Proinflammatory cytokines mediate pancreatic beta-cell specific alterations to Golgi morphology via iNOS-dependent mitochondrial inhibition

Abstract

Type 1 diabetes (T1D) is caused by the selective autoimmune ablation of pancreatic {beta}-cells. Emerging evidence reveals {beta}-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 {beta}-cells Golgi structure and function. The structural modifications include Golgi compaction and loss of the inter-connecting ribbon resulting in Golgi fragmentation. Our data demonstrate that iNOS generated nitric oxide (NO) is necessary and sufficient for {beta}-cell Golgi re-structuring. Moreover, the unique sensitivity of the {beta}-cell to NO-dependent mitochondrial inhibition results in {beta}-cell specific Golgi alterations that are absent in other cell types, including -cells. Collectively, our studies provide critical clues as to how {beta}-cell secretory functions are specifically impacted by cytokines and NO that may contribute to the development of {beta}-cell autoantigens relevant to T1D.