Multiple pathways contribute to the pathophysiological development of type 1 diabetes (T1D), however, the exact mechanisms involved are unclear. We performed differential gene expression analysis in pancreatic islets of non-obese diabetic (NOD) mice versus age-matched congenic NOD.B10 controls to identify genes that may contribute to disease pathogenesis. Novel genes related to extracellular matrix development and glucagon and insulin signaling/secretion were changed in NOD mice during early inflammation. During “respective” insulitis, the expression of genes encoding multiple chemosensory olfactory receptors genes were upregulated, and during “destructive” insulitis, the expression of genes involved in antimicrobial defense and iron homeostasis were downregulated. Islet inflammation reduced the expression of Hamp that encodes hepcidin. Hepcidin is expressed in beta cells and serves as the key regulator of iron homeostasis. We showed that Hamp and hepcidin levels were lower, while iron levels were higher in the pancreas of 12-week old NOD versus NOD.B10 mice, suggesting that a loss of iron homeostasis may occur in the islets during the onset of “destructive” insulitis. Interestingly, we showed that the severity of NOD disease correlates with dietary iron intake. NOD mice maintained on low iron diets had a lower incidence of hyperglycemia while those maintained on high iron diets had an earlier onset and higher incidence of disease, suggesting that high iron exposure combined with a loss of pancreatic iron homeostasis may exacerbate NOD disease. This mechanism may explain the link seen between high iron exposure and the increased risk for T1D in humans.

This article contains supplementary material online at https://doi.org/10.2337/figshare.19607322.

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