Biobehavioral Studies of Obesity, Weight loss and Recidivism

肥胖、减肥和累犯的生物行为研究

基本信息

批准号：
10001929
负责人：
Ranganath Muniyappa
金额：
$ 4.96万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10001929
关键词：
Address Adipocytes Adipose tissue Adiposis Dolorosa Adult Affect African African American American Behavioral Beta Cell Blood Blood Glucose Blood specimen Body Composition Body Weight Body Weight decreased Cell physiology Child Chronic Clinical Clinical Research Closure by clamp Coin Collaborations Communities Comorbidity Consumption Degenerative polyarthritis Deuterium Development Diabetes Mellitus Eating Eating Behavior Economics Education Energy Metabolism Enrollment Ethnic Origin European Evaluation Excision Family Fasting Fatty acid glycerol esters Fostering Functional disorder Gastric Inhibitory Polypeptide Gene Expression Genetic Genetic Techniques Genetic screening method Glucose Glucose Clamp Health Heart Diseases Hepatic Hispanics Homeostasis Human Hyperglycemia Hypertension Impairment Individual Inflammation Infusion procedures Insulin Insulin Resistance Intervention Intervention Studies Intestinal Hormones Intestinal Secretions Intravenous Life Expectancy Lipoma Liver diseases Lymphedema Madelung Neck Magnetic Resonance Spectroscopy Malignant Neoplasms Measurement Measures Mental Depression Metabolic Metabolism Methodology Methods Modeling Multiple Symmetrical Lipomatosis Muscle Mutation Natural History Non-Insulin-Dependent Diabetes Mellitus OGTT Obesity Oral Overweight Pain Pathway interactions Patient Care Patients Phenotype Physical activity Plasma Policies Population Prediabetes syndrome Predictive Value Predisposing Factor Procedures Protocols documentation Public Opinion Race Relapse Reporting Research Resources Risk Factors Sleep Apnea Syndromes South Asian Specimen Stroke Structure of beta Cell of islet Techniques Testing Time Tissue Sample Tracer United States United States National Institutes of Health Urinary Incontinence Urine Variant Weight adult obesity base biobank biobehavior cardiovascular health clinical care design diabetes risk economic impact epidemiology study exome sequencing food marketing glucagon-like peptide 1 glucose disposal glucose production healthy volunteer high risk improved incretin hormone indexing insulin secretion insulin sensitivity insulin sensitivity/resistance intravenous glucose tolerance test islet mathematical model multidisciplinary non-diabetic patient oriented research racial and ethnic recidivism recruit response stable isotope trait translational study volunteer

Address Adipocytes Adipose tissue Adiposis Dolorosa Adult Affect African African American American Behavioral Beta Cell Blood Blood Glucose Blood specimen Body Composition Body Weight Body Weight decreased Cell physiology Child Chronic Clinical Clinical Research Closure by clamp Coin Collaborations Communities Comorbidity Consumption Degenerative polyarthritis Deuterium Development Diabetes Mellitus Eating Eating Behavior Economics Education Energy Metabolism Enrollment Ethnic Origin European Evaluation Excision Family Fasting Fatty acid glycerol esters Fostering Functional disorder Gastric Inhibitory Polypeptide Gene Expression Genetic Genetic Techniques Genetic screening method Glucose Glucose Clamp Health Heart Diseases Hepatic Hispanics Homeostasis Human Hyperglycemia Hypertension Impairment Individual Inflammation Infusion procedures Insulin Insulin Resistance Intervention Intervention Studies Intestinal Hormones Intestinal Secretions Intravenous Life Expectancy Lipoma Liver diseases Lymphedema Madelung Neck Magnetic Resonance Spectroscopy Malignant Neoplasms Measurement Measures Mental Depression Metabolic Metabolism Methodology Methods Modeling Multiple Symmetrical Lipomatosis Muscle Mutation Natural History Non-Insulin-Dependent Diabetes Mellitus OGTT Obesity Oral Overweight Pain Pathway interactions Patient Care Patients Phenotype Physical activity Plasma Policies Population Prediabetes syndrome Predictive Value Predisposing Factor Procedures Protocols documentation Public Opinion Race Relapse Reporting Research Resources Risk Factors Sleep Apnea Syndromes South Asian Specimen Stroke Structure of beta Cell of islet Techniques Testing Time Tissue Sample Tracer United States United States National Institutes of Health Urinary Incontinence Urine Variant Weight adult obesity base biobank biobehavior cardiovascular health clinical care design diabetes risk economic impact epidemiology study exome sequencing food marketing glucagon-like peptide 1 glucose disposal glucose production healthy volunteer high risk improved incretin hormone indexing insulin secretion insulin sensitivity insulin sensitivity/resistance intravenous glucose tolerance test islet mathematical model multidisciplinary non-diabetic patient oriented research racial and ethnic recidivism recruit response stable isotope trait translational study volunteer

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项目摘要

In the last year, we have focused our study on 1)the phenotype of rare obesity variants; 2)the predictive value of commonly used tests to assess insulin sensitivity; and 3)the incretin response in healthy volunteers and insulin resistant subjects over different ethnic and racial backgrounds. Rare Obesity Variants Patients with rare obesity variants including Dercum's disease, multiple symmetric lipomatosis (Madelungs disease) and severe lipedema are currently being recruited for study. These are overlapping, heterogeneous conditions that most often manifest in adulthood and usually occur in the setting of generalized obesity. Dercum's disease is notable for painful adipose tissue and lymphedema. There are familial forms of each of these conditions although no consistent genetic defect has been found. Clinical care for these patients has been largely symptomatic including excision of painful lipomas and treatment of lymphedema. Using genetic techniques, we plan to study the pathways that are modified in the fat of these patients with unique phenotypes and apply whole exome sequencing to determine the genetic cause in families that carry these traits. Impact of Race and Ethnicity on Commonly Used Measurements of Insulin Sensitivity African Americans are highly prone to develop diabetes. It is widely accepted that insulin resistance is a major predisposing factor. Consequently, accurately quantifying insulin sensitivity/resistance is important in this population. Among the many available methods for measuring insulin sensitivity in humans, the hyperinsulinemic euglycemic glucose clamp is widely accepted as the reference method because it directly measures whole body glucose disposal at a given level of insulinemia under steady-state conditions. However, the glucose clamp is labor intensive, technically demanding, and time consuming, making it impractical for use in large epidemiological and clinical studies. As a consequence, a number of simple surrogate indices of insulin sensitivity/resistance derived from fasting blood insulin and glucose concentrations e.g., quantitative insulin sensitivity check index (QUICKI), homeostasis model assessment (HOMA), 1/fasting insulin or oral glucose tolerance tests have been developed. These surrogate indices are extensively employed in large clinical, epidemiological, and interventional studies. However, ethnicity and BMI may affect validity of fasting-based surrogate indices of insulin sensitivity. In fact, recent studies suggest major limitations in fasting and OGTT-derived indices of insulin sensitivity in individuals of African descent. Multiple studies, solely on the basis of FSIVGTT and OGTT, have reported higher insulin resistance in non-diabetic adults and children of African heritage than those of a European-based ethnicity. In a recent study, a hyperinsulinemic-euglycemic clamp done in parallel with OGTT was discrepant in healthy, non-diabetic African Americans; whereas direct measurement of glucose disposal rate by hyperinsulemic-euglycemic clamp was identical between the African- and European-American. The specific aim of this study is to measure total body insulin sensitivity as reflected by glucose disposal during hyperinsulinemic-euglycemic clamp and to delineate basal hepatic insulin sensitivity by measuring fasting hepatic glucose production (assessed after a steady state infusion of deuterium glucose as tracer 6,62H2 glucose). The glucose disposal will be compared to the SI insulin sensitivity index by mathematical modeling of plasma insulin and glucose measurements obtained during FSIVGTT using the Bergman minimal model among people of African and European descent. Similarly, the study investigated differences in insulin sensitivity in Hispanics and South Asians. Both these populations have high risk for developing diabetes. Insulin sensitivity and beta cell function was measured during IVGTT and mixed meal tolerance tests. Incretin effect The term incretin effect (INtestinal seCRETion of INsulin) was coined to describe the observation that oral glucose administration induces a more robust insulin response when compared to an isoglycemic intravenous glucose infusion. Glucagon like peptide 1(GLP-1) and Glucose dependent Insulinotropic peptide (GIP) are intestinal hormones released in response to oral food intake which in turn stimulate pancreatic beta-cells to release insulin and thus are responsible for part of the incretin effect. Impaired incretin effect due to reduced islet responses to the incretin hormones, is an early and frequently observed abnormality in dysglycemic and insulin resistant states. Traditionally, incretin effect has been measured using an isoglycemic clamp technique where a fixed oral glucose load is given on first day of testing. On the second day, isoglycemic intravenous glucose is infused to match the blood glucose measurements during the oral glucose load. Our approach uses a 1-day procedure by giving an oral glucose load during a hyperglycemic clamp. Insulin response after the oral glucose load is used to calculate the incretin effect. Measuring incretin effect in African Americans and South Asians is necessary to understand the pathophysiology of pancreatic beta cell function and to study the effects of various interventions on beta-cell dysfunction.

在去年，我们将研究重点放在1）稀有肥胖变体的表型上； 2）常用测试的预测值以评估胰岛素敏感性； 3）在不同种族和种族背景下，健康志愿者和胰岛素耐药受试者的肠降血凝素反应。罕见的肥胖变体目前正在招募患有少量肥胖变异的患者，包括双尾病，多发性脂肪瘤病（Madelungs病）和严重的脂肪EMATE。这些是重叠的异质条件，通常在成年中表现出来，通常发生在广义肥胖的情况下。 Dercum氏病在疼痛的脂肪组织和淋巴水肿方面值得注意。尽管未发现一致的遗传缺陷，但每种情况都有家族形式。这些患者的临床护理在很大程度上是有症状的，包括切除疼痛脂肪瘤和治疗淋巴水肿。使用遗传技术，我们计划研究这些具有独特表型的患者脂肪中修饰的途径，并应用整个外显子组测序以确定携带这些特征的家族的遗传原因。种族和种族对胰岛素敏感性常用测量的影响非裔美国人很容易发生糖尿病。人们普遍认为，胰岛素抵抗是主要的诱发因素。因此，准确量化胰岛素敏感性/抗性在该人群中很重要。在测量人类胰岛素敏感性的许多可用方法中，高胰岛素血糖葡萄糖夹被广泛接受为参考方法，因为它在稳态条件下直接测量给定胰岛素血症的全身葡萄糖处置。但是，葡萄糖夹是劳动密集型，技术要求和耗时的，使其不切实际地用于大型流行病学和临床研究。结果，许多简单的替代液位的胰岛素敏感性/抗药性/抗药性是由禁食血液胰岛素和葡萄糖浓度得出的，例如定量胰岛素敏感性检查指数（QUICKI），稳态模型评估（HOMA），1/1/斋戒胰岛素或口服胰岛素耐受性耐受性测试已开发出来。这些替代指数广泛用于大型临床，流行病学和介入研究。但是，种族和BMI可能会影响胰岛素敏感性的基于禁食的替代指标的有效性。实际上，最近的研究表明，非洲血统个体中禁食和OGTT衍生的胰岛素敏感性指标的主要局限性。仅基于FSIVGTT和OGTT的多项研究，与欧洲种族相比，非糖尿病成年人和非洲遗产的儿童的胰岛素抵抗性更高。在最近的一项研究中，与OGTT并行进行的高胰岛素血糖夹在健康的非糖尿病非裔美国人中是不差异的。非洲裔美国人和欧洲裔美国人之间通过高渗血性糖夹的直接测量葡萄糖处置率是相同的。这项研究的具体目的是测量体内胰岛素全体胰岛素敏感性，如高胰岛素血糖夹夹期间的葡萄糖处置所反映的，并通过测量禁食肝葡萄糖的产生来描述基础肝胰岛素敏感性（在稳定的葡萄糖稳定输注后，评估了葡萄糖作为诱导蛋白的诱导剂6,62 glucose tracer 6,62 glucose theute state Intection Insection Intece Intece state Intate Intufusion。通过使用非洲和欧洲血统中的伯格曼最小模型，通过对FSIVGTT获得的血浆胰岛素和葡萄糖测量的数学模型，将葡萄糖处置与SI胰岛素灵敏度指数进行比较。同样，该研究研究了西班牙裔和南亚人中胰岛素敏感性的差异。这两个人群患糖尿病的风险很高。在IVGTT和混合膳食耐受性测试期间测量了胰岛素敏感性和β细胞功能。泌尿素效应创造了统一的肠降直直染素作用（胰岛素的肠分泌），以描述与等渗静脉内葡萄糖输注相比，口服葡萄糖给药会诱导更健壮的胰岛素反应。胰高血糖素（例如肽1（GLP-1）和葡萄糖依赖性胰岛素肽（GIP）是对口服食物摄入响应释放的肠道激素，进而刺激胰腺β细胞释放胰岛素，从而释放胰岛素，从而造成肠蛋白作用的一部分。由于胰岛激素的胰岛反应减少而导致的降直降蛋白作用受损，是早期且经常观察到的异常异常，在血糖和胰岛素抵抗状态下。传统上，肠降凝蛋白效应是使用均质性夹具技术测量的，该技术在测试的第一天给出了固定的口服葡萄糖负荷。在第二天，在口服葡萄糖负荷过程中注入异体血糖静脉注射葡萄糖以匹配血糖测量。我们的方法通过在高血糖夹期间给出口服葡萄糖负荷来使用1天的手术。口服葡萄糖载荷后的胰岛素反应用于计算肠降血糖素效应。对于了解胰腺β细胞功能的病理生理学，必须测量非洲裔美国人和南亚人的肠静脉效应，并研究各种干预措施对β细胞功能障碍的影响。