Proinflammatory cytokines mediate pancreatic β-cell specific alterations to Golgi integrity via iNOS-dependent mitochondrial inhibition

Type 1 diabetes (T1D) is caused by the selective autoimmune ablation of pancreatic β-cells. Emerging evidence reveals β-cell secretory dysfunction arises early in T1D development and may contribute to diseases etiology; however, the underlying mechanisms are not well understood. Our data reveal that proinflammatory cytokines elicit a complex change in the β‑cell’s Golgi structure and function. The structural modifications include Golgi compaction and loss of the inter-connecting ribbon resulting in Golgi fragmentation. We further show that Golgi structural alterations coincide with persistent altered cell-surface glycoprotein composition. Our data demonstrate that iNOS generated nitric oxide (NO) is necessary and sufficient for β-cell Golgi re-structuring. Moreover, the unique sensitivity of the β-cell to NO-dependent mitochondrial inhibition results in β-cell specific Golgi alterations that are absent in other cell types, including α-cells. Examination of human pancreas samples from autoantibody positive and T1D donors with residual β-cells further revealed alterations in β-cell, but not α-cell, Golgi structure that correlate with T1D progression. Collectively, our studies provide critical clues as to how β-cell secretory functions are specifically impacted by cytokines and NO that may contribute to the development of β-cell autoantigens relevant to T1D.