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

Abstract

Abstract/SummaryBackground 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:ASATAbdominal subcutaneous adipose tissueDIRECTDiabetes Research on Patient StratificationEUEuropean UnionMMTTMixed-meal tolerance testMRIMagnetic resonance imaginghpfVMHigh-pass filtered vector magnitudeIAATIntra-abdominal adipose tissueIGRImpaired glucose regulationIMIInnovative Medicines InitiativeMEmultiechoNGRNormal glucose regulationOGTTOral glucose tolerance testPAPhysical activityTAATTotal abdominal adipose tissueT2DType 2 Diabetes

Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

“…The IMI DIRECT consortium is a collaboration among investigators from a range of European academic institutions and pharmaceutical companies 14 . Liver iron was measured using a T2*-based multi-echo MRI technique 21 . DNA extraction was carried out using Maxwell 16 Blood DNA purification kits and a Maxwell 16 semi-automated nucleic acid purification system (Promega).…”

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“…In short, there has been much discourse within the literature concerning Ahlqvist et al [1] findings of five separate new classifications of type 2 diabetes [3,9]. Both B Ahlqvist et al [1] and Koivula et al [10] indicate the current characterizations of type 2 diabetes may well be improved via further research, use of specific biomarkers, genotypes and genetic risk scores. These investigators also maintain that since C-peptide levels remained stable within the clusters of newly diagnosed and those living with long term diabetes this indicated discrete subtypes versus different stages of the disease [1].…”

PS-202-Genome-wide association studies of abdominal MRI scans identifies loci associated with liver fat and liver iron in the UK Biobank

“…[14] Liver iron was measured using a T2*-based multiecho MRI technique. [21] DNA extraction was carried out using Maxwell 16 Blood DNA purification kits and a Maxwell 16 semi-automated nucleic acid purification system (Promega). Genotyping was conducted using the Illumina HumanCore array (HCE24 v1.0) and genotypes were called using Illumina's GenCall algorithm.…”