Grant: Operating Grant

Type 1 diabetes (T1D) develops when a patient's immune cells destroy the insulin-producing cells in the pancreas, resulting in lifelong insulin injections and decreased lifespan. T1D arises from complex interactions between a patient's genes and the environment. The gut is the major site of interaction between the immune system and environment. Environmental factors encountered in the gut such as microbes and diet play an important role in T1D development and feeding an antigen-free diet prevents T1D in diabetes-prone rats. We have found that cathelicidin (CAMP), an antimicrobial protein, was increased in the gut of rats fed a protective antigen-free diet vs. a wheat-based, T1D-promoting diet. CAMP was also identified in the insulin-producing beta cells in the pancreas. Thus, CAMP is a common factor in both the gut and the pancreas. After injecting CAMP, treated diabetes-prone rats displayed increased regeneration of beta-cells and increased beneficial, probiotic gut bacteria. Additionally, our research has shown that injection of a chemical called CoPP protected diabetes-prone rats from T1D, increased antimicrobial proteins in pancreas and induced anti-inflammatory M2 macrophages. The action of CAMP and CoPP likely occurs through activation of protective immune responses in the gut and pancreas. We expect that antimicrobial proteins and M2 macrophages are key players in regulating the immune system and beta-cells to prevent T1D. In this grant, we propose to investigate the involvement of antimicrobial proteins, M2 anti-inflammatory macrophages and gut microbiota in T1D development in diabetes-prone rats fed a protective or diabetes-promoting diet to understand the sequence of events that links environment to beta-cell destruction. Insight into the function of antimicrobial peptides and anti-inflammatory immune cells could provide insight into T1D development, prevention, and treatment.