Junior Research Group: Type 1 diabetes pathology

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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 type 1 diabetes 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 identify opportunities for therapeutic intervention before beta cells are completely destroyed.

To increase our understanding of the pathogenesis of human type 1 diabetes, we work in close collaboration with The Network for Pancreatic Donors with Diabetes (nPOD, www.jdrfnpod.org/), a biorepository that provides valuable tissues for research purposes. We use cutting-edge microscopy techniques and equipment to study human tissues and specially, the pancreas, from healthy and diabetic donors.

Our recent observations have shown that there is a change in the subcellular localization of proinsulin in individuals at risk of developing type 1 diabetes, indicating a potential defect in proinsulin processing early on in the disease process. We are interested in studying if there is a defect in proinsulin processing and if post-translational modifications might occur during this process, leading to the formation of new proteins that could be recognized by the immune system and specially, by CD8 T cells, the main cell type implicated in the destruction of insulin-producing beta cells. These cells can be found in the islets of Langerhans predominantly when beta cells are still present but additionally infiltrate the exocrine pancreas in high numbers even when beta cells have been completely destroyed. We are working on identifying if these cells recognize beta cells antigens and their exact localization in the pancreas, spleen and lymph nodes in order to better understand the pathogenesis of the disease. We are also trying to elucidate whether viral infections make the islets more accessible for these destructive T cells or vice versa.

Lastly, we are strongly interested on investigating key mechanisms of viral infection and their role on disease pathogenesis, possible molecular mimicry, induction of inflammatory cytokines and related molecules, and the immune response against enteroviruses.

We are strongly committed to advance our understanding of the pathogenesis of type 1 diabetes in order to move the field forward.

Contact person: Teresa Rodriguez-Calvo, Dr. med. Vet (DVM), PhD.
Phone: +49 89 3187-1578