Type 2 diabetes patients are a diverse group, and refining how they are classified would help individualise their treatment regimens. The course of the disease and the effectiveness of different medicines vary from one patient to another. It is also not clear why some at-risk people (such as those with obesity) develop the condition while others do not. Finding biomarkers would help in both identifying who is at risk of developing the disease, and determining individual patients’ likelihood of responding well to a particular treatment.
Main outcomes of DIRECT
The DIRECT consortium carried out deep phenotyping of patient groups from around Europe, in order to study extreme phenotypes of patients with very rapid or very slow glycaemic deterioration (either from prediabetes to diabetes, or through diabetes). They also sought to understand the extent to which certain therapeutic interventions result in improvement in glycaemia. They were able to perform clustering of type 2 diabetes-based and baseline characteristics, and explore the molecular signature associated with diabetes progression. It allowed them to identify processes that caused or contributed to the development of T2D and how they are linked to how the disease progresses.
Tests, clinical trials, omics
The project developed tests to predict who will get diabetes, whose condition will deteriorate rapidly after diagnosis, and who will respond well or badly to certain drugs. They also used machine learning to create prediction models for non-alcoholic fatty liver disease based on clinical data and omics data. They carried out analysis of plasma metabolite profiling at the beginning and again at 18 months, which gave them an objective measure of diet, as well as the link between glycaemic deterioration, cardio-metabolic health, pre-diabetics and T2D.
These biomarkers were tested in prospective clinical trials, paving the way for their use as new diagnostic tests as well as in the creation of personalised therapies. They enrolled approximately 2,300 pre-diabetics and 850 early T2D patients for extensive baseline and longitudinal, physiological, imaging and molecular phenotyping, and followed up at 48 and 36 months, respectively.
DIRECT established a multi-site trial infrastructure with a web-based accessible interface to allow for recruitment centres to upload and manage clinical and case report form data for all recruited patients.
Large-scale analysis of whole blood transcriptome revealed a large number of associations between transcriptomic modules and measures of insulin sensitivity and glucose tolerance, pointing to a major overlap of immune and metabolic processes. In a meta-analysis in genome-wide association studies that included approximately 5,500 subjects of European ancestry from six different cohorts treated with sulphonylureas, a gene variant with glycaemic response to sulphonylureas at a genome-wide scale was identified. They also identified 25 omics features from transcriptomics, metabolomics and proteomics data linked to early diabetes remission after obesity surgery.
Liver fat predictor
DIRECT developed liver fat prediction models (predictliverfat.org) and identified biological features that appear to affect liver fat accumulation. Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes serious health complications in T2D. Early diagnosis is important, as this can help prevent irreversible damage to the liver and, ultimately, hepatocellular carcinomas. Using the baseline data from 1,514 participants, they expanded the etiological understanding and developed a diagnostic tool for NAFLD using machine learning. Multi-omic (genetic, transcriptomic, proteomic, and metabolomic) and clinical (liver enzymes and other serological biomarkers, anthropometry, and measures of beta-cell function, insulin sensitivity, and lifestyle) data were used as input.
Sulphonylurea and GLP-1R Agonist response
In large-scale analyses of trial and observational data, DIRECT identified novel mechanisms for why patients respond differently to two commonly used diabetes drugs: sulphonylulreas and GLP-1R Agonists. They identified genetic variants that alter response to these drugs – which provides insight into how these drugs work or are transported in the body, and importantly, have the potential to be used for targeted therapy in clinical management of diabetes in the near future.
Central database and biobank
During the project, all data was stored in a single secure server to enable high-performance analytics. The consortium built a central biobank to enable future biomarker discovery and replication for use in other IMI projects. The database with more than 40 terabytes of data is located in Denmark, while the biobank consisting of 300,000 samples is stored in the UK.
The work carried out under the DIRECT project boosted the industry’s understanding of the underlying causes of T2D, and is helping it to develop tailored treatments that can be targeted to the right patients. The work carried out in DIRECT complements the efforts of other IMI diabetes projects IMIDIA and SUMMIT.
Achievements & News
A large study, part-funded by the Innovative Medicines Initiative (IMI) through the DIRECT, SUMMIT and BEAT-DKD projects, identified a protein...
Scientists have identified a genetic variant that affects how well diabetes patients respond to the drug metformin. As well as paving the way for a more personalised approach to diabetes treatment, the findings also reveal how metformin actually works. The study, funded in part by IMI’s diabetes projects DIRECT and SUMMIT, was published in the journal Nature Genetics. ###For 50 years, metformin has helped type 2 diabetes patients worldwide to control their blood sugar levels and avoid the heart, eye and kidney problems that often come with diabetes. However, over a third of patients do not respond to normal doses of the drug. Furthermore, despite its widespread use, little is known about how metformin works. In this study, researchers analysed the genomes of over 13 000 people in a hunt for genetic variants associated with different responses to metformin. They found that a variant of the gene SLC2A2 is associated with a stronger response to the drug. This gene is behind the creation of a protein called GLUT2 that is involved in transporting glucose around the body, and people with the gene variant were found to have lower levels of this protein in their liver and other tissues, impairing their bodies’ ability to handle glucose. Metformin reverses this deficiency, explaining why these people respond so well to the drug. What’s more, the genetic variant had a stronger effect in overweight people. In fact, overweight people with two copies of the variant had a response that was equivalent to taking an extra 500 mg dose of metformin. ‘This is an exciting discovery that demonstrates how a patient’s genetics can determine how well, or poorly, a drug works,’ said Ewan Pearson of the University of Dundee and the DIRECT project. ‘We need to undertake further clinical studies before we can change the way we use metformin, but this finding suggests that some patients should be treated with higher doses than others to achieve the same effect. This really does move us a step closer to truly targeted therapy in the treatment of diabetes.’
IMI’s three diabetes projects – IMIDIA, SUMMIT and DIRECT – are set to deepen their cooperation following the signature of a new Memorandum of Understanding (MoU) that formally creates the ‘IMI Diabetes Platform’.### ‘With a combined budget of €100 million and the involvement of over 300 leading experts in diabetes, this is one of the world’s leading initiatives in this area focusing on overcoming key bottlenecks for novel therapies and improved disease management,’ the projects write in a press release announcing the MoU. ‘The importance of the findings of the IMI diabetes projects will be strongly increased by the multiple opportunities for information exchange now enabled by the implementation of a formal collaboration framework for the IMI Diabetes Platform.’ The projects have already been collaborating informally for some time. For example, they jointly organised a symposium to present their results at the recent annual meeting of the European Association for the Study of Diabetes (EASD) in Barcelona.
IMI currently has three projects working on diabetes – DIRECT, SUMMIT, and IMIDIA – which have a combined budget of just over €100 million. The projects tackle diabetes in different ways.### For example, IMIDIA focuses on studying the pancreatic beta cells which are responsible for producing insulin; it aims to use this knowledge develop treatments that can slow down the progress of diabetes. Meanwhile, SUMMIT’s work addresses the urgent need for new treatments to tackle the complications associated with diabetes, such as eye, kidney, and blood vessel problems. Finally, DIRECT takes a personalised medicine approach to diabetes, as it works to identify different varieties of diabetes and effective treatments to tackle them. The projects already work together on an informal basis (as evidenced by their new joint leaflet produced with the support of the IMI Executive Office). However, IMIDIA and SUMMIT have now taken their collaboration to a new level with the signature of a Memorandum of Understanding (MoU). The MoU covers the handling of intellectual property, the transfer of knowledge and materials, and confidentiality. The projects believe that the MoU could serve as a template for collaboration between other IMI projects in the future.
ParticipantsShow participants on map
- Boehringer Ingelheim Internationalgmbh, Ingelheim, Germany
- Eli Lilly And Company LTD, Basingstoke, United Kingdom
- Institut De Recherches Internationales Servier Iris, Suresnes, France
- Novo Nordisk A/S, Bagsvaerd, Denmark
- Sanofi-Aventis Deutschland GMBH, Frankfurt / Main, Germany
Universities, research organisations, public bodies, non-profit groups
- Academisch Ziekenhuis Leiden, Leiden, Netherlands
- Centre Hospitalier Regional Et Universitaire De Lille, Lille, France
- Centre National De La Recherche Scientifique Cnrs, Paris, France
- Consiglio Nazionale Delle Ricerche, Roma, Italy
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Barcelona, Spain
- Danmarks Tekniske Universitet, Kgs. Lyngby, Denmark
- Eberhard Karls Universitaet Tuebingen, Tuebingen, Germany
- Helmholtz Zentrum Muenchen Deutsches Forschungszentrum Fuer Gesundheit Und Umwelt GMBH, Neuherberg, Germany
- Imperial College Of Science Technology And Medicine, London, United Kingdom
- Itä-Suomen yliopisto, Kuopio, Finland
- Kobenhavns Universitet, Copenhagen, Denmark
- Kungliga Tekniska Hoegskolan, Stockholm, Sweden
- Lunds Universitet, Lund, Sweden
- Stichting Vumc, Amsterdam, Netherlands
- The University Of Exeter, Exeter, United Kingdom
- Universitaet Ulm, Ulm, Germany
- Universite De Geneve, Genève 4, Switzerland
- University Of Bath, Bath, United Kingdom
- University Of Dundee, Dundee, United Kingdom
- University Of Newcastle Upon Tyne, Newcastle upon Tyne, United Kingdom
- University of Oxford, Oxford, United Kingdom
- Hospital Clinico Y Provincial De Barcelona, Barcelona, Spain
- Universite De Lille Ii - Droit Et Sante, Lille, France
|Name||IHI funding in €|
|Academisch Ziekenhuis Leiden||543 444|
|Centre Hospitalier Regional Et Universitaire De Lille||201 071|
|Centre National De La Recherche Scientifique Cnrs||1 406 405|
|Consiglio Nazionale Delle Ricerche||186 288|
|Consorci Institut D'Investigacions Biomediques August Pi I Sunyer||275 635|
|Danmarks Tekniske Universitet||1 753 950|
|Eberhard Karls Universitaet Tuebingen||4 800|
|Helmholtz Zentrum Muenchen Deutsches Forschungszentrum Fuer Gesundheit Und Umwelt GMBH||1 817 759|
|Imperial College Of Science Technology And Medicine||385 603|
|Itä-Suomen yliopisto||1 635 413|
|Kobenhavns Universitet||1 093 889|
|Kungliga Tekniska Hoegskolan||2 097 994|
|Lunds Universitet||1 570 964|
|Stichting Vumc||1 072 269|
|The University Of Exeter||1 734 738|
|Universitaet Ulm||100 000|
|Universite De Geneve||1 225 700|
|University Of Bath||215 444|
|University Of Dundee||1 805 896|
|University Of Newcastle Upon Tyne||378 085|
|University of Oxford||1 864 143|
|Name||Funding in €|
|Hospital Clinico Y Provincial De Barcelona||8 965|
|Universite De Lille Ii - Droit Et Sante||10 188|
|Total Cost||21 388 643|