Dysregulated cellular metabolism predisposes to Type 1 Diabetes

Type 1 Diabetes (T1D) is an autoimmune disease caused by T-cell mediated destruction of the b-cells in the pancreas, but the initial events leading to activation of islet-specific T cells in susceptible individuals are poorly understood. Environmental factors likely play an important role in the breakdown of immune tolerance that causes T1D but a convincing model linking the initiation of autoreactive T cell responses with an environmental insult is still missing. Our preliminary data reveal aberrant responses to fatty acids and inflammatory cytokine stimulation in fibroblasts and immune cells from human T1D patients and pre-diabetic NOD mice, suggesting an underlying metabolic predisposition to autoimmunity. Therefore, we will analyze metabolism in PBMCs from T1D subjects and immune cells from NOD mice. Metabolic defects may lead to inappropriate responses to elevations in cytokines and free fatty acids, for example during viral infection, ultimately triggering autoimmunity. The objectives of this proposal are (1) to determine whether immune cell types in T1D patients and NOD mice are broadly affected by the metabolic phenotype or if this re-wiring is limited to specific immune cell subsets; (2) to test if increased lipid accumulation, lipid peroxidation and Ca2+ signal transduction can be reversed in affected immune cells using bezafibrate, medium-chain triglycerides and catalase or glutathione peroxidase overexpression, and determine the functional significance of such interventions on autoimmune responses. Importantly, our novel concept has direct translational potential to develop new strategies for early diagnosis and prevention of T1D in at-risk individuals by measuring and correcting cellular metabolic parameters.

Relevance to public health

Type 1 Diabetes (T1D) is an autoimmune disease caused by the complex interplay of genetic, immunologic and environmental factors. We discovered that immune cells of diabetic patients and mice show dysregulated metabolic pathways. In this project we aim to explore how this altered metabolism promotes autoimmunity and to test whether interventions that correct cellular metabolism can be used as a novel therapy for T1D, a disease that is globally on the rise.