Type 2 diabetes transmission by a prion-like mechanism

Some of the most prevalent human diseases, such as Type 2 diabetes (T2DM), Alzheimer´s disease (AD), and Parkinson disease (PD) are part of the group of protein misfolding disorders (PMDs), and they share the characteristic accumulation of misfolded protein aggregates in affected tissues. The presence of misfolding protein aggregates in tissues leads to extensive cell death. Prion protein, in prion diseases, is perhaps the best archetype of PMDs; it has been deeply studied the role of the misfolded protein in the pathogenesis of the disease. Indeed, it has been shown that misfolded prion protein acts as the infectious agent to transmit the disease to another host. T2DM is a metabolic disorder triggered by impairment in the glucose metabolism. It is due to the fail in the secretion and/or action of insulin in the peripheral tissues. Islet amyloid polypeptide (IAPP) and insulin play an important role regulating glucose metabolism. These hormones are co-expressed and co-secreted by β cells in the islets of Langerhans. It has been shown that IAPP sequence has a high propensity to form aggregates. Fibrillogenic property shared with all the others proteins involved in PMDs pathologies. Prion-like mechanism is a recently described phenomenon, where a misfolded protein is able to induce the misfolding and aggregation of homologous proteins. Once misfolded, the process follows the same mechanism of aggregation followed by all proteins in PMDs, providing evidences that protein misfolding could be induced by the prion-like mechanism. Prion diseases are the only PMD known to be transmissible human to human. Previous results, from us and other laboratories, have indicated that proteins, such as Aβ, Tau and α-synuclein, have the capability to induce/accelerate their pathologies under experimental conditions, by a prion-like mechanism. Compelling evidence suggest that IAPP aggregates, found in more than 90% of Type 2 Diabetes patients, may play a crucial role in β cell dysfunction and death. Owing to structural and biochemical similarities of IAPP aggregates with other self-propagating pathogenic protein aggregates, I hypothesized that IAPP aggregates may transmit pathology associated to T2DM in animal models. The main objective of my thesis project is to comprehensively demonstrate whether IAPP aggregates may transmit the T2DM pathology by a prion-like mechanism. The results obtained in this thesis may contribute to understand the etiology of T2DM, improve health policies, and develop new therapeutic strategies for the treatment of the disease.