Endocrine Abstracts

Innate immunity contributes to inducing functional inhibition and apoptosis of pancreatic beta-cells in the pathogenesis of both Type 1 diabetes (T1D) and Type 2 diabetes (T2D). The past four decades has provided overwhelming circumstantial evidence from in vitro studies and animal models that innate immune cells and cytokines are key effectors in beta-cell killing. Pro-inflammatory cytokines activate signaling pathways that reprogram the beta-cell transcriptome and proteome, adversely affecting most functions of the cell and triggering death by the intrinsic (mitochondrial) death pathway. On the other hand, these signaling pathways also elicit numerous adaptive and protective responses that may guide development of preventive therapies. Researchers increasingly agree that environmental stressors that enhance insulin biosynthetic demand may lead to increased proinsulin misfolding, misprocessing and posttranslational modifications, triggering inflammation and neoepitope formation and presentation in the beta-cell. This novel concept attracts focus to beta-cell stress as an initiating event in the development of both T1D and T2D. There is clinical proof-of-concept that blocking the action of the pro-inflammatory cytokines interleukin-1 (IL-1) or tumor necrosis factor (TNF) improves glycaemia and beta-cell function in T2D and T1D, respectively, and meta-analyses on >2000 T2D patients substantiates the efficacy of IL-1 blockade. Yet, anti-cytokine biologics have not yet been adopted in clinical practice. This lecture will review key basic and clinical findings supporting the importance of inflammatory beta-cell damage in the pathogenesis of T1D and T2D, and will highlight central barriers that prevent clinical translation.