Type 2 diabetes is a highly heterogeneous condition largely because when hyperglycaemia is discovered it is a diagnosis made after exclusion of other known causes. The phenotype of people who develop diabetes is highly variable, as is the rate at which their subsequent diabetes progresses, how they respond to diabetes therapy and who develops micro- and macrovascular complications. This variable development, progression and treatment response of diabetes is likely to reflect subtypes of diabetes with different pathophysiology.
Thus there is a need to:
- identify biomarkers that can stratify populations by risk of progression to allow targeted intervention
- identify biomarkers that can be used to assess change in underlying beta-cell function and/or mass in response to a treatment intervention
- develop new mechanistic hypotheses for disease progression or response to treatment intervention leading to new therapies or to a better use of existing therapies
- carry out stratified trials of existing and newly-developed therapies with putative beneficial effects on beta-cell survival which will be more powered in high risk groups
- define groups of type 2 diabetes patients who do not respond or are intolerant to a treatment
The overarching aims of the consortium are to identify biomarkers that address current bottlenecks in diabetes drug development and to develop a stratified medicines approach to the treatment of type 2 diabetes with either existing or novel therapies. The identification and validation of important biomarkers for glycaemic deterioration and treatment response may be used to predict and monitor the effect of therapeutic interventions in subtypes of diabetes with different pathophysiology.
Specific DIRECT objectives divided into Work Packages (WPs)
Two key phenotyping work packages will focus on glycaemic deterioration (WP2) and therapeutic response (WP3). For each, the DIRECT consortium brings considerable existing resource, which will be augmented by large-scale prospective cohort collection with intensive physiological and imaging phenotyping.
To maximise the likelihood of finding biomarkers suitable for patient stratification we will concentrate our phenotyping and multi-level genomic analysis (WP4) on the extreme phenotype of rapid and slow glycaemic deterioration, and extreme glycaemic response to therapeutic intervention.
Additional data will be added, such as existing studies on acute response to intravenous beta-cell scretagogues, and functional genomics on human islets, liver, muscle and adipose tissue, to maximise the power and utility of an innovative integrated biology approach (WP5). To enable a computational multi-level integration across phenotypes and data types, a robust and secure data repository will be developed.
To facilitate rapid deployment of biomarkers into drug development and clinical trials, high throughput assays for biomarkers that arise from the discovery phase of DIRECT will be developed and validated (WP6).
As the ultimate aim of DIRECT is patient stratification, biomarkers arising from the discovery phase will be used to design one or more prospective clinical trials (WP7&8).
Results of the DIRECT consortium will be communicated to its target audience (WP1) such as scientific community, lay public, patient organisations and agencies.