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Iron in beta cell function

铁在β细胞功能中的作用

基本信息

批准号：
9296128
负责人：
Elizabeth Ann Leibold
金额：
$ 37.88万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9296128
关键词：
3&apos Untranslated Regions 5&apos Untranslated Regions Beta Cell Binding Blindness Blood Glucose Cell Death Cell Line Cell physiology Cells Complement DNA Damage DNA biosynthesis Defect Development Diabetes Mellitus Elements Endoplasmic Reticulum Ensure Eukaryotic Cell Ferritin Functional disorder Generations Genes Genetic Translation Glucose Glucose Intolerance Goals Growth Hematological Disease Heme Hemoglobin Homeostasis Hormones Human Hyperglycemia Impairment Individual Insulin Iron Iron Regulatory Protein 2 Kidney Failure Knock-out Knockout Mice Lead Messenger RNA Metabolic Diseases Mitochondria Molecular Morphology Mus Neurodegenerative Disorders Non-Insulin-Dependent Diabetes Mellitus Organism Pancreas Pathogenesis Pathway interactions Peripheral Nervous System Diseases Phenotype Post-Transcriptional Regulation Process Proinsulin Proteins RNA Reactive Oxygen Species Respiration Role Secretory Vesicles Signal Transduction Structure of beta Cell of islet Sulfur TFRC gene Tissues Toxic effect Translations Transmission Electron Microscopy Vertebrates Work cardiovascular disorder risk cell growth regulation cofactor disorder risk endoplasmic reticulum stress improved insight insulin secretion iron deficiency iron metabolism islet mitochondrial dysfunction multicatalytic endopeptidase complex novel strategies prevent response stem uptake

项目摘要

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.

抽象的糖尿病的特点是胰腺β细胞无法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充分了解，但知之甚少。已知胰岛素原在胰腺 β 细胞中加工成成熟胰岛素。在人类中，循环升高胰岛素原与胰岛素原加工受损和 2 型糖尿病 (T2D) 的发生有关。我们研究人员发现，小鼠体内铁调节蛋白 2 (Irp2) 基因被定向删除，从而导致细胞内铁含量耗尽，出现高血糖、葡萄糖不耐症和葡萄糖受损刺激胰腺β细胞分泌胰岛素。 Irp2-/- 小鼠的胰腺胰岛素原含量增加，胰岛素含量降低并减少胰岛素分泌，表明细胞内铁失调体内平衡导致 β 细胞中胰岛素原加工缺陷。我们建议细胞内的耗竭 β细胞中的铁会损害线粒体功能和内质网（ER）稳态，导致缺陷胰岛素原加工。我们计划鉴定 Irp2 缺陷型 β 细胞中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。