Diabetes affects over 425 million people worldwide. It’s a chronic metabolic disease in which blood glucose levels are too high. It is divided into two types: type 1 diabetes (in which the body does not make enough insulin) and type 2 (where the body does not adequately respond to insulin). Over time, having too much glucose in the blood can damage the eyes, kidneys, nerves, heart and blood vessels.
There is currently no cure for diabetes, and treatment options are limited, even though they have somewhat improved over the recent decades thanks to knowledge about the functioning of beta cells. Type 2 diabetes is the more common kind of diabetes that develops primarily among adults. The primary cause of type 2 diabetes is probably pancreatic islet beta cell dysfunction and viability, which is caused by a mixture of genetic and environmental factors.
The consortium IMIDIA brought together 8 EFPIA companies, 12 academic institutions and one SME. The project sought to address the key bottlenecks in the development of beta cell focused therapies, to accelerate the path to improved diabetes management and ultimately pave the way to curing the disease.
Human cells rather than rodent cells
IMIDIA researchers wanted to study the underlying molecular mechanisms and changes in human diabetic beta cells. One of the main problems in diabetes research was the lack of a human pancreatic beta cell line that could be studied in the lab. Instead, rodent beta cell lines were used in all diabetes-related research. The first major breakthrough for the IMIDIA project was the development of a human pancreatic beta cell line that behaved in the same way as beta cells in the body.
Thanks to the pharmaceutical industry’s validation of the human pancreatic beta cell line, the biotechnology SME Endocells SARL, an IMIDIA partner, patented the finding as an innovative research tool. That allowed them to further develop the cell lines, making them available to other IMI projects and for further collaboration in industry and academia. This is one of many examples of the important role that SMEs play in public-private partnership research projects, with their broad expertise in developing such tools, diagnostic equipment, database models, and applications that are core technologies of many biotechnology SMEs.
For the IMIDIA team, this was one of the most significant achievements. They worked on six different scientific work packages that focused on novel approaches, like imaging biomarkers, systems biology and pathway analysis. Usable human pancreatic beta cells represented a unique tool for large-scale drug discovery and provided a preclinical model for cell-replacement therapy in diabetes.
IMIDIA’s goal was to develop patient-relevant disease models in vitro and in vivo as well as biomarkers to monitor disease progression and treatment. Researchers were also tasked with identifying novel paths for the regeneration, maintenance and protection of insulin-producing pancreatic beta cells as a means to speed up the discovery of more effective strategies to prevent and treat diabetes.
A biobank of islets and pancreatic tissues
One challenge for the consortium was to define which genes are abnormally expressed in the beta cells of diabetic subjects compared to those of non-diabetic subjects. The transformed character of these genes could account for beta cell failure in diabetes. For the first time, researchers based their analysis not only on cells collected from non-diabetic and diabetic organ donors, for which the availability of clinical information is limited, but also on cells from patients undergoing pancreatic surgery.
To identify changes in type 2 diabetic islets, the consortium established a unique and comprehensive multicentre biobank of human islets and pancreas tissues from pre-diabetic organ donors and healthy, non-diabetic individuals.
Identification of disruptive genes
Comparative analysis identified 19 genes whose expression was altered in islets of both diabetic organ donors and diabetic surgery patients. Nine of these 19 genes had never previously been shown to be dysregulated in diabetic islets. The genes are not dysregulated in cells taken from people with pre-diabetes, suggesting that their altered activity levels are the consequence, rather than the cause, of beta cell failure.
Moreover, IMIDIA scientists identified a gene that disrupts insulin secretion in individuals with a rare form of type 2 diabetes called maturity-onset diabetes of the young (MODY). The gene produces a protein called PASK (PAS kinase). Normally, when blood sugar levels are low, insulin production is close to zero. However, in people with the mutated form of PASK, insulin production at low blood sugar levels is high. The researchers believe that this may render other tissues in the body less responsive to insulin, causing problems when blood sugar levels rise. This represented the first demonstration in humans that the PASK protein plays a key role in insulin secretion, meaning that it could be used in diabetes treatment.
During the course of the project, IMIDIA scientists received additional support in the order of USD 1 million (EUR 0.9 million) in funding from JDRF. JDRF is the world's largest charity and patient organisation, and supporter of research to cure, treat, and prevent type 1 diabetes. The additional support allowed IMIDIA participants to expand their research efforts into the role and survival of beta cells in diabetes, to ultimately speed up the search for a cure for diabetes.
Achievements & News
The IMIDIA consortium has identified a novel signature of 19 genes whose activity is faulty in people with type 2 diabetes. The findings are published in the journal Diabetologia. In people with type 2 diabetes, the islet cells in the pancreas do not respond adequately to produce the hormone insulin, leading to elevated blood glucose levels and an inability to keep blood glucose levels stable. ###The scientists arrived at the signature after analysing and comparing gene activity levels in the largest collection of pancreatic islet cells from diabetic patients, people with pre-diabetes, and non-diabetic healthy individuals. Their work uncovered 19 genes with ‘dysregulated’ activity levels in the cells taken from people with type 2 diabetes. Of these, 10 had been identified in previous research, but 9 had never been picked up as being dysregulated in pancreatic islets before. Interestingly, the genes are not dysregulated in cells taken from people with pre-diabetes, suggesting that their altered activity levels are the consequence of, rather than the cause of islet cell failure. ‘We believe that our data provides novel molecular insights into what is going wrong in diabetic beta cells and sets new standards for how studies in this field shall be carried out in the future,’ said Michele Solimena of Dresden University of Technology, one of the leading investigators of the study. ‘Ultimately, we are confident that our approach will provide a new view for how exposure of beta cells to nutrient overload wears their function overtime, hence impairing their ability to satisfy the excessive demand of insulin to maintain metabolic homeostasis.’ Looking to the future, the researchers are keen to find out which genes are dysregulated before the onset of diabetes; this is a focus on the new IMI project RHAPSODY.
Researchers from IMI’s IMIDIA project have uncovered clues that could help to identify people at risk of developing diabetes. Diabetes arises when the beta cells of the pancreas fail to produce enough insulin to regulate blood sugar levels correctly. There is currently no cure for diabetes, and a lot of research focuses on improving our understanding of the underlying causes of the disease.### Writing in the journal Molecular Metabolism, the researchers explain how they have identified a gene called Elovl2 that appears to play a key role in insulin secretion. According to the team, Elovl2 codes for an enzyme that makes a poly-unsaturated fatty acid called DHA. The researchers confirmed its role in insulin secretion in both mice and human cell lines. A second paper, in Cell Reports, demonstrates that the levels of certain lipids (fats) in people’s blood plasma appear to be raised up to nine years before diagnosis. Scientists from the Swiss Institute of Bioinformatics (SIB) were involved in both papers. In a press release, they point out that the studies brought together academic teams, pharmaceutical companies, and a small to medium-sized enterprise (SME), and that the results were cross validated through the IMIDIA project. ‘The findings therefore highlight the instrumental role of public-private partnerships, such as the IMI, in enabling such advances and improve public health,’ they conclude.
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 project IMIDIA has secured additional support of up to $1 million (approx. € 750 000) in funding from the US-based JDRF, the world’s largest supporter of research to cure, treat, and prevent type 1 diabetes (T1D).### The additional support allows IMIDIA participants to expand their research efforts that are focused on speeding up the search for a cure for diabetes. The first two JDRF-funded projects are already underway, and more are in the pipeline. JDRF will support projects that address issues not covered by IMIDIA’s original work plan, thereby ensuring that the funds will be used for novel research. ‘IMI is an attractive partner for JDRF, because through their IMIDIA project, we share a common goal of accelerating the development of better treatments and cures for type 1 diabetes,’ commented Adrianne Wong, Senior Scientist for Cure Therapies at JDRF.
- Read the joint IMI - IMIDIA– JDRF press release
An article in Cell Metabolism on the urgent need to develop novel treatments for diabetes and obesity highlights the IMI project IMIDIA as the way forward.### "Future success requires a closer relationship between industry and academia as well as active knowledge sharing between research groups through multiparty partnerships and consortia," the paper reads. "The Innovative Medicines Initiative for Diabetes is an excellent example." The paper also underscores the need for more personalised medicine in diabetes; this will be addressed in the IMI project DIRECT, which will be launched shortly.
Scientists from the IMI project IMIDIA have identified a gene that disrupts insulin secretion in individuals with a rare form of type 2 diabetes called maturity onset diabetes of the young (MODY).### The gene produces a protein called PASK (PAS kinase). Normally, when blood sugar levels are low, insulin production is close to zero. However, in people with the mutated form of PASK, insulin production at low blood sugar levels is rather high. The researchers believe that this may render other tissues in the body less responsive to insulin, causing problems when blood sugar levels rise. The findings, published in the Journal of Biological Chemistry, represent the first demonstration in humans that the PASK protein plays a key role in insulin secretion. The discovery may have implications for diabetes treatment. ‘PASK is an interesting potential drug target since the structure of the protein lends itself to the binding of small molecules,’ explains Guy Rutter of Imperial College London in the UK, who lead the research. ‘The development of such compounds may provide new regulators of insulin secretion which may be of value in the clinic in years to come.’
Researchers from the IMI project IMIDIA have generated a human pancreatic beta cell line that not only survives in the lab, but behaves in much the same way as beta cells in the body.### When pancreatic beta cells malfunction, the result is diabetes. Scientists are therefore keen to study these cells in the lab to determine the underlying causes of diabetes and work out ways of treating and even curing it. Until now, researchers have had to rely on rodent beta cell lines for studies in the lab. Writing in the Journal of Clinical Investigation, IMIDIA researchers explain how they generated the novel human cell line and state: ‘These cells represent a unique tool for large-scale drug discovery and provide a preclinical model for cell replacement therapy in diabetes.’
IMI diabetes projects sign Memorandum of Understanding
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
- Astrazeneca AB, Södertälje, Sweden
- Boehringer Ingelheim Internationalgmbh, Ingelheim, Germany
- Eli Lilly And Company LTD, Basingstoke, United Kingdom
- F. Hoffmann-La Roche AG, Basel, Switzerland
- Institut De Recherches Servier, Suresnes, France
- Novartis Pharma AG, Basel, Switzerland
- Novo Nordisk A/S, Bagsvaerd, Denmark
- Sanofi-Aventis Deutschland GMBH, Frankfurt / Main, Germany
Universities, research organisations, public bodies, non-profit groups
- Centre National De La Recherche Scientifique Cnrs, Paris, France
- Commissariat A L Energie Atomique Et Aux Energies Alternatives, Paris, France
- Imperial College Of Science Technology And Medicine, London, United Kingdom
- Institut National De La Sante Et De La Recherche Medicale, Paris, France
- Medizinische Hochschule Hannover, Hannover, Germany
- SIB Institut Suisse De Bioinformatique, CH-660-0733998-3, Genève, Switzerland
- Technische Universitaet Dresden, Dresden, Germany
- Universita Di Pisa, Pisa, Italy
- Universite De Geneve, Genève 4, Switzerland
- Universite De Lausanne, Lausanne, Switzerland
- Universite Paris Diderot - Paris 7, Paris, France
- Vrije Universiteit Brussel, Brussel, Belgium
Small and medium-sized enterprises (SMEs)
- SARL Endocells, Paris, France
|Name||IHI funding in €|
|Centre National De La Recherche Scientifique Cnrs||470 356|
|Commissariat A L Energie Atomique Et Aux Energies Alternatives||412 000|
|Imperial College Of Science Technology And Medicine||1 079 744|
|Institut National De La Sante Et De La Recherche Medicale||504 340|
|Medizinische Hochschule Hannover||490 300|
|SARL Endocells||466 000|
|SIB Institut Suisse De Bioinformatique, CH-660-0733998-3||450 961|
|Technische Universitaet Dresden||666 800|
|Universita Di Pisa||491 040|
|Universite De Geneve||834 340|
|Universite De Lausanne||1 274 479|
|Universite Paris Diderot - Paris 7||623 600|
|Vrije Universiteit Brussel||296 800|
|Total Cost||8 060 760|