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: www.predictliverfat.org;
- 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.