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
Koivula R., Forgie I., Kurbasic A., Viñuela A., Heggie A., Giordano G., Hansen T., Hudson M., Koopman A., Rutters F., Siloaho M., Allin K., Brage S., Brorsson C., Dawed A., Masi FD., Groves C., Kokkola T., Mahajan A., Perry M., Rauh S., Ridderstråle M., Teare H., Thomas L., Tura A., Vestergaard H., White T., Adamski J., Bell J., Brunak S., Dekker J., Dermitzakis E., Froguel P., Frost G., Gupta R., Hansen T., Hattersley A., Jablonka B., Laakso M., McDonald T., Pedersen O., Schwenk J., Pavo I., Mari A., McCarthy M., Ruetten H., Walker M., Pearson E., Franks P., for the IMIDIRECT Consortium None.
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