Risk Factors and Etiology of Obesity and Type 2 Diabetes

胰岛素作用减弱、胰岛素分泌受损和肥胖增加是2型糖尿病发生的重要危险因素。即使在空腹和两小时血糖浓度都正常的情况下，这些危险因素也存在，这表明胰岛素分泌减少在2型糖尿病的发展中起着非常早期的作用。我们还证明，基于我们的正常血糖-高胰岛素钳夹的计算，胰岛素清除量的减少增加了糖尿病的风险，独立于胰岛素的作用和分泌。我们还发现，与胰岛素分泌和胰岛素作用密切相关的1小时血糖浓度，与2小时血糖浓度一样，可以很好地预测糖尿病的发展，并预测糖尿病视网膜病变。 先前基于这项研究的体重增加预测因素包括较高的呼吸商、较高的胰岛素介导的葡萄糖摄取量、较低的游离T3和相对较低的能量消耗。能量消耗的可变性是体重变化的中介，我们继续评估与代谢率相关的因素。我们之前已经证实，相对于身体尺寸较低的能量消耗预测了较大的队列中体重和脂肪质量的增加，并进行了较长时间的随访。使用5岁和10岁时测量的静息能量消耗，我们证明了10岁时相对较低的静息能量消耗(而不是5岁时)预示着身体质量指数的更大增长，这表明代谢率对儿童后期体重的影响。使用我们整个房间的间接量热计的数据，我们最近证明，从1985年到2005年，自发的体力活动或坐立不安行为减少，这表明增加了久坐的生活方式，甚至对自发的运动也有影响。 食物的热效应和唤醒的能量成本是重叠的，很难衡量能量消耗的组成部分。通过检查代谢室的时间点数据，我们能够估计出这些成分(我们称之为清醒喂养的生热作用(AFT))，它们约占总能量消耗的10%。我们发现，较低的AFT预测体重增加，但仅在BMI为29公斤/米的个体中。这表明与肥胖相关的隔热增加导致代谢大量营养素的成本较低。随着个人体重的增加，他们的能量消耗会比基于他们增加的体重而预期的增加得更多。我们发现，空腹血糖升高可能是肝脏葡萄糖产量增加的一个标志，这解释了EE高于预期的部分原因，并预测体重增加较少。 鉴于能量消耗和底物氧化继续在维持能量平衡方面发挥重要作用，我们继续调查解释这些测量中个体间差异的因素。在细胞水平上，我们发现在脂肪细胞中，较高的体外脂肪分解与较高的全身脂肪氧化和较少的体重增加有关。我们还发现，神经鞘脂(这是细胞信号中重要的细胞膜成分)和内源性大麻素在骨骼肌中的浓度与较低的能量消耗和体重增加有关。在中介分析中，鞘氨酸甲硫氨酸对能量消耗的影响是由内源性大麻素脱氢酶介导的。 遗传因素是肥胖及其危险因素的基础。黑素皮质素4受体基因的突变与人类体重指数的增加和24小时能量消耗的降低有关。携带MC4R突变的个体在儿童时期体重增加速度加快，但在成年后没有，这表明这种突变在早期生活中的影响更大。此外，我们发现MC4R突变的存在独立于体重预测儿童糖尿病的发展。MC4R导致过度吞噬和体重增加的机制尚不清楚。一种可能的媒介是脑源性神经营养因子(BDNF)，它是MC4R信号的下游效应因子，与儿童过度吞噬和体重增加有关。然而，血清BDNF在有和没有MC4R突变的个体之间没有差别。最近发现了一种更常见的MC4R单核苷酸多态(SNP)，它与西南部血统的美洲原住民BMI增加有关。这种常见的SNP位于启动子区域附近，也与较低的能量消耗和更多的随意食物摄入有关。 通过全基因组测序，我们还发现参与多巴胺合成的D-氨基酸氧化酶基因中的一个终止密码子与较低的24小时和睡眠EE相关。

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. We have also demonstrated that reduced insulin clearance based on calculations from our euglycemic-hyperinsulinemic clamp measures increased risk for diabetes independent of insulin action and secretion. We have also found that the one-hour glucose concentration, which correlates well with insulin secretion and insulin action, is just as good a predictor of the development of diabetes as the 2-hour glucose concentration and predicts diabetic retinopathy. 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 that lower energy expenditure relative to body size predicted weight and fat mass gain in a larger cohort with longer follow-up. Using resting energy expenditure measured at 5 and 10 years of age, we demonstrated that relatively lower resting energy expenditure at age 10 (but not at age 5) predicted greater increase in body mass index indicating an effect of metabolic rate on weight in late childhood. Using data from our whole room indirect calorimeters, we have recently demonstrated that spontaneous physical activity or fidgeting behavior declined from 1985 to 2005 indicating an effect of increasing sedentary lifestyle even on unprompted movement. 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. Given that energy expenditure and substrate oxidation continue to play an important role in maintaining energy balance, we have continued to investigate factors which explain the inter-individual variance in these measurements. On a cellular level, in adipocytes we found that higher in vitro lipolysis is associated with higher whole-body lipid oxidation and less weight gain. We have also found that sphingolipid (which are cell membrane components important in cellular signaling) and endocannabinoid concentrations in skeletal muscle are associated with lower energy expenditure and weight gain. In mediation analysis, sphingomeylins effect on energy expenditure was mediated by the endocannabinoid anandamide. 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. 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) in MC4R has been identified that is associated with increased BMI in Native Americans of southwestern heritage. This common SNP is near the promoter region and is also associated with lower energy expenditure and increased ad libitum food intake. Using whole genome sequencing, we also found that a stop codon in the gene D-amino acid oxidase, an enzyme involved in dopamine synthesis is associated with lower 24h and sleeping EE.