权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of Fatty Acid Oxidation Defects in Insulin Sensitivity

脂肪酸氧化缺陷在胰岛素敏感性中的作用

基本信息

批准号：
8883308
负责人：
Melanie B Gillingham
金额：
$ 67.99万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-27 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8883308
关键词：
3-Hydroxyacyl-CoA dehydrogenase Address Adipose tissue Age Amino Acids Animal Model Appearance Biopsy Biopsy Specimen Blood Control Groups Cross-Over Studies Defect Deposition Development Diet Dietary Fats Disease Enzymes Etiology Euglycemic Clamping Exhibits Fasting Fat emulsion Fatty Acids Fatty acid glycerol esters Glucose Glucose Clamp Glycerol Goals Hepatic Human Infusion procedures Inherited Insulin Insulin Resistance Insulin Signaling Pathway Intake Intracellular Accumulation of Lipids Lipids Liver Magnetic Resonance Spectroscopy Measurement Measures Mediating Mediator of activation protein Medium chain fatty acid Metabolic Metabolic Pathway Methodology Mitochondria Mitochondrial Diseases Muscle Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Outcome Oxidoreductase Pathway interactions Patients Pharmacologic Substance Play Protein Deficiency Proteins Randomized Recruitment Activity Regulation Research Design Role Saline Skeletal Muscle Solutions Study Subject Testing Tissues Very Long Chain Fatty Acid Visit acyl-CoA dehydrogenase amino acid metabolism fatty acid metabolism fatty acid oxidation glucose disposal glucose metabolism glucose production insulin sensitivity insulin signaling lipid metabolism long chain fatty acid metabolomics mitochondrial dysfunction novel novel strategies organic acid oxidation patient population prevent public health relevance sex uptake

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial dysfunction has been implicated in the etiology and expression of insulin resistance and type 2 diabetes in animal models and humans under conditions of high fat loads either from the diet, endogenous release by adipose tissue, or both. However, controversy exists as to whether insulin resistance under these conditions results from intrinsic defects in mitochondrial energy utilization or abnormalities in free fatty aid (FFA) flux and amino acid metabolism, including the potential role of accumulated metabolic intermediates to impair insulin signaling. To address these controversies, we propose two aims that will formally test the hypothesis that intrinsic defects in mitochondrial function involving long-chain, but not medium-chain, FAO will prevent intralipid-induced insulin resistance using advanced metabolomics methodology in combination with hyperinsulinemic-euglycemic clamps and analyses of insulin signaling in muscle and fat biopsies. Study subjects will be recruited from a unique population of patients with inherited defects in one of three mitochondrial enzymes in the fatty acid oxidation pathway (FAO), including oxidation of long-chain fatty acids (very long-chain acylCoA dehydrogenase (VLCAD), or trifunctional protein (TFP), including long-chain 3-hydroxy acylCoA dehydrogenase (LCHAD) deficiencies), and, finally, medium-chain fatty acids (medium-chain acyl CoA dehydrogenase, or MCAD). These patients and age, sex, and BMI-matched healthy controls will undergo testing on separate visit study dates during which they receive co-infusions of either intralipid, shown to induce ectopic lipid accumulation and insulin resistance in previous studies, or a control infusion of glycerol and saline. These detailed studies in patients with FAO disorders compared to controls will give us a unique opportunity to better understand the interface between fatty acid metabolism and regulation of insulin sensitivity in humans. Not only will these studies address current controversies and gaps in our understanding in this field, but by including measurements of both cellular and systemic metabolomics, they may also help inform on-going development of potential pharmaceutical targets for the treatment of insulin resistance and type 2 diabetes.