Iron in beta cell function

摘要 糖尿病的特征在于胰腺β细胞不能产生和分泌足够的胰岛素， 满足身体的需要。虽然调节胰岛素分泌的机制已被很好地理解， 已知胰岛素原在胰腺β细胞中加工为成熟胰岛素。在人类中， 胰岛素原与受损的胰岛素原加工和2型糖尿病（T2 D）的发展有关。我们 发现铁调节蛋白2（Irp 2）基因靶向缺失的小鼠， 细胞内铁含量耗尽，发展为高血糖症、葡萄糖耐受不良和葡萄糖受损- 刺激胰腺β细胞的胰岛素分泌。Irp 2-/-小鼠显示胰腺胰岛素原含量增加， 降低胰岛素含量和减少胰岛素分泌，表明细胞内铁的失调， 内稳态导致β细胞中胰岛素原加工的缺陷。我们认为，细胞内 β细胞中的铁损害线粒体功能和内质网（ER）稳态，导致缺陷性 胰岛素原加工我们计划在Irp 2缺陷的β细胞中鉴定这些通路的特定功能变化 这将为β细胞功能障碍的分子机制提供新的见解。

ABSTRACT Diabetes mellitus is characterized by an inability of pancreatic β cells to produce and secrete sufficient insulin to meet the needs of the body. While the mechanisms regulating insulin secretion are well understood, less is known about the processing of proinsulin to mature insulin in pancreatic β cells. In humans, elevated circulating proinsulin is associated with impaired proinsulin processing and the development of type 2 diabetes (T2D). We have discovered that mice with a targeted deletion of the iron regulatory protein 2 (Irp2) gene, which leads to a depletion of intracellular iron content, develop hyperglycemia, glucose intolerance and impaired glucose- stimulated insulin secretion from pancreatic β cells. Irp2-/- mice display increased pancreatic proinsulin content, decreased insulin content and reduced insulin secretion, suggesting that dysregulation of intracellular iron homeostasis causes a defect in proinsulin processing in β cells. We propose that the depletion of intracellular iron in β cells impairs mitochondrial function and endoplasmic reticulum (ER) homeostasis, leading to defective proinsulin processing. We plan to identify specific functional changes in these pathways in Irp2 deficient β cells that will give new insight into molecular mechanisms that can be targeted in β cell dysfunction.