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.