Using Systems Biology to Understand Islet Adaptation and Failure Diabetes

利用系统生物学了解胰岛适应和衰竭型糖尿病

• 批准号: 7303800
• 负责人: CHARLES F BURANT
• 金额: $ 50.8万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7303800
• 关键词: Animal Model; Animals; Arts; Beta Cell; Bioinformatics; Biology; Blood capillaries; Calcium Signaling; Cells; Cellular biology; Characteristics; Citric Acid Cycle; Compatible; Complement; Computing Methodologies; Condition; Coupled; Data; Data Analyses; Development; Diabetes Mellitus; Diet; Dietary Intervention; Electrospray Ionization; Environment; Face; Failure; Fatty Acids; Fatty acid glycerol esters; Female; Gene Expression; Genes; Glucose; Goals; Human; Hyperinsulinism; In Vitro; Individual; Insulin; Insulin Resistance; Investigation; Ions; Islets of Langerhans; Lead; Lipid Peroxidation; Lipids; Liquid Chromatography; Living Donors; Measures; Metabolic Marker; Metabolism; Methods; Mining; Mitochondria; Modeling; Molecular Profiling; Non-Insulin-Dependent Diabetes Mellitus; Nucleotides; Numbers; Nutrient; Organ; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Pathway; Oxygen Consumption; Paper; Pathway interactions; Phase; Phospholipids; Physiological; Play; Population; Property; Proteins; Publishing; RNA; Rattus; Research Personnel; Resistance; Role; Screening procedure; Series; Signal Transduction; Sucrose; System; Systems Biology; Techniques; Testing; Time; Tissues; Translating; Unsaturated Fats; Validation; Work; Zucker Rats; aqueous; capillary; computerized tools; diabetic; feeding; glucose tolerance; human tissue; improved; in vivo; insight; insulin secretion; islet; knowledge base; mass spectrometer; metabolomics; mitochondrial dysfunction; novel; nutrition; oxidation; programs; research study; response; saturated fat; tool; two-dimensional

DESCRIPTION (provided by applicant): The pancreatic islet is a dynamic tissue which can increase insulin secretion in response to increased secretory demand. The adaptation is due to both increased intrisic islet secretory capacity and expansion of beta-cell mass in response to excess nutrition. The development of type 2 diabetes is due to the inability of beta-cells to maintain insulin secretion in the face of prevailing insulin resistance. The complexy underlying biology of islet adaptation and failure is still incompletely understood but lends itself to a global, intradisciplinary approach. In this application we will use both an animal models and human tissue to test our hypothesis that increases in glucose and fatty acid flux to the islet results in anaplerosis which will augment the secretion of insulin in the short term and generate signals that result in longer term adaptation, including expansion of the beta-cell mass. In addition, we propose that in a genetically susceptible islet, specific changes in the metabolome occur, when exposed to a specific nutrient mix, that results in islet failure. In Specific Aim 1 we will examine the temporal effect of a control, diabetogenic and non- diabetogenic high fat/high sucrose diets on physiological parameters of islet function in vivo and in vitro. Initial studies will use islets from female control, Zucker Fatty Rats and Zucker Diabetic Fatty Rats exposed to diabetogenic and non-diabetogenic diets for varying periods of time. In Aim 2, relevant islet metabolites, induding anaplerotic and cataplerotic intermediates, lipid species and oxidative stress markers will be measured under different in vitro conditions to examine the adaptation/maladaptation of the islet following different dietary interventions. In Aim 3, the temporal changes in gene expression profiles under erent dietary conditions will be evaluated and integrated with the metabolomic, lipomic and functional data to using new computational methods to provide a systems overview of the effects of the diets on islet function. In Aim 4, we will translate the techniques and tools that we develop to evaluate the funtion and metabolism of human islets isolated from living donors with known physiological status. The results of these investigation will lead to an integrated understanding of how nutrients interact with genetically resistant and susceptible islets to increase secretion an how adaptation fails leading to diabetes. The studies will also provide the first insights into the ways in which human islets react to specific nutrient challenges.

描述（由申请人提供）：胰岛是一种动态组织，可以响应增加分泌需求而增加胰岛素分泌。适应性是由于响应过量营养而增加的主体胰岛分泌能力和β细胞质量的扩展所致。 2型糖尿病的发展是由于β细胞在面对胰岛素耐药性的情况下无法维持胰岛素分泌。胰岛适应和失败的复杂生物学的复杂生物学仍未完全理解，但可以采用一种全球的内部学科方法。在此应用中，我们将同时使用动物模型和人体组织来测试我们的假设，该假设增加了葡萄糖和脂肪酸通量到胰岛的增加导致卵巢症会导致短期分泌，这将在短期内增加胰岛素的分泌并产生信号，从而导致更长的适应性，包括β细胞质量的扩展。此外，我们建议在遗传易感的小岛中，代谢组的特异性变化（暴露于特定的营养混合物）会导致胰岛失败。在特定目标1中，我们将检查对照，糖尿病和非糖尿病性高脂肪/高蔗糖饮食对体内和体外胰岛功能的生理参数的时间影响。最初的研究将使用女性控制，Zucker Fatty大鼠和Zucker糖尿病脂肪大鼠的胰岛胰岛，这些大鼠在不同的时间内暴露于糖尿病生成和非糖尿病饮食。在AIM 2中，相关的胰岛代谢产物，依从性疾病和催化的中间体，脂质物种和氧化应激标志物将在不同的体外条件下测量，以检查不同饮食干预后胰岛的适应/疾病。在AIM 3中，将评估基因表达谱的时间变化，并与代谢组，脂肪组和功能数据进行评估，并使用新的计算方法来提供饮食对胰岛功能影响的系统概述。在AIM 4中，我们将翻译我们开发的技术和工具，以评估与具有已知生理状态的活体捐助者分离的人类胰岛的功能和代谢。这些研究的结果将导致人们对养分如何与遗传耐药性和易感胰岛相互作用以增加分泌的综合理解，以增加适应性失败的失败。这些研究还将为人类胰岛对特定养分挑战做出反应的方式提供首次见解。