Objective
1. To investigate the mechanism involved in insulin synthesis during the course of type 1 diabetes in human beta cells.
2. To study if there is a defect in the enzymes that process the insulin precursors, leading to the accumulation of unprocessed proteins, the introduction of processing errors and to a deficit in insulin production.
3. To determine which protein fragments are recognized by the immune system, causing their activation and leading to beta cell destruction.
Our overall objective is to build a comprehensive study that explores two of the main players in type 1 diabetes: the beta cell and the immune system. Previous studies have mainly focused on one or the other but it is now clear that a combination of different expertise and lines of investigation will be the most successful strategy to achieve our goal: increase our understanding of the disease and find suitable therapeutic approaches.
Background Rationale
Type 1 diabetes is an autoimmune disease in which clinical symptoms arise as a result of beta cell destruction and insulin deficiency. While genetic and environmental factors contribute to the disease, in recent years it has become increasingly evident that beta cells might be contributing to their own destruction and might have an active role in type 1 diabetes development. Insulin production occurs thanks to processing enzymes, which transform the precursors of insulin (preproinsulin and proinsulin) into insulin. Under physiological circumstances, proinsulin processing is highly efficient with approximately 95% of proinsulin being transformed into insulin and c-peptide and only a small amount of proinsulin goes outside the beta cell. However, high amounts of proinsulin have been detected in the serum of patients at risk of developing the disease and after diagnosis, indicating a possible disruption of insulin synthesis. One of the consequences of this disruption might be the accumulation of incorrectly processed proinsulin in beta cells, which might become visible for the immune system. Several studies have shown that lymphocytes from patients with type 1 diabetes are able to recognize parts of the proinsulin molecule and destroy beta cells. Understanding how aberrant proinsulin could be produced and how the immune system recognizes it will be important in order to identify opportunities for therapeutic intervention before beta cells are completely destroyed.
Description of Project
Type 1 diabetes is an autoimmune disease in which clinical symptoms arise as a result of insulin deficiency. While genetic and environmental factors contribute to the disease, in recent years it has become increasingly evident that beta cells might be contributing to their own destruction and might have an active role in type 1 diabetes development. Insulin production occurs thanks to processing enzymes, which transform the precursor of insulin (proinsulin) into insulin. Our hypothesis is that there might be a defect in the activity of these enzymes that would cause the accumulation of large amounts of proinsulin (which is not being transformed to insulin) and might also introduce insulin processing errors. These errors would lead to protein modifications that would be recognized by the immune system. Therefore, our objective is to investigate the mechanisms involved in proinsulin and insulin synthesis, the enzymes that process them and which protein fragments (modified or not) are recognized by lymphocytes, causing their activation and leading to beta cell destruction. Consequently, we propose to study the biological processes that accompany insulin synthesis not only from the beta cell perspective but also from the side of the immune system, providing a more comprehensive understanding of the pathogenesis of type 1 diabetes. Ultimately, this work should help to develop novel therapeutic approaches targeting beta cell dysfunction possibly in combination with antigen specific therapies.
Anticipated Outcome
Based on our preliminary studies and the expertise of our collaborators, we anticipate that this work will bring us closer to understand how proinsulin and insulin are produced in beta cells and if there is an enzymatic defect that could lead to the aberrant accumulation of proinsulin, potentially increasing the activation of the autoimmune response that ultimately causes beta cell destruction.
Relevance to T1D
Our work is extremely relevant to type 1 diabetes, not only because is focused on beta cells, how they process proinsulin and produce insulin and how this might change during disease development, but also because it looks at the image that beta cells show to the immune system and how they might be targeted for destruction. On one hand, if a processing defect is detected in beta cells, a drug that effectively stimulates proinsulin processing enzymes could be an extremely valuable tool for increasing insulin production. On the other hand, if a predominant type of lymphocyte is detected, this could prompt the development of specific therapies that focus on avoiding the appearance and activation of these cells. Potential therapies should therefore target dysfunctional beta cells when they still have the ability to be functionally rescued but also the immune system in order to avoid inflammation and ultimately beta cell destruction.