SUMMIT

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.’

• Read the University of Dundee’s press release
• Read the University of California San Francisco news item

Diabetes project SUMMIT will hold a symposium entitled ‘A leap forwards for diabetes complications’ in Malmö, Sweden on 22 April 2015. SUMMIT is working to improve our ability to identify and treat diabetes patients at greatest risk of diabetes complications such as eye, kidney, and cardiovascular disease.### At the symposium, members of the SUMMIT team will present highlights from their research, while speakers from outside the project will put SUMMIT’s findings into a broader context. Participation in the symposium is free but registration is obligatory.

• Download the agenda (which also includes information on registration).

Scientists from the IMI project SUMMIT have shed new light on the causes and development of atherosclerosis in diabetes. Diabetic patients often suffer from a widespread and aggressive form of atherosclerosis, with a high risk for myocardial infarction, peripheral vascular disease and stroke.### Despite the enormous burden caused to patients, the molecular mechanisms leading to accelerated damage are still unclear.

Led by Professor Maria Gomez, researchers at Lund University in Sweden have made a giant step forward in unveiling the causes and development of atherosclerosis in diabetic mice. Specifically, the team revealed that a protein called nuclear factor of activated T-cells (NFAT) causes atherosclerosis in diabetic mice. Furthermore, when the team blocked the activity of NFAT, this halted progression of the atherosclerosis. The researchers also believe that these findings may constitute a novel therapeutic target to reverse diabetic macrovascular complications.

SUMMIT is one of the three research consortia in IMI’s Diabetes Platform, together with DIRECT (DIabetes REsearCh on patient stratification) and IMIDIA (Innovative Medicines Initiative for Diabetes). SUMMIT’s key objective is to develop procedures, technologies and tools to make clinical trials testing of novel medications in diabetic complications shorter and more focused.

• Learn more on page five of the Summit Newsletter
• Read the research article published in PLOS ONE 

IMI diabetes project SUMMIT has developed a revolutionary new ultrasound device capable of identifying patients at imminent risk of a heart attack or stroke. Atherosclerosis occurs when plaques of fatty material build up on the inside walls of blood vessels.### If a plaque breaks up, the resulting blood clot could block the blood vessel and so cause a stroke or heart attack. People with diabetes are at a greater risk of both conditions. Currently, detecting plaques that are at risk of breaking up involves expensive, risky procedures as medical devices are inserted into the blood vessels themselves. The SUMMIT method is non-invasive, and for the patient it works in much the same way as a normal ultrasound, such as that used on pregnant women, although in reality it is much more complex. The SUMMIT team is now validating the new ultrasound technique at four centres across Europe. Although SUMMIT developed the device with diabetic patients in mind, it could be used on all patients at risk of heart attacks and stroke. The researchers behind the device applied for a patent earlier this year. ‘We are hoping to get a first response to our patent application by the end of the year,’ said Isabel Gonçalves of the University Hospital in Malmö-Skåne, one of the inventors of the device. ‘In my view our innovation is going to be a big hit if it continues giving positive results in the rest of the tests.’
 - Find out more about the SUMMIT ultrasound device, as well as other news from the project, in the latest issue of the SUMMIT Newsletter

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.

Scientists from the IMI-funded SUMMIT project have developed a software tool that beats the current state of the art when it comes to scanning multiple genomes for mutations that could raise people’s risk of developing a specific disease or condition. ###Scientists regularly scan and compare the genomes of large numbers of people, some healthy and some with the disease under investigation, hunting for Single Nucleotide Polymorphisms (SNPs – mutations where just one letter of the DNA code is changed) that could help to explain people’s genetic predisposition to the disease. Writing in the journal BMC Bioinformatics, the SUMMIT researchers set out how they tested their new ‘Bag of Naïve Bays’ (BoNB) software to identify SNPs that could predict the development of type 1 diabetes. They also compared BoNB’s performance against that of two other algorithms used in these studies. Not only did BoNB successfully identify the genetic markers already known to be associated with a raised risk of type 1 diabetes, it outperformed the two other algorithms tested in terms of predicted risk accuracy. The SUMMIT team will now use BoNB to identify the genetic factors that raise people’s risk of developing diabetes-related complications, such as eye, kidney, and blood vessel problems. The source code of the BoNB algorithm is available online.

EFPIA member companies Sanofi-Aventis and Pfizer have joined IMI project SUMMIT, which is investigating new ways of identifying the diabetes patients at greatest risk of developing complications such as heart disease and stroke, and damage to the blood vessels, kidneys and eyes.### The development of novel biomarkers (biological markers) and imaging technologies will help to better predict and monitor the progression of such complications and assess the efficacy of treatments. This will help to shorten clinical trials of novel medications. Among other things, Sanofi-Aventis will contribute to SUMMIT’s efforts to develop tools to identify patients at risk of kidney problems and atherosclerosis (hardening of the arteries). For example, it will develop an imaging probe to assess levels of calcification within atherosclerotic plaques in an experimental model of arterial stiffness. Pfizer will also contribute to SUMMIT’s work into the genes and proteins behind kidney disease in diabetics; their involvement will allow the partners to expand work that will help identify the patients who are more likely to develop kidney problems and progress rapidly through the stages of kidney disease. 

‘We took the lead over US-based projects’ – an interview with SUMMIT project coordinators
Before SUMMIT started in 2009, ongoing research on diabetic complications in Europe was scattered amongst various countries. Fast forward six years, and Europe – by joining forces and activities – has climbed to the top of the research ladder in this field, ### coming close to or even surpassing similar research projects in the US. In an interview with the IMI Programme Office, SUMMIT project coordinator Michael Mark of Boehringer-Ingelheim, and scientific coordinator Leif Groop of Lund University, explain how SUMMIT contributed to the diabetes complications field. ‘This IMI project also showed that academic centres and pharmaceutical industry can work together in a structured and collaborative way – something that has never been done before in this field,’ said Mark. ‘This IMI framework was new for the European academia as well as for the industry, but thanks to it we are now well positioned to compete or even surpass our colleagues in the US.’
 - Read the full interview
 - Find out more about the project's achievements in the project factsheet
 - Visit the project website
(January 2017)

IMI diabetes projects deepen cooperation
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.
(October 2013)