Triggers of the autoimmune response that leads to type 1 diabetes (T1D) remain poorly understood. A possibility is that parallel changes in both T cells and target cells provoke autoimmune attack. We previously documented greater Ca2+ transients in fibroblasts from T1D subjects than non-T1D after exposure to fatty acids (FA) and tumor necrosis factor α (TNFα). These data indicate that metabolic and signal transduction defects present in T1D can be elicited ex vivo in isolated cells. Changes that precede T1D, including inflammation, may activate atypical responses in people that are genetically predisposed to T1D. To identify such cellular differences in T1D, we quantified a panel of metabolic responses in fibroblasts and peripheral blood cells (PBMCs) from age-matched T1D and non-T1D subjects, as models for non-immune and immune cells, respectively. Fibroblasts from T1D subjects accumulated more lipid, had higher LC-CoA levels and converted more FA to CO2, with less mitochondrial proton leak in response to oleate alone or with TNFα, using the latter as a model of inflammation. T1D-PBMCs contained and also accumulated more lipid following FA exposure. In addition, they formed more peroxidized lipid than controls following FA exposure. We conclude that both immune and non-immune cells in T1D subjects differ from controls in terms of responses to FA and TNFα. Our results suggest a differential sensitivity to inflammatory insults and FA that may precede and contribute to T1D by priming both immune cells and their targets for autoimmune reactions.
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This work was supported by the Zoltan Kohn Endowment, the National Center for Advancing Translational Sciences, National Institutes of Health, through BU-CTSI Grant Number 1UL1TR001430 and the following grants from the National Institute of Health: DK46200-24, DK099618-01, DK074778-09, DK056690-12, DK035914-27 to BEC; R01DK108056 and R01 DE025383 to BSN; and NIDDK P30DK057521 (BADERC) to HD.
Jones, Albert R. IV; Coleman, Emily L.; Husni, Nicholas R.; Deeney, Jude T.; Raval, Forum; Steenkamp, Devin; Dooms, Hans; Nikolajczyk, Barbara S.; and Corkey, Barbara E., "Type 1 Diabetes Alters Lipid Handling and Metabolism in Human Fibroblasts and Peripheral Blood Mononuclear Cells" (2017). Clinical and Translational Science Faculty Publications. 1.