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Mechanisms of cadmium-induced dysglycemia

镉诱发血糖异常的机制

基本信息

批准号：
9377975
负责人：
Joshua Edwards
金额：
$ 44.67万
依托单位：
MIDWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9377975
关键词：
Address Agonist Animal Model Animals Antibodies Antioxidants Apoptosis Apoptotic Beta Cell Binding Biological Assay Blood Glucose Cadmium Calcium Calcium Channel Calcium Channel Blockers Carcinogens Caspase Cell Adhesion Molecules Cell Death Cell Line Cell physiology Cell-Cell Adhesion Cells Chronic Data Development Diabetes Mellitus Divalent Cations Dose E-Cadherin Energy Metabolism Environmental Pollutants Environmental Pollution Epithelial Cells Extracellular Domain Female Fluorescence Fluorescent Probes Functional disorder Gene Expression Glucose Glutathione Disulfide Goals Hazardous Substances Human Impairment In Vitro Individual Industrial Waste Injury Insulin Islets of Langerhans Kidney Knowledge Label Lactate Dehydrogenase Liver Mediating Mediator of activation protein Microscopy Modeling Necrosis Neurons Non-Insulin-Dependent Diabetes Mellitus Occupational Exposure Oxidative Stress Pathogenesis Patients Play Poisoning Population Prediabetes syndrome Preparation Process Production Publishing RNA Interference Rattus Reporting Role Serum Small Interfering RNA Structure of beta Cell of islet Testing Time Zinc base beta catenin biological adaptation to stress bone cell type cellular targeting cytotoxic diabetic diabetogenic epidemiology study experimental study fluorophore glutathione peroxidase heme oxygenase-1 imaging study in vivo inhibitor/antagonist insulin secretion islet live cell imaging male protein expression response superoxide dismutase 1 urinary voltage

项目摘要

Project Summary/Abstract Cadmium (Cd) is a ubiquitous environmental and industrial pollutant that currently ranks seventh on the US EPA/ATSDR Priority List of Hazardous Substances and is a known human carcinogen that causes kidney, liver and bone damage. Cd is associated with diabetes mellitus (DM) and prediabetes in epidemiological and experimental studies. In a study of the US population, 25% of individuals that were diabetic or prediabetic had elevated urinary Cd levels. It is unknown how Cd disrupts blood glucose levels. However, Cd exposure is associated with low serum insulin levels in individuals with occupational exposure and Cd has been shown to impair glucose-stimulated insulin secretion in animal studies. For a large subsection of patients with DM impaired glucose-stimulated insulin, secretion occurs in the progression of type II DM. The overall aim of the proposed project is to determine the mechanism by which Cd causes impaired glucose-stimulated insulin release. Normal insulin secretion and pancreatic β-cell function are dependent upon cell-cell adhesion; especially important is the role of the calcium-dependent cell adhesion molecule, E-cadherin. Cd has been shown to disrupt E-cadherin mediated cell-cell adhesion in the kidney. Initial studies will establish a range of doses and duration of exposure of Cd that result in necrotic and/or apoptotic cell death in isolated islets and the pancreatic β-cell line, MIN6. Subsequent studies will be determined if impaired glucose-stimulated insulin release is a response to a generalized Cd-induced oxidative stress response or altered energy status (ADP/ATP) at doses and durations of exposure below those that cause cell death. Live cell imaging studies will be utilized with sensitive fluorophores to detect changes in the production of mediators of oxidative stress. Studies outlined in Aim two will determine the ability of Cd to cause loss of E-cadherin mediated cell-cell adhesion in relation to glucose- stimulated insulin release in isolated islets and the MIN6 cell line. Additional studies will examine the effects of E-cadherin antibodies that bind to the extracellular domain and siRNA of E-cadherin to experimentally disrupt cell-cell adhesion to determine if there are synergistic effects of Cd on inhibiting glucose-stimulated insulin release. Aim three will determine if Cd causes voltage-gated calcium channel blockade resulting in subsequent impaired glucose-stimulated insulin release in isolated islets and MIN6 cells. Additional studies will determine if there are synergistic effects of Cd to impair glucose-stimulated insulin release in the presence or absence of the L-type voltage-gated calcium channel blockers. Also, live cell imaging will be utilized with fluorophores that selectively detect changes of intracellular Cd, zinc or calcium. In Aims two and three, in vivo studies using a well-characterized model of long term Cd poisoning will be used to verify the in vitro findings. Overall, these studies will identify the mechanism of the diabetogenic effects of Cd, a widespread environmental contaminant that is associated with DM and prediabetes.

项目总结/摘要镉（Cd）是一种普遍存在的环境和工业污染物，目前在美国排名第七 EPA/ATSDR危险物质优先清单，是一种已知的人类致癌物质，可导致肾脏、肝脏和骨骼损伤。镉与糖尿病（DM）和糖尿病前期有关，实验研究在一项对美国人群的研究中，25%的糖尿病或糖尿病前期患者尿镉水平升高。目前尚不清楚镉如何破坏血糖水平。然而，镉暴露是与职业接触者血清胰岛素水平低有关，在动物研究中损害葡萄糖刺激胰岛素分泌。对于大部分DM受损患者，葡萄糖刺激的胰岛素分泌发生在II型DM的进展中。建议的总体目标项目是确定镉导致葡萄糖刺激胰岛素释放受损的机制。正常胰岛素分泌和胰腺β细胞功能依赖于细胞-细胞粘附;特别重要的是，钙依赖性细胞粘附分子E-cadherin的作用。镉已被证明破坏E-钙粘蛋白介导的细胞间粘附。初步研究将确定一系列剂量和暴露持续时间镉导致分离的胰岛和胰腺β细胞系MIN 6的坏死和/或凋亡性细胞死亡。随后的研究将确定葡萄糖刺激的胰岛素释放受损是否是对胰岛素抵抗的反应。剂量和持续时间下的全身性Cd诱导的氧化应激反应或能量状态改变（ADP/ATP）低于导致细胞死亡的水平。活细胞成像研究将使用敏感的荧光团来检测氧化应激介质产生的变化。目标二中概述的研究将决定镉引起与葡萄糖相关的E-钙粘蛋白介导的细胞-细胞粘附丧失的能力，在分离的胰岛和MIN 6细胞系中刺激胰岛素释放。更多的研究将检查 E-钙粘蛋白抗体结合E-钙粘蛋白的细胞外结构域和siRNA，以实验性地破坏细胞-细胞粘附，以确定是否存在镉对抑制葡萄糖刺激的胰岛素的协同作用 release.目的三将确定镉是否引起电压门控钙通道阻滞，导致随后的在分离的胰岛和MIN 6细胞中葡萄糖刺激的胰岛素释放受损。进一步的研究将确定，在存在或不存在镉的情况下，镉对葡萄糖刺激的胰岛素释放有协同作用， L型电压门控钙通道阻滞剂。此外，活细胞成像将与荧光团一起使用，选择性检测细胞内镉、锌或钙的变化。在目的二和三中，使用长期镉中毒的良好表征模型将用于验证体外结果。总的来说，这些研究将确定镉（一种广泛存在的环境污染物）致糖尿病效应的机制与糖尿病和前驱糖尿病相关的疾病