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Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: an overview of the data from the epidemiological studies within the IMI DIRECT Consortium

View ORCID ProfileRobert W. Koivula, Ian M. Forgie, Azra Kurbasic, View ORCID ProfileAna Viñuela, Alison Heggie, Giuseppe N. Giordano, View ORCID ProfileTue H. Hansen, Michelle Hudson, Anitra Koopman, Femke Rutters, Maritta Siloaho, Kristine H. Allin, Søren Brage, Caroline A. Brorsson, Adem Y. Dawed, Federico De Masi, Christopher J. Groves, Tarja Kokkola, View ORCID ProfileAnubha Mahajan, Mandy H. Perry, Simone P. Rauh, Martin Ridderstråle, Harriet J. A. Teare, Louise Thomas, Andrea Tura, Henrik Vestergaard, View ORCID ProfileTom White, Jerzy Adamski, Jimmy Bell, Søren Brunak, Jacqueline Dekker, Emmanouil T. Dermitzakis, Philippe Froguel, Gary Frost, Ramneek Gupta, Torben Hansen, Andrew Hattersley, Bernd Jablonka, Markku Laakso, Timothy J. McDonald, Oluf Pedersen, View ORCID ProfileJochen M. Schwenk, Imre Pavo, Andrea Mari, View ORCID ProfileMark I. McCarthy, Hartmut Ruetten, Mark Walker, Ewan Pearson, View ORCID ProfilePaul W. Franks, for the IMIDIRECT Consortium
doi: https://doi.org/10.1101/300244
Robert W. Koivula
1Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Lund University, Malmö, Sweden
2Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
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Ian M. Forgie
3Molecular and Clinical Medicine, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom
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Azra Kurbasic
1Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Lund University, Malmö, Sweden
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Ana Viñuela
4Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
5Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland
6Swiss Institute of Bioinformatics, Geneva, Switzerland
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Alison Heggie
7Institute of Cellular Medicine (Diabetes), Newcastle University, Newcastle upon Tyne, United Kingdom
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Giuseppe N. Giordano
1Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Lund University, Malmö, Sweden
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Tue H. Hansen
8The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen
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Michelle Hudson
9NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, UK
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Anitra Koopman
10Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, the Netherlands
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Femke Rutters
10Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, the Netherlands
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Maritta Siloaho
11Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Finland
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Kristine H. Allin
8The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen
12Department of Clinical Epidemiology, Bispebjerg and Frederiksberg Hospital, the Capital Region, Copenhagen, Denmark
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Søren Brage
13Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
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Caroline A. Brorsson
14Department of Bio and Health Informatics, Technical University of Denmark, Lyngby, Denmark
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Adem Y. Dawed
3Molecular and Clinical Medicine, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom
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Federico De Masi
14Department of Bio and Health Informatics, Technical University of Denmark, Lyngby, Denmark
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Christopher J. Groves
2Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
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Tarja Kokkola
11Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Finland
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Anubha Mahajan
15Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
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Mandy H. Perry
16NIHR Exeter Clinical Research Facility, University of Exeter Medical School and Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
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Simone P. Rauh
10Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, the Netherlands
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Martin Ridderstråle
17Department of Clinical Sciences, Clinical Obesity, Skåne University Hospital Malmö, Lund University, Malmo, Sweden
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Harriet J. A. Teare
18HeLEX, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Headington, Oxford, UK
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Louise Thomas
19Research Centre for Optimal Health, Department of Life Sciences, University of Westminster, London, U.K
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Andrea Tura
20Institute of Neurosciences, National Research Council, Padova, Italy
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Henrik Vestergaard
8The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen
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Tom White
21MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK
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Jerzy Adamski
22Institute of Epidemiology II, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH) Neuherberg, Germany
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Jimmy Bell
19Research Centre for Optimal Health, Department of Life Sciences, University of Westminster, London, U.K
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Søren Brunak
14Department of Bio and Health Informatics, Technical University of Denmark, Lyngby, Denmark
23The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
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Jacqueline Dekker
10Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, the Netherlands
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Emmanouil T. Dermitzakis
4Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
5Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland
6Swiss Institute of Bioinformatics, Geneva, Switzerland
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Philippe Froguel
24Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, United Kingdom
25CNRS, Pasteur Institute of Lille, University of Lille, Lille, France
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Gary Frost
26Nutrition and Dietetics Research Group, Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, Hammersmith Campus, London W12 0NN, UK
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Ramneek Gupta
14Department of Bio and Health Informatics, Technical University of Denmark, Lyngby, Denmark
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Torben Hansen
8The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen
13Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
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Andrew Hattersley
16NIHR Exeter Clinical Research Facility, University of Exeter Medical School and Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
27Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
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Bernd Jablonka
28Sanofi-Aventis Deutschland GmbH, R&D, Frankfurt am Main, Germany
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Markku Laakso
11Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Finland
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Timothy J. McDonald
16NIHR Exeter Clinical Research Facility, University of Exeter Medical School and Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
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Oluf Pedersen
8The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen
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Jochen M. Schwenk
29Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology, Stockholm, Sweden
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Imre Pavo
30Eli Lilly Regional Operations GmbH, Vienna, Austria
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Andrea Mari
21MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK
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Mark I. McCarthy
2Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
15Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
31NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK
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Hartmut Ruetten
28Sanofi-Aventis Deutschland GmbH, R&D, Frankfurt am Main, Germany
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Mark Walker
7Institute of Cellular Medicine (Diabetes), Newcastle University, Newcastle upon Tyne, United Kingdom
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Ewan Pearson
3Molecular and Clinical Medicine, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom
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Paul W. Franks
1Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Lund University, Malmö, Sweden
2Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
32Department of Nutrition, Harvard School of Public Health, Boston, USA
33Department of Public Health & Clinical Medicine, Section for Medicine, Umeå University Hospital, Umeå, Sweden
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Abstract/Summary

Background and aims: Understanding the aetiology, clinical presentation and prognosis of type 2 diabetes (T2D) and optimizing its treatment might be facilitated by biomarkers that help predict a person’s susceptibility to the risk factors that cause diabetes or its complications, or response to treatment. The IMI DIRECT (Diabetes Research on Patient Stratification) Study is a European Union (EU) Innovative Medicines Initiative (IMI) project that seeks to test these hypotheses in two recently established epidemiological cohorts. Here, we describe the characteristics of these cohorts at baseline and at the first main follow-up examination (18-months).

Materials and methods: From a sampling-frame of 24,682 European-ancestry adults in whom detailed health information was available, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm and enrolled into a prospective cohort study (n=2127) undertaken at four study centres across Europe (Cohort 1: prediabetes). We also recruited people from clinical registries with recently diagnosed T2D (n=789) into a second cohort study (Cohort 2: diabetes). The two cohorts were studied in parallel with matched protocols. Endogenous insulin secretion and insulin sensitivity were modelled from frequently sampled 75g oral glucose tolerance (OGTT) in Cohort 1 and with mixed-meal tolerance tests (MMTT) in Cohort 2. Additional metabolic biochemistry was determined using blood samples taken when fasted and during the tolerance tests. Body composition was assessed using MRI and lifestyle measures through self-report and objective methods.

Results: Using ADA-2011 glycaemic categories, 33% (n=693) of Cohort 1 (prediabetes) had normal glucose regulation (NGR), and 67% (n=1419) had impaired glucose regulation (IGR). 76% of the cohort was male, age=62(6.2) years; BMI=27.9(4.0) kg/m2; fasting glucose=5.7(0.6) mmol/l; 2-hr glucose=5.9(1.6) mmol/l [mean(SD)]. At follow-up, 18.6(1.4) months after baseline, fasting glucose=5.8(0.6) mmol/l; 2-hr OGTT glucose=6.1(1.7) mmol/l [mean(SD)]. In Cohort 2 (diabetes): 65% (n=508) were lifestyle treated (LS) and 35% (n=271) were lifestyle + metformin treated (LS+MET). 58% of the cohort was male, age=62(8.1) years; BMI=30.5(5.0) kg/m2; fasting glucose=7.2(1.4)mmol/l; 2-hr glucose=8.6(2.8) mmol/l [mean(SD)]. At follow-up, 18.2(0.6) months after baseline, fasting glucose=7.8(1.8) mmol/l; 2-hr MMTT glucose=9.5(3.3) mmol/l [mean(SD)].

Conclusion: The epidemiological IMI DIRECT cohorts are the most intensely characterised prospective studies of glycaemic deterioration to date. Data from these cohorts help illustrate the heterogeneous characteristics of people at risk of or with T2D, highlighting the rationale for biomarker stratification of the disease - the primary objective of the IMI DIRECT consortium.

ASAT
Abdominal subcutaneous adipose tissue
DIRECT
Diabetes Research on Patient Stratification
EU
European Union
MMTT
Mixed-meal tolerance test
MRI
Magnetic resonance imaging
hpfVM
High-pass filtered vector magnitude
IAAT
Intra-abdominal adipose tissue
IGR
Impaired glucose regulation
IMI
Innovative Medicines Initiative
ME
multiecho
NGR
Normal glucose regulation
OGTT
Oral glucose tolerance test
PA
Physical activity
TAAT
Total abdominal adipose tissue
T2D
Type 2 Diabetes
Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 16, 2018.
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Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: an overview of the data from the epidemiological studies within the IMI DIRECT Consortium
Robert W. Koivula, Ian M. Forgie, Azra Kurbasic, Ana Viñuela, Alison Heggie, Giuseppe N. Giordano, Tue H. Hansen, Michelle Hudson, Anitra Koopman, Femke Rutters, Maritta Siloaho, Kristine H. Allin, Søren Brage, Caroline A. Brorsson, Adem Y. Dawed, Federico De Masi, Christopher J. Groves, Tarja Kokkola, Anubha Mahajan, Mandy H. Perry, Simone P. Rauh, Martin Ridderstråle, Harriet J. A. Teare, Louise Thomas, Andrea Tura, Henrik Vestergaard, Tom White, Jerzy Adamski, Jimmy Bell, Søren Brunak, Jacqueline Dekker, Emmanouil T. Dermitzakis, Philippe Froguel, Gary Frost, Ramneek Gupta, Torben Hansen, Andrew Hattersley, Bernd Jablonka, Markku Laakso, Timothy J. McDonald, Oluf Pedersen, Jochen M. Schwenk, Imre Pavo, Andrea Mari, Mark I. McCarthy, Hartmut Ruetten, Mark Walker, Ewan Pearson, Paul W. Franks, for the IMIDIRECT Consortium
bioRxiv 300244; doi: https://doi.org/10.1101/300244
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Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: an overview of the data from the epidemiological studies within the IMI DIRECT Consortium
Robert W. Koivula, Ian M. Forgie, Azra Kurbasic, Ana Viñuela, Alison Heggie, Giuseppe N. Giordano, Tue H. Hansen, Michelle Hudson, Anitra Koopman, Femke Rutters, Maritta Siloaho, Kristine H. Allin, Søren Brage, Caroline A. Brorsson, Adem Y. Dawed, Federico De Masi, Christopher J. Groves, Tarja Kokkola, Anubha Mahajan, Mandy H. Perry, Simone P. Rauh, Martin Ridderstråle, Harriet J. A. Teare, Louise Thomas, Andrea Tura, Henrik Vestergaard, Tom White, Jerzy Adamski, Jimmy Bell, Søren Brunak, Jacqueline Dekker, Emmanouil T. Dermitzakis, Philippe Froguel, Gary Frost, Ramneek Gupta, Torben Hansen, Andrew Hattersley, Bernd Jablonka, Markku Laakso, Timothy J. McDonald, Oluf Pedersen, Jochen M. Schwenk, Imre Pavo, Andrea Mari, Mark I. McCarthy, Hartmut Ruetten, Mark Walker, Ewan Pearson, Paul W. Franks, for the IMIDIRECT Consortium
bioRxiv 300244; doi: https://doi.org/10.1101/300244

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