ORIGINAL: Type 1 diabetes (T1D) 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 and the enzymes that process them. Consequently, we propose to study the biological processes that accompany insulin synthesis from a beta cell perspective, 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.
ADDENDUM: 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.