The Role of Granular Acidification in the Pathogenesis of Type 1 Diabetes - PROJECT SUMMARY Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing beta cells in the pancreas, leading to lifelong dependence on insulin therapy. Despite decades of research, the exact triggers that initiate this autoimmune process remain elusive. This grant proposal aims to investigate a novel mechanism that may explain the development and progression of T1D, focusing on the formation and role of hybrid insulin peptides (HIPs) in beta cells. HIPs are unique autoantigens that form when pieces of insulin get linked to other beta cell proteins. These hybrid molecules are not encoded in the genome and may be recognized as foreign by the immune system, potentially triggering an autoimmune response against beta cells. Previous research has shown that HIPs are present in a major mouse model of T1D and human patients, and that immune cells reactive to HIPs can be found in the blood and pancreatic tissue of individuals with T1D. The researchers propose that the formation of HIPs is influenced by various stressors that affect beta cells, such as changes in blood glucose levels or exposure to inflammatory molecules. They hypothesize that these stressors alter the internal environment of beta cells, particularly the acidity levels within insulin-containing granules, leading to increased HIP production. This process may explain why some individuals develop T1D more rapidly than others and why the disease can progress in a variable manner. To test these hypotheses, the research team will conduct a series of experiments using human pancreatic islets and immune cells from T1D patients. They will investigate how different stressors affect HIP formation and examine the relationship between cellular stress, HIP production, and the recognition of beta cells by the immune system. Advanced techniques in mass spectrometry and immunology will be employed to identify new HIPs and characterize their potential role in triggering autoimmunity. Understanding the mechanisms of HIP formation and their role in T1D development could have significant implications for the prediction, prevention, and treatment of the disease. If successful, this research may lead to new strategies for identifying individuals at high risk of developing T1D before symptoms appear, as well as novel approaches to protect beta cells from immune attack. Furthermore, insights gained from this study could potentially inform the development of therapies aimed at preventing or slowing the progression of T1D, ultimately improving the lives of millions affected by this chronic condition. By elucidating the complex interplay between beta cell stress, HIP formation, and autoimmune activation, this research has the potential to fundamentally change our understanding of T1D pathogenesis and open new avenues for intervention in this challenging autoimmune disorder.
