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
Authors: Koivula Robert W. , Forgie Ian M. , Kurbasic Azra , Viñuela Ana , Heggie Alison , Giordano Giuseppe N. , Hansen Tue H. , Hudson Michelle , Koopman Anitra , Rutters Femke , Siloaho Maritta , Allin Kristine H. , Brage Søren , Brorsson Caroline A. , Dawed Adem Y. , Masi Federico De , Groves Christopher J. , Kokkola Tarja , Mahajan Anubha , Perry Mandy H. , Rauh Simone P. , Ridderstråle Martin , Teare Harriet J. A. , Thomas Louise , Tura Andrea , Vestergaard Henrik , White Tom , Adamski Jerzy , Bell Jimmy , Brunak Søren , Dekker Jacqueline , Dermitzakis Emmanouil T. , Froguel Philippe , Frost Gary , Gupta Ramneek , Hansen Torben , Hattersley Andrew , Jablonka Bernd , Laakso Markku , McDonald Timothy J. , Pedersen Oluf , Schwenk Jochen M. , Pavo Imre , Mari Andrea , McCarthy Mark I. , Ruetten Hartmut , Walker Mark , Pearson Ewan , Franks Paul W. ,   for the IMIDIRECT Consortium
Published: April 2018

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.

Abbreviations:

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