Functional Genomics Analysis of Islets from Recent and Longstanding T1D Reveals the Need for Distinct Approaches to Therapy

Our current understanding of the pathogenesis of T1D arose in large part from studies using the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D). Of concern, therapeutic interventions shown to significantly dampen or even reverse disease in mouse models have not successfully translated into interventions in human T1D. The present study addresses this disconnect in research translation by directly analyzing human donor islets from individuals with T1D, aiming to provide insight into disease mechanisms and identify potential target pathways for therapeutic intervention. We obtained human islets from a young individual with short-duration T1D, an older individual with long-duration T1D and three non-diabetic donors, and performed unbiased functional genomic analysis by high depth RNA sequencing on these unique cases. This analysis identified several inflammatory pathways upregulated in short-duration disease, which surprisingly included many components of innate immunity. Subsequent manipulation of one of these pathways/factors in NOD mice resulted in a significant reduction in diabetes progression when inhibition occurred early in disease progression. Taken together our data demonstrates that the direct analysis of human islets is essential for identifying relevant and promising novel targets for translation into effective therapeutic interventions for human T1D. 5 human islets of Langerrhans preparations. 3 in normo-glycemic individual, one individual with a long duration type 1 diabetes and one individual with short duration type 1 diabetes