Type 1 diabetes (T1D) is the most common incurable, early onset, chronic disease. Disease etiology includes autoimmunity against the β cells accompanied by progressive abnormalities in insulin secretion and action ultimately requiring life-long management with exogenous insulin. Preservation of functional pancreatic β cells reduces complications risk and improves mental health, thus new treatments preventing disease onset and/or prolonging β cell function and survival, would reduce the burden of T1D in both Australia and globally.
The receptor for advanced glycation end products (RAGE), is an important protein for host-pathogen defense and is present on cell types implicated in the development of T1D including T cells, macrophages, dendritic cells and pancreatic islet cells. RAGE also has a shortened isoform, soluble RAGE (sRAGE) that inhibits cell membranous RAGE signal transduction by competitive binding of RAGE ligands. Changes in RAGE expression are associated with T1D risk and T cells from these at-risk individuals who progress to T1D, have greater RAGE expression, which enhances cytokine production and survival. Increases in circulating RAGE ligands, AGEs, are also an independent risk factors and improve T1D risk prediction in UK population and twin-based studies and impact beta cell function. Blockade of RAGE ligands prediabetes reduces T1D onset in murine models. Single nucleotide polymorphisms in the RAGE gene (AGER) also decrease circulating soluble RAGE (sRAGE) concentrations and increases the risk for T1D. This decline in circulating sRAGE also coincides with the onset of autoimmunity, seen as seropositivity for autoantibodies against islet auto-antigens in at-risk individuals. Targeting T1D using soluble RAGE slows the development of T1D incidence and reprograms the immune system eliciting its effects via T regulatory (Treg) cells. The contribution of AGE-RAGE pathway to T1D and how it may be targeted, forms the basis of this presentation.