a9d415105414681a7613750f24d6c,
title = "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",
author = "Koivula, {Robert W.} and Naeimeh Atabaki-Pasdar and Giordano, {Giuseppe N.} and Tom White and Jerzy Adamski and Bell, {Jimmy D.} and Joline Beulens and S{\o}ren Brage and S{\o}ren Brunak and {De Masi}, Federico and Dermitzakis, {Emmanouil T.} and Forgie, {Ian M.} and Gary Frost and Torben Hansen and Hansen, {Tue H.} and Andrew Hattersley and Tarja Kokkola and Azra Kurbasic and Markku Laakso and Andrea Mari and McDonald, {Timothy J.} and Oluf Pedersen and Femke Rutters and Schwenk, {Jochen M.} and Teare, {Harriet J.A.} and Thomas, {E. Louise} and Ana Vinuela and Anubha Mahajan and McCarthy, {Mark I.} and Hartmut Ruetten and Mark Walker and Ewan Pearson and Imre Pavo and Franks, {Paul W.} and {for the IMI DIRECT Consortium}",
note = "Funding Information: IP is an employee of Eli Lilly GmbH, Vienna, Austria. HR is an employee of Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany. This does not alter our adherence to Diabetologia{\textquoteright}s policies on sharing data and materials. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. MIMcC has served on advisory panels for Pfizer, Novo Nordisk and Zoe Global, received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly and research funding from AbbVie, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Pfizer, Roche, Sanofi-Aventis, Servier and Takeda. As of June 2019, MIMcC is an employee of Genentech, and a holder of Roche stock. All other authors declare that there is no duality of interest associated with their contribution to this manuscript. Funding Information: The work leading to this publication has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115317 (DIRECT), resources of which are composed of financial contribution from the European Union{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution. RWK was funded by a STAR Novo Nordisk co-financed PhD fellowship and a Novo Nordisk Foundation (NNF18OC0031650) postdoctoral fellowship. TW was funded by a PhD fellowship from MedImmune. SBra was funded by the UK Medical Research Council (MC_UU_12015/3). This study was undertaken as part of a research programme supported by the European Commission (CoG-2015_681742_NASCENT). IMI DIRECT has received funding from EFPIA members, including Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Servier Laboratories and Sanofi-Aventis. No study funders were involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication. Funding Information: Open access funding provided by Lund University. We thank all the participants in IMI DIRECT for their contribution to the study. More information on IMI DIRECT is available on http://www.direct-diabetes.org/. Publisher Copyright: {\textcopyright} 2020, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2020",
month = apr,
day = "1",
doi = "10.1007/s00125-019-05083-6",
language = "English",
volume = "63",
pages = "744--756",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer Verlag",
number = "4",
}