Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: rationale and design of the epidemiological studies within the IMI DIRECT Consortium

Abstract

Aims/hypothesis: The DIRECT (Diabetes Research on Patient Stratification) Study is part of a European Union Framework 7 Innovative Medicines Initiative project, a joint undertaking between four industry and 21 academic partners throughout Europe. The Consortium aims to discover and validate biomarkers that: (1) predict the rate of glycaemic deterioration before and after type 2 diabetes onset; (2) predict the response to diabetes therapies; and (3) help stratify type 2 diabetes into clearly definable disease subclasses that can be treated more effectively than without stratification. This paper describes two new prospective cohort studies conducted as part of DIRECT.

Methods: Prediabetic participants (target sample size 2,200-2,700) and patients with newly diagnosed type 2 diabetes (target sample size ~1,000) are undergoing detailed metabolic phenotyping at baseline and 18 months and 36 months later. Abdominal, pancreatic and liver fat is assessed using MRI. Insulin secretion and action are assessed using frequently sampled OGTTs in non-diabetic participants, and frequently sampled mixed-meal tolerance tests in patients with type 2 diabetes. Biosamples include venous blood, faeces, urine and nail clippings, which, among other biochemical analyses, will be characterised at genetic, transcriptomic, metabolomic, proteomic and metagenomic levels. Lifestyle is assessed using high-resolution triaxial accelerometry, 24 h diet record, and food habit questionnaires.

Conclusions/interpretation: DIRECT will yield an unprecedented array of biomaterials and data. This resource, available through managed access to scientists within and outside the Consortium, will facilitate the development of new treatments and therapeutic strategies for the prevention and management of type 2 diabetes.

Fig. 1

Overview of the biomarker discovery strategy in the two prospective studies of the DIRECT consortium (Studies 1 and 2). Persons at high risk of glycaemic deterioration before (Study 1) or soon after (Study 2) the onset of type 2 diabetes are enrolled and followed for between 18 and 36 months. Those whose glycaemic control deteriorates least and most are selected for biomarker discovery. Discovered biomarkers are subsequently fed back to improve risk prediction models, which will be validated in other epidemiological studies and clinical trials organised by the DIRECT Consortium and its partners

Fig. 2

Overview of the timeline of the DIRECT WP2 Study 1 and Study 2 protocols. Core assessments (CORE) are: anthropometry; fasting blood; MRI^b; faecal microbiome; urine; physical activity; diet; quality of life; diabetes family history; medication history. Dashed lines indicate data assimilated from existing cohorts and registers. m, months; U-CP, urinary C-peptide; y, years. ^aOnly a subset of the original sample population will be invited to attend the 36m visit; ^bcarried out in a subset of the sample population. Black squares, deep-phenotype study visit; white squares, minor study visit