This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Type 1 diabetes is caused by a loss of the insulin producing cells of the pancrease, by a process in the body called 'autoimmune', in which the body destroys it's own cells. The cause of the autoimmune destruction of these insulin producing cells in Type 1 diabetes is unclear. One theory is that proteins or other chemicals acting as 'antigens' absorbed through the intestine may be involved. A protein in the body, called zonulin, enables absorption of particles from the intestine. Zonulin has been found to be increased in an amimal model of Type 1 diabetes. The question in Type 1 diabetes is what are the environmental triggers, and how do these triggers interact with the immune system. It is the interaction between the environmental factors and genetics that causes the abnormal immune response that is responsible for the onset of the disease. Hypothesis: In humans, an increase in the protein zonulin leads to increase in intestinal absorption, which in turn allows passage of the particles through the intestinal barrier that act as triggers of the autoimmune response that causes destruction of the insulin productn cells and therefore causes Type 1 diabetes.
Specific Aims /Methods:
Aim 1. To establish whether blood zonulin levels correlates with increased intestinal absorption in Type 1 diabetes Children with Type 1 diabetes and their first degree relatives (parents and siblings) will be studied to evaluate zonulin levels to establish whether a correlation with age of onset of diabetes, duration of diabetes, presence of the antibodies related to diabetes development, and genetic typing. Changes in zonulin over time within individuals, and in relationship to blood sugar control will also be evaluated. Absorption will be evaluated by measuring absorption of a sugar that is not usually found in the body.
Aim 2. To study the function of the intestinal absorption system in Type 1 diabetes at the molecular level: Italian collaborators have performed intestinal biopsies of Type 1 diabetes patients and elevated zonulin levels, and these samples will be studied by us for the level of genetic expression of key structural elements and for the structure of the intestine wall by electron microscopy. Significance: These studies have significance to Type 1 diabetes in gaining more insights into the cause of Type 1 diabetes. This will then lead to potential therapies to prevent the autoimmune destruction of insulin producing cells. Preliminary animal studies show that zonulin action (and therefore intestinal absorption of particles) can be blocked and progression to destruction of insulin producting cells/Type 1 diabetes is also blocked.
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