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：
10248164
负责人：
Ranganath Muniyappa
金额：
$ 68.2万
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/10248164
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 Research Closure by clamp Coin Collaborations Communities 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 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 clinical center comorbidity design diabetes risk economic impact epidemiology study exome sequencing food marketing genetic testing 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

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.

去年，我们的研究重点是：1）罕见肥胖变异的表型； 2）评估胰岛素敏感性的常用测试的预测价值； 3）不同民族和种族背景的健康志愿者和胰岛素抵抗受试者的肠促胰岛素反应。罕见的肥胖变异目前正在招募患有罕见肥胖变异的患者进行研究，包括德库姆病、多发性对称性脂肪增多症（马德隆病）和严重脂肪水肿。这些是重叠的、异质的病症，最常出现在成年期，并且通常发生在全身性肥胖的情况下。德库姆氏病以脂肪组织疼痛和淋巴水肿而闻名。尽管尚未发现一致的遗传缺陷，但每种疾病都有家族形式。这些患者的临床护理主要是对症治疗，包括切除疼痛的脂肪瘤和治疗淋巴水肿。我们计划利用遗传技术研究这些具有独特表型的患者脂肪中发生改变的途径，并应用全外显子组测序来确定携带这些特征的家族的遗传原因。种族和民族对常用胰岛素敏感性测量的影响非裔美国人非常容易患糖尿病。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/耐受性对于该人群非常重要。在测量人类胰岛素敏感性的许多可用方法中，高胰岛素正常血糖葡萄糖钳夹被广泛接受作为参考方法，因为它直接测量稳态条件下给定胰岛素血症水平下的全身葡萄糖消耗。然而，葡萄糖钳夹是劳动密集型、技术要求高且耗时的，使得其在大型流行病学和临床研究中使用不切实际。因此，从空腹血液胰岛素和葡萄糖浓度衍生出许多简单的胰岛素敏感性/抗性替代指数，例如定量胰岛素敏感性检查指数（QUICKI）、稳态模型评估（HOMA）、1/空腹胰岛素或口服葡萄糖耐量测试已被开发出来。这些替代指数广泛应用于大型临床、流行病学和介入研究中。然而，种族和体重指数可能会影响基于空腹的胰岛素敏感性替代指数的有效性。事实上，最近的研究表明，非洲人后裔的禁食和 OGTT 衍生的胰岛素敏感性指数存在重大局限性。多项仅基于 FSIVGTT 和 OGTT 的研究表明，非洲裔非糖尿病成人和儿童的胰岛素抵抗程度高于欧洲种族。在最近的一项研究中，在健康、非糖尿病的非洲裔美国人中，与 OGTT 并行进行的高胰岛素-正常血糖钳夹试验结果存在差异；而通过高胰岛素-正常血糖钳夹直接测量的葡萄糖处理率在非洲裔美国人和欧洲裔美国人之间是相同的。本研究的具体目的是测量高胰岛素正常血糖钳夹过程中葡萄糖处理所反映的全身胰岛素敏感性，并通过测量空腹肝葡萄糖产生来描绘基础肝脏胰岛素敏感性（在稳态输注氘葡萄糖作为示踪剂 6 后进行评估， 62H2 葡萄糖）。将通过在 FSIVGTT 期间使用伯格曼最小模型在非洲和欧洲血统人群中获得的血浆胰岛素和葡萄糖测量值进行数学建模，将葡萄糖处置与 SI 胰岛素敏感性指数进行比较。同样，该研究调查了西班牙裔和南亚裔的胰岛素敏感性差异。这两个人群患糖尿病的风险都很高。在 IVGTT 和混合膳食耐受测试期间测量胰岛素敏感性和 β 细胞功能。肠促胰素作用肠促胰素效应（胰岛素的肠分泌）一词是为了描述与等血糖静脉注射葡萄糖相比，口服葡萄糖诱导更强烈的胰岛素反应这一观察结果而创造的。胰高血糖素样肽 1 (GLP-1) 和葡萄糖依赖性促胰岛素肽 (GIP) 是响应口服食物摄入而释放的肠道激素，进而刺激胰腺 β 细胞释放胰岛素，从而部分发挥肠促胰岛素作用。由于胰岛对肠促胰岛素激素的反应降低而导致肠促胰岛素作用受损，是血糖异常和胰岛素抵抗状态下早期且经常观察到的异常现象。传统上，肠促胰岛素的作用是使用等血糖钳技术来测量的，其中在测试的第一天给予固定的口服葡萄糖负荷。第二天，静脉注射等血糖葡萄糖以匹配口服葡萄糖负荷期间的血糖测量值。我们的方法采用 1 天的程序，在高血糖钳夹期间给予口服葡萄糖负荷。口服葡萄糖负荷后的胰岛素反应用于计算肠促胰岛素效应。测量非裔美国人和南亚人的肠促胰素作用对于了解胰腺 β 细胞功能的病理生理学以及研究各种干预措施对 β 细胞功能障碍的影响是必要的。