Proinflammatory Cytokines Mediate Pancreatic β-Cell-Specific Alterations to Golgi Integrity via iNOS-Dependent Mitochondrial Inhibition.

UNLABELLED: 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 interconnecting ribbon resulting in Golgi fragmentation. We further show that Golgi structural alterations coincide with persistent altered cell surface glycoprotein composition. Our data demonstrate that inducible nitric oxide synthase (iNOS)-generated nitric oxide (NO) is necessary and sufficient for β-cell Golgi restructuring. 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.

ARTICLE HIGHLIGHTS: Proinflammatory cytokines drive disruptions in Golgi structure and function in human, mouse, and rat β-cells. Golgi alterations result from inducible nitric oxide synthase (iNOS)- and nitric oxide (NO)-dependent inhibition of mitochondrial metabolism. α-Cell Golgi structure is insensitive to cytokine- and NO-mediated metabolic inhibition. Analysis of human donor tissue shows early Golgi alteration in β-cells from autoantibody-positive donors, which persists in residual β-cells from T1D donors.