Diabetes research on patient stratification
Diabetes research on patient stratification


Start Date
End Date
IMI1 - Call 3
Grant agreement number

Type of Action: 
RIA (Research and Innovation Action)

IMI Funding
21 388 643
EFPIA in kind
18 816 527
6 278 957
Total Cost
46 484 127


Type 2 diabetes patients are a diverse group; in some, the disease progresses rapidly, while in others it takes a slower course. Similarly, a treatment that works well in one patient may prove less effective in another. This has led researchers to acknowledge that there are actually a number of different sub-types of type 2 diabetes. The goal of the IMI-funded DIRECT project was to identify these sub-types and determine most appropriate treatments for them. The project brought together Europe’s leading researchers from academia, healthcare, and the pharmaceutical industry.

Key achievements

The DIRECT project

  • enrolled ~2300 prediabetics and ~850 early T2D patients and follow-up for 48 and 36 months, respectively;
  • established a central biobank with 300,000 samples that will be a source for replication/biomarker identification in other IMI projects;
  • established most comprehensively phenotyped cohorts to date with 40 TB of data: fsOGTT, MMTT, MRI-imaging (liver, pancreas fat), physical activity (accelerometry), diet (questionnaire), multiomics: genetic, metabolomics, proteomics, lipidomics, stool sequencing and RNA-seq;
  • conducted Integrative analysis across phenotype and multiomic levels to identify biomarkers of drug response and glycaemic deterioration;
  • developed a publically available prediction tool to predict liver fat:;
  • identified robust genetic predictors of glycaemic response to GLP-1RA and novel mechanisms of action.


Some 285 million people worldwide have type 2 diabetes, and that figure is set to rise to 439 million by 2030. It arises when the body cannot make enough insulin (the hormone responsible for managing blood sugar levels), or when the body fails to respond to insulin. Although type 2 diabetes is a chronic, lifelong condition, it can be managed through a combination of medicines and lifestyle changes. If left unmanaged, patients’ blood sugar levels become too high, triggering damage to the cardiovascular system, kidneys, eyes, and nerve endings.

Although there are a number of risk factors for type 2 diabetes (such as obesity), it is not always clear why some people develop the condition while others do not. Furthermore, the course of the disease and the effectiveness of different medicines vary from one patient to another. In other words, there are a number of different kinds of type 2 diabetes, and that is where the DIRECT project comes in.

Variations on a theme
The focus of the DIRECT project was patient stratification, which involved identifying different subgroups of patients. The project developed and validated tests to predict who will get diabetes, whose condition will deteriorate rapidly after diagnosis, and who will respond well or badly to certain drugs. The tests would then allow the DIRECT project to determine which existing drugs are effective for different varieties of type 2 diabetes.

DIRECT gathered large amounts of data as well as samples from people at risk of diabetes, people with diabetes, and people undergoing diabetes treatment. This enabled the project team to identify biomarkers (biological markers such as the level of a certain molecule in the blood) associated with different sub-types of type 2 diabetes and different rates of disease progression. These biomarkers were then tested in prospective clinical trials, paving the way for their use as new diagnostic tests as well as in the creation of personalised therapies.

Getting the right treatments to the right patients.

The tests developed by DIRECT will ultimately usher in a new era of personalised medicine for diabetes patients. In practice, this means doctors will be able to diagnose their patients more accurately and tailor treatments to suit their own particular sub-type of type 2 diabetes. In this way, patients will be able to manage their condition more effectively and hopefully avoid the complications associated with diabetes. Furthermore, patients who are at risk of diabetes could be identified and monitored.

A boost for the drug development sector
The work carried out under the DIRECT project substantially boosted the industry’s understanding of the underlying causes of type 2 diabetes, helping it to develop tailored treatments that can be targeted to the right patients.

Pieces of a pharma puzzle
The work carried out in DIRECT complements the efforts of IMI’s other diabetes projects. IMIDIA (‘Improving beta-cell function and identification of diagnostic biomarkers for treatment monitoring in diabetes’) is studying the beta cells of the pancreas, which are responsible for producing insulin, with a view to developing a cure for diabetes. Meanwhile SUMMIT (‘Surrogate markers for micro- and macro-vascular hard endpoints for innovative diabetes tools’) is developing tools to identify the patients at greatest risk of developing complications relating to diabetes.

Achievements & News

Scientists uncover gene variant that affects workings of diabetes drug
September 2016

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 diabetes projects deepen cooperation
October 2013

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 diabetes projects sign Memorandum of Understanding
November 2012

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.

Participants Show participants on map

EFPIA companies
  • Boehringer Ingelheim Internationalgmbh, Ingelheim, Germany
  • Eli Lilly and Company Limited, Basingstoke, United Kingdom
  • Institut De Recherches Internationales Servier, 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
Third parties
  • Hospital Clinico Y Provincial De Barcelona, Barcelona, Spain
  • Universite De Lille Ii - Droit Et Sante, Lille, France
Project coordinator
Hartmut Ruetten
Sanofi-Aventis Deutschland GmbH
Managing entity
Ewan Pearson
University of Dundee