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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.

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。