1666-P: Increased Levels of Autophagy in a Rodent Model of Type 1 Diabetes

Beta-cell apoptosis is a hallmark of type 1 diabetes (T1D) and type 2 diabetes (T2D). In T2D loss of autophagy has been associated to increased apoptosis and diminished beta-cell mass. In autoimmunity, dysfunctional autophagy alters negative selection of T cells in thymus driving autoreactive immune cells into periphery. Autophagy contributes to presentation of antigens in antigen presenting cells shaping the repertoire of peptides presented to T cells. The aim of this project is to investigate the role of autophagy in the etiology of T1D. To investigate the effect of spermidine (SPD, a known inducer of autophagy) in vivo, non-obese diabetic (NOD) mice received spermidine (10 mM; n=30) or pure drinking water (n=28) from the age of 4 weeks until the age of 35 weeks or diabetes onset. Mice were analyzed for diabetes rate, autophagy markers (LC3-II to LC3-I ratio and p62) and immune cell phenotype in spleen and blood. Spermidine led to a higher diabetes rate in SPD group (80 %) compared to control group (60,7 %) with p-value of 0,026 (log-rank test). Autophagy was induced by diabetes (plasma glucose > 200 mg/dL) and by age. Autophagy levels were higher at 21-35 weeks in old diabetic animals compared to nondiabetic animals at 35 weeks and compared to young diabetic animals at 14-20 weeks (p< 0,0001, and p< 0,0001, respectively). Spermidine treatment increased autophagy levels in pancreas, but diabetic mice at 21-35 weeks still had higher autophagy levels compared to nondiabetic animals at week 35. (LC3-II/LC3-I: p < 0,05; p62: p < 0,05). Spermidine elevated the frequency of natural killer cells in spleen (p < 0,01) and blood (p < 0,01), natural killer T cells (p < 0,01), naïve CD4+ T cells (p < 0,01), naïve CD8+ T cells (p < 0,01) and central memory CD4+ T cells (p < 0,01) in blood. Our experiments indicate that autophagy is induced upon T1D and spermidine-induced autophagy might increase diabetes incidence. Immune cell phenotyping revealed that spermidine promotes immune cells potentially provoking inflammation.