Pathogenesis of the Metabolic Syndrome

代谢综合征的发病机制

• 批准号: 8391095
• 负责人: W Timothy GARVEY
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391095
• 关键词: 1,2-diacylglycerol; 2,4-thiazolidinedione; Abdomen; Activity Cycles; Address; Adipose tissue; Affect; African American; Amino Acids; Biological Markers; Biopsy; Blood Circulation; Body Composition; Body Weight decreased; Carbohydrates; Carboxylic Acids; Cardiovascular Diseases; Ceramides; Complex; DEXA; Data; Defect; Development; Diet; Diglycerides; Disease; Energy Metabolism; Euglycemic Clamping; European; Fatty Acids; Generations; Glucose; Glucose Clamp; Goals; Grant; Health Care Costs; Heart Diseases; Hormones; Hour; Human; Human Volunteers; Hydroxyl Radical; Hyperinsulinism; Indirect Calorimetry; Individual; Inflammatory; Insulin; Insulin Receptor; Insulin Resistance; Link; Lipid Peroxidation; Lipid Peroxides; Lipids; Measures; Mediating; Medicine; Metabolic; Metabolic syndrome; Metabolism; Mitochondria; Molecular; Muscle; NADH dehydrogenase (ubiquinone); NF-kappa B; NMR Spectroscopy; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pattern; Phosphorylation; Physiological; Pioglitazone; Plasma; Population; Prediabetes syndrome; Process; Protein-Serine-Threonine Kinases; Proteins; Reactive Oxygen Species; Research; Research Design; Resolution; Respiration; Rest; Rodent; Role; Serine; Signal Transduction; Skeletal Muscle; Stress; Technology; Testing; Thiazolidinediones; Tissues; Translational Research; Triglycerides; Urine; Veterans; acylcarnitine; adiponectin; base; cytokine; desensitization; diabetic; glucose metabolism; improved; insulin sensitivity; insulin signaling; intervention effect; lipid metabolism; long chain fatty acid; metabolomics; non-diabetic; novel; novel diagnostics; organic acid; oxidation; prevent; public health relevance; respiratory; response; theories; weight maintenance

DESCRIPTION (provided by applicant): The spectrum of cardiometabolic disease encompasses the Metabolic Syndrome, Pre-diabetes, Type 2 Diabetes (T2DM), and cardiovascular disease, and these diseases are responsible for a huge burden of patient suffering and health care costs among veterans and the US population in general. Insulin resistance at the level of skeletal muscle is central to the underlying pathogenesis of all these disease manifestations. Regarding the mechanism of insulin resistance, the conventional hypothesis is that oxidation of long-chain fatty acids (LCFA) is impaired while availability is increased, and this results in the accumulation of intramyocellular lipid (IMCL) and metabolites of LCFAs such as diacylglycerol, LCFA-CoAs, and ceramides. These latter compounds activate various serine kinases, such as PKC or IKK2 (in association with activation of NF-:B), which then phosphorylate insulin receptor substrate (IRS) molecules resulting in impaired insulin signal transduction. However, our preliminary data point to an alternative or complementary pathophysiological process. The first clue was that IMCL was completely independent of insulin sensitivity in African Americans, while oxidative stress related to lipid peroxidation in muscle was predictive of insulin resistance in both European- and African-Americans. The second clue was provided by metabolomic studies of plasma obtained from normal controls and insulin-resistant patients with T2DM. The metabolomic profile in T2DM was consistent with incomplete oxidation of long-chain fatty acids (LCFA) as evidenced by accumulation of medium chain acylcarnitines, rather than increased LCFAs and accumulation as IMCL triglyceride, together with decreased tri-carboxylic acid (TCA) cycle activity and diminished anaplerosis. Given these observations, we wish to test a novel hypothesis that the abnormal metabolome is the result of intrinsic mitochondrial defects that both impair FA oxidation and generate reactive oxygen species (ROS). Activation of serine kinases is then mediated either directly by medium-chain acylcarnitines and/or by peroxidized lipids generated by mitochondrial ROS that activate inflammatory pathways (e.g., NG-:B). In this proposal, we will test these hypotheses in humans. Normoglycemic insulin sensitive and insulin resistant subjects, and patients with T2DM will be metabolically characterized by hyperinsulinemic clamps, body composition, IMCL, energy expenditure and substrate oxidation rates, and will be studied before and after perturbations that alter insulin sensitivity including short-term very low calorie diet, after stabilization following 10% weight loss, and insulin-sensitizing thiazolidinedione treatment. Metabolomic profiles will be assessed for acylcarnitines, fatty acids, organic acids, amino acids, and LCFA-CoAs in plasma, urine, and in biopsied muscle tissue. In addition, mitochondria isolated from muscle will be functionally studied for substrate oxidation capacity using high resolution respirometry, reactive oxygen species generation, and activity of individual respiratory complexes. Oxidative stress will be measured in muscle by hydroxyl-nonenal and protein carbonyls. The effect of oxidative stress and/or metabolomic analytes to activate inflammatory pathways in muscle leading to serine phosphorylation and desensitization of IRS and insulin signaling will be examined. These studies represent a state-of-the-art application of new metabolomics technologies, combined with molecular studies of mitochondrial function and insulin signaling, in human muscle, and will test new hypotheses regarding the link between abnormal lipid metabolism and insulin resistance. These data will predictably identify new diagnostic biomarkers for insulin resistance and T2DM, and advance our understanding of molecular mechanisms underlying human insulin resistance.

描述(由申请人提供)： 心脏代谢性疾病包括代谢综合征、糖尿病前期、2型糖尿病(T2 DM)和心血管疾病，这些疾病给退伍军人和普通美国人带来了巨大的患者痛苦和医疗费用负担。骨骼肌水平的胰岛素抵抗是所有这些疾病表现的潜在发病机制的核心。关于胰岛素抵抗的机制，传统的假设是长链脂肪酸(LCFA)的氧化受到损害，而可利用性增加，这导致心肌细胞内脂质(IMCL)和LCFA的代谢物如二酰甘油、LCFA-COAS和神经酰胺积累。后一类化合物激活多种丝氨酸激酶，如PKC或IKK2(与核因子-B的激活有关)，然后使胰岛素受体底物(IRS)分子磷酸化，导致胰岛素信号转导受损。然而，我们的初步数据指出了另一种或互补的病理生理过程。第一条线索是，在非裔美国人中，IMCL完全独立于胰岛素敏感性，而与肌肉中脂质过氧化相关的氧化应激在欧洲人和非裔美国人中都预示着胰岛素抵抗。第二条线索来自对正常对照组和胰岛素抵抗2型糖尿病患者血浆的代谢组学研究。T2 DM患者的代谢特征与长链脂肪酸(LCFA)的不完全氧化一致，表现为中链酰基肉碱的积累，而不是LCFA的增加和IMCL甘油三酯的积累，以及三羧酸(TCA)循环活性的降低和停滞的减少。鉴于这些观察，我们希望检验一个新的假说，即异常代谢组是内在线粒体缺陷的结果，线粒体缺陷既损害FA氧化又产生活性氧物种(ROS)。然后，丝氨酸激酶的激活直接由中链酰肉碱和/或由线粒体ROS产生的过氧化脂质来介导，这些过氧化脂质激活了炎症途径(例如NG-：B)。在这项提案中，我们将在人体上测试这些假说。正常血糖的胰岛素敏感和胰岛素抵抗患者以及T2 DM患者将以高胰岛素钳夹、身体成分、IMCL、能量消耗和底物氧化率为代谢特征，并将在改变胰岛素敏感性的扰动前后进行研究，包括短期极低卡路里饮食、减重10%后稳定下来，以及胰岛素增敏性噻唑烷二酮治疗。将对血浆、尿液和肌肉组织中的酰肉碱、脂肪酸、有机酸、氨基酸和LCFA-COAS的代谢谱进行评估。此外，从肌肉中分离的线粒体将使用高分辨率呼吸测量法、活性氧物种的产生和单个呼吸复合体的活性来研究底物氧化能力的功能。肌肉中的氧化应激反应将通过羟基-壬烯醛和蛋白质羰基来测量。氧化应激和/或代谢分析物激活肌肉中的炎症通路，导致丝氨酸磷酸化和IRS和胰岛素信号的脱敏的效果将被检验。这些研究代表了新的代谢组学技术在人类肌肉中的最新应用，结合了线粒体功能和胰岛素信号的分子研究，并将测试关于脂代谢异常与胰岛素抵抗之间联系的新假说。这些数据将可预测地识别新的胰岛素抵抗和T2 DM的诊断生物标志物，并促进我们对人类胰岛素抵抗潜在的分子机制的理解。