Risk Factors and Etiology of Obesity and Type 2 Diabetes

肥胖和 2 型糖尿病的危险因素和病因

• 批准号: 9356171
• 负责人: Jonathan Krakoff
• 金额: $ 14.21万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 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/9356171
• 关键词: 10 year old; Accounting; Adult; Affect; Age; Alleles; Antibodies; Arousal; Autoimmunity; Biopsy; Body Size; Body Weight; Body Weight Changes; Body mass index; Brain-Derived Neurotrophic Factor; Child; Childhood; Cross-Sectional Studies; Data; Development; Diabetes Mellitus; Eating; Energy Metabolism; Etiology; Fasting; Fatty acid glycerol esters; Food Energy; Frequencies; Genes; Genetic; Glucose; Goals; Gold; HLA-DRB1; Haplotypes; Hepatic; Hour; Human; Hyperphagia; Individual; Insulin; Investigation; Length; Life; Longitudinal Studies; Macronutrients Nutrition; Measurement; Measures; Mediating; Mediator of activation protein; Melanocortin 4 Receptor; Metabolic; Muscle; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obesity; PPARG gene; Pharmaceutical Preparations; Pilot Projects; Pima Indian; Promoter Regions; Proteins; Receptor Gene; Rest; Risk Factors; Role; Serum; Signal Transduction; Single Nucleotide Polymorphism; Structure of beta Cell of islet; System; T-Cell Receptor; T-Cell Receptor Genes; Testing; Thermogenesis; Time; Visit; Weight; Weight Gain; Work; adipocyte differentiation; awake; base; blood glucose regulation; cohort; cost; diabetes risk; diabetic; fasting plasma glucose; feeding; follow-up; glucose production; glucose uptake; insulin secretion; metabolic rate; novel; respiratory; sex

Decreased insulin action, impaired insulin secretion and increased adiposity are important risk factors for development of type 2 diabetes. These risk factors are present even when individuals have both normal fasting and two hour glucose concentrations indicating a very early role for decreased insulin secretion in the development of type 2 diabetes. In previous work we found that a bimodally expressed gene in muscle tissue, HLA-DRB1, was associated with lower risk for diabetes and higher insulin secretion in Pima Indians. As this protective HLA haplotype system indicates involvement of autoimmunity in progression to type 2 diabetes in Pima Indians we performed a pilot study in individuals with and without the HLA-DRB1 locus who were also discordant for diabetes status, examining both immunoprofiling of over 9,000 potential proteins and T-cell receptor genes. From among those 9,000 proteins study we selected 80 antibodies with significantly increased concentrations in those with diabetes and tested these in a larger cohort of 45 individuals with diabetes and lacking HLA-DRB1 and 45 individuals with normal glucose regulation with the HLA-DRB1 allele. These individuals were matched for age and sex. Of the selected proteins, 11 again had higher signals in those with diabetes. One of the identified antibodies was to PPARG, a nuclear receptor involved in adipocyte differentiation and a target of anti-diabetic medications. We have selected these 11 antibodies plus three additional proteins to test as possible antibodies that are markers of autoimmunity in 450 individuals with type 2 diabetes and 450 who have normal glucose regulations. Preliminary analysis indicates that 2 of these antibodies have a higher signal in individuals with diabetes regardless of LHLA-DRB1 status. We also sequenced the complementary defining region 3 (CDR3) in the T cell receptor in these same individuals. We found that several genes which combine to define the CDR3 region differed significantly in frequency between those with and without diabetes and we found that the length of the CDR3 region is shorter in those with diabetes. We then sequenced CDR3 regions in a larger number of individuals without the protective HLA haplotype and normal glucose regulation at the time of the visit who also have measures of insulin action and secretion. In this larger co-hort we confirmed that one of the genes more frequent in those with diabetes (V gene 7-8) in the initial cohort predicted development of diabetes, as did shorter CDR3 length. Previous predictors of weight gain based on this study have included, higher respiratory quotient, higher insulin mediated glucose uptake, lower free T3, and relatively lower energy expenditure. Variability in energy expenditure is a mediator of weight change, and we have continued to evaluate factors related to metabolic rate. We had previously confirmed this association between lower energy expenditure relative to body size as a predictor of weight gain in a larger cohort with longer follow-up. Furthermore, we were able to demonstrate that lower energy expenditure also predicted gain in fat mass. In a different analysis of weight trajectories in adulthood, we were also able to demonstrate a weight stable group had relatively higher 24 hour energy expenditure compared to all the groups who gained weight, regardless of starting weight. Using resting energy expenditure measured at 5 and 10 years of age, we were also able to demonstrate that relatively lower resting energy expenditure at age 10 (but not at age 5) predicted greater weight gain indicating an effect of metabolic rate on weight in childhood. The thermic effect of food and the energy cost of arousal are overlapping and difficult to measure components of energy expenditure. By examining time point data from our metabolic chambers, we were able to estimate these components (which we termed awake fed thermogenesis (AFT)) which accounted for approximately 10% of total energy expenditure. We found that lower AFT predicted weight gain, but only in individuals with BMI 29 kg/m. This indicates that increased insulation associated with adiposity leads to lower cost of metabolizing macronutrients. As individuals gain weight, their energy expenditure increases more than would be expected based on their increased weight. We have found that increased fasting plasma glucose which may be a marker for increase hepatic glucose production explains part of the large than expected increased EE, and predicted less weight gain. Genetic factors underlie adiposity and its risk factors. Mutations in the melanocortin 4 receptor gene are associated with increased body mass index and lower 24 hour energy expenditure in humans. Individuals with MC4R mutations have accelerated weight gain in childhood but not in adulthood indicating a more potent effect of this mutation in early life. Furthermore, we found that presence of MC4R mutations predicted development of diabetes in childhood independent of body weight. In an analysis of weight gain trajectories in childhood we have confirmed that children with MC4R mutations cluster into the highest weight gain trajectory. The mechanism by which MC4R leads to hyperphagia and weight gain is not clear. One possible mediator is brain derived neurotrophic factor (BDNF) a downstream effector of MC4R signaling which has been implicated in childhood hyperphagia and weight gain. However, serum BDNF did not differ between individuals with and without MC4R mutations. Recently a more common single nucleotide polymorphism (SNP) has been identified that is associated with increased BMI in Pima Indians. This common SNP is near the promoter region and is also associated with lower energy expenditure and increased ad libitum food intake.

胰岛素作用减少，胰岛素分泌受损和肥胖增加是2型糖尿病发展的重要危险因素。 即使个体同时禁食和两个小时的葡萄糖浓度，也存在这些危险因素，这表明胰岛素分泌在2型糖尿病的发展中的作用非常早。 在先前的工作中，我们发现肌肉组织中的双峰表达基因HLA-DRB1与PIMA印第安人的糖尿病风险较低和较高的胰岛素分泌有关。由于这种保护性HLA单倍型系统表明自身免疫性参与PIMA印第安人的2型糖尿病，因此在患有和没有HLA-DRB1基因座的个体中进行了一项试验研究，这些人对糖尿病的状态也不一致，他们对9,000多个潜在的蛋白质和T-Cell受体基因进行了免疫促进剂的影响。从这9,000种蛋白质研究中，我们选择了80种糖尿病患者浓度显着升高的抗体，并在45个糖尿病患者的较大队列中对其进行了测试，并且缺乏HLA-DRB1和45个患有HLA-DRB1等位基因的正常葡萄糖调节的个体。这些人与年龄和性别相匹配。在选定的蛋白质中，有11个在糖尿病患者中再次具有较高的信号。确定的抗体之一是PPARG，这是一种参与脂肪细胞分化的核受体，也是抗糖尿病药物的靶标。 我们选择了这11种抗体以及另外三种蛋白质来测试可能是450名​​2型糖尿病患者和450例患有正常葡萄糖法规的人的自身免疫标记。初步分析表明，这些抗体中的2种在糖尿病患者中具有较高的信号，而与LHA-DRB1状态无关。 我们还测序了这些个体中T细胞受体中的互补定义区域3（CDR3）。我们发现，定义CDR3区域的几个基因在患有和没有糖尿病患者之间的频率上显着差异，我们发现CDR3区域的长度在患有糖尿病患者中的长度较短。然后，我们在访问时对较大的个体进行了CDR3区域的测序，没有保护性HLA单倍型和正常的葡萄糖调节。在这个较大的同伴中，我们证实了其中一个基因在糖尿病患者（V基因7-8）中更频繁的初始队列中预测了糖尿病的发展，而较短的CDR3长度也是如此。 基于这项研究的体重增加的先前预测因素包括更高的呼吸商，较高的胰岛素介导的葡萄糖吸收，较低的游离T3和相对较低的能量消耗。 能量消耗的变异性是体重变化的中介者，我们继续评估与代谢率有关的因素。我们以前曾证实，相对于体型较低的能量消耗之间的这种关联是较大的队列中体重增加的预测指标，随访时间更长。此外，我们能够证明较低的能量消耗还可以预测脂肪质量的增益。在成年期重量轨迹的不同分析中，与所有增加体重的组相比，无论起动重量如何，我们还能够证明体重稳定组的24小时能量消耗相对较高。 使用在5岁和10岁时测得的静息能量消耗，我们还能够证明，1​​0岁（但未在5岁时）的静息能量消耗相对较低，预测体重增加更大，这表明代谢率对童年的体重产生影响。 食物的热效应和唤醒的能量成本是重叠的，难以测量能量消耗的组成部分。通过检查我们的代谢室的时间点数据，我们能够估算这些成分（我们称为醒来的热生成（AFT）），该组件约占总能量消耗的10％。我们发现较低的AFT预测体重增加，但仅在BMI 29 kg/m的个体中。这表明与肥胖相关的绝缘材料增加会导致代谢大营养素的成本较低。随着个人的体重增加，基于体重的增加，其能量消耗的增加超出了预期。我们发现，空腹血糖增加的增加，这可能是增加肝葡萄糖产生的标志物，这解释了大于预期的大型EE的一部分，并且预测体重增加较小。 遗传因素是肥胖及其危险因素的基础。黑色皮质素4受体基因中的突变与人体的体重指数增加和24小时能量消耗有关。具有MC4R突变的个体在童年时期加速了体重增加，但在成年期并非表明这种突变在早期生命中具有更有效的作用。此外，我们发现MC4R突变的存在预测了糖尿病在儿童时期的发展，而不是体重。在对儿童体重增加轨迹的分析中，我们已经确认患有MC4R突变的儿童群簇为最高的体重增加轨迹。 MC4R导致倍率和体重增加的机制尚不清楚。一种可能的介体是脑衍生的神经营养因子（BDNF），它是MC4R信号的下游效应子，该效应已与儿童的心脏和体重增加有关。但是，有MC4R突变和没有MC4R突变的个体之间的血清BDNF没有差异。最近，已经确定了一种更常见的单核苷酸多态性（SNP），该多态性与PIMA印第安人中BMI的增加有关。这种常见的SNP在启动子区域附近，也与较低的能量消耗和增加的食物摄入有关。