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 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 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 β-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.

中文翻译：

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鉴定 1 型糖尿病发病机制中的新疾病相关基因和途径：胰腺铁稳态的潜在缺陷。

多种途径导致 1 型糖尿病 (T1D) 的病理生理发展；然而，所涉及的确切机制尚不清楚。我们对 NOD 小鼠的胰岛与年龄匹配的同源 NOD.B10 对照进行差异基因表达分析，以确定可能导致疾病发病机制的基因。在早期炎症过程中，NOD 小鼠中与细胞外基质发育、胰高血糖素和胰岛素信号/分泌相关的新基因发生了变化。在“各自的”胰岛炎期间，编码多种化学感应嗅觉受体的基因的表达上调，而在“破坏性”胰岛炎期间，涉及抗菌防御和铁稳态的基因的表达下调。胰岛炎症减少了编码铁调素的 Hamp 表达。铁调素在 β 细胞中表达，是铁稳态的关键调节剂。我们发现，与 NOD.B10 小鼠相比，12 周龄 NOD 小鼠的胰腺中 Hamp 和铁调素水平较低，而铁水平较高，这表明在“破坏性”发作期间，胰岛中可能会出现铁稳态的丧失。胰岛炎。有趣的是，我们发现 NOD 疾病的严重程度与膳食铁摄入量相关。维持低铁饮食的 NOD 小鼠高血糖发生率较低，而维持高铁饮食的 NOD 小鼠发病较早且发病率较高，这表明高铁暴露与胰腺铁稳态丧失相结合可能会加剧 NOD 疾病。这种机制可以解释高铁暴露与人类患 T1D 风险增加之间的联系。