Grant: Operating Grant

Objective: To understand the role of the gastrointestinal tract and food proteins in the development of autoimmune type 1 diabetes (T1D) by studying the link between a damaged gut immune system and destruction of insulin-producing cells in the pancreas. Background: We have shown in diabetes-prone rats that some diets protect against diabetes, while others containing wheat promote the disease. These rats have a leaky gut barrier, which allows large amounts of food proteins to contact the immune cells in the gut, possibly triggering an immune attack on the insulin-producing cells in the pancreas. Treatment with a drug to block gut leakiness prevents T1D, suggesting that the defects in the gut barrier and immune system are important in understanding how diabetes occurs. Hypothesis: We propose that defects in controls for the gut immune responses to food proteins and a leaky gut barrier, enable an immune attack on the insulin-producing cells in the pancreas. Project Design: We will study the cells that control the immune response in the gut of a well described rat model of T1D to examine these questions. We will inject diabetes-prone animals with antibodies to block the function of key regulatory cells called CD163 macrophages to see whether this will increase the incidence of T1D. Various immune regulatory cells will also be examined in gut biopsy samples from human patients and controls. We will also treat animals fed protective and diabetes-promoting diets with drugs that prevent gut leakiness to study the effect of these treatments on diabetes development and the number and function of the immune cells that populate the gut. Significance: These studies will reveal the role of the gut in T1D, and whether changes in the regulation of gut immune cell populations affect gut leakiness and contribute to disease development. This will increase our understanding of the basic causes of T1D and could provide new avenues for treatment or prevention of diabetes.