The role of pH in the pathogenesis of type 1 diabetes

ABSTRACT Type 1 Diabetes (T1D) is an autoimmune disease where the body’s immune system mistakenly destroys insulin-producing beta cells in the pancreas. While we know that immune cells called CD4 T cells mediate this destruction, we do not fully understand what triggers them to attack. Our research focuses on unique antigens called Hybrid Insulin Peptides (HIPs) that form in insulin-producing cells and may be critical targets of these attacking immune cells. We recently made an important discovery about how these HIPs form. Inside insulin- producing cells are small compartments that normally maintain a specific acid level. We found that in humans, these compartments need to become more acidic than usual for HIPs to form. This happens naturally in mice, which is why scientists can easily study HIPs in mouse diabetes. However, in humans, the compartments may only become acidic enough to form HIPs during times of stress or infection. This discovery led us to propose a new understanding of how T1D develops. Instead of a single triggering event causing continuous destruction of insulin-producing cells, we think the disease progresses in cycles. During infections or other stressful events, the compartments become more acidic, leading to HIP formation. The immune system then attacks cells containing these HIPs. When the infection clears, HIP formation stops, and the destruction temporarily halts until the next triggering event. This explains why some patients develop diabetes quickly while others take years or decades, and why some insulin-producing cells survive even in long-term diabetic patients. Our research will investigate how these compartments become more acidic and how this leads to HIP formation. We will also test whether we can prevent HIP formation by not only controlling the acid levels in these compartments but also by blocking the enzymes responsible for HIP-formation. This could lead to new treatments for T1D that work by preventing HIPs from forming during infections or stress, rather than trying to suppress the entire immune system. Such treatments could help people at risk for developing T1D and protect transplanted insulin-producing cells derived from stem cells from being destroyed by the immune system. This research could transform our understanding of how T1D develops and lead to innovative treatments that prevent the disease by targeting its underlying cause. By focusing on the formation of HIPs rather than broadly suppressing the immune system, we hope to develop more precise and effective therapies with fewer side effects.