Risk Factors and Etiology of Obesity and Type 2 Diabetes

胰岛素作用降低、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。 这些风险因素存在，即使当个体具有正常的空腹和两小时葡萄糖浓度时，也表明胰岛素分泌减少在2型糖尿病发展中的非常早期的作用。我们还证明，根据我们的正常血糖-高胰岛素钳夹计算，胰岛素清除率降低可增加糖尿病风险，而与胰岛素作用和分泌无关。我们还发现，与胰岛素分泌和胰岛素作用密切相关的1小时葡萄糖浓度与2小时葡萄糖浓度一样，是糖尿病发展的良好预测因子，并可预测糖尿病视网膜病变。 先前基于该研究的体重增加的预测因子包括较高的呼吸商、较高的胰岛素介导的葡萄糖摄取、较低的游离T3和相对较低的能量消耗。 能量消耗的变化是体重变化的一个中介，我们继续评估与代谢率相关的因素。我们之前已经证实，在一个更大的队列中，较低的能量消耗相对于身体尺寸预测体重和脂肪量增加，随访时间更长。使用在5岁和10岁时测量的静息能量消耗，我们证明了在10岁时（但不是在5岁时）相对较低的静息能量消耗预测了体重指数的较大增加，表明代谢率对儿童后期体重的影响。使用我们整个房间间接热量计的数据，我们最近证明，自发的身体活动或坐立不安的行为从1985年到2005年下降，表明久坐不动的生活方式的影响，即使是自发的运动。 食物的热效应和唤醒的能量消耗是重叠的，很难测量能量消耗的组成部分。通过检查来自我们的代谢室的时间点数据，我们能够估计这些组分（我们称之为清醒进食产热（AFT）），其占总能量消耗的约10%。我们发现，较低的AFT预测体重增加，但仅适用于BMI 29 kg/m的个体。这表明与肥胖相关的绝缘增加导致代谢大量营养素的成本降低。随着个体体重的增加，他们的能量消耗增加超过了基于他们体重增加的预期。我们发现，空腹血糖升高可能是肝葡萄糖生成增加的标志物，这部分解释了比预期更大的EE增加，并预测体重增加较少。 鉴于能量消耗和底物氧化在维持能量平衡方面继续发挥重要作用，我们继续研究解释这些测量中个体间差异的因素。在细胞水平上，在脂肪细胞中，我们发现体外脂解作用越高，全身脂质氧化越高，体重增加越少。我们还发现，鞘脂（这是细胞信号传导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，鞘氨醇对能量消耗的影响是由内源性大麻素anandamide介导的。 遗传因素是肥胖症及其危险因素的基础。黑皮质素4受体基因突变与人体体重指数增加和24小时能量消耗降低有关。具有MC 4 R突变的个体在儿童期体重增加加速，但在成年期没有，这表明这种突变在早期生活中的影响更强。此外，我们发现MC 4 R突变的存在预测了儿童期糖尿病的发展，与体重无关。MC 4 R导致食欲过盛和体重增加的机制尚不清楚。一种可能的介质是脑源性神经营养因子（BDNF），其是MC 4 R信号传导的下游效应物，其与儿童期的暴食和体重增加有关。然而，血清BDNF没有不同的个体之间有和没有MC 4 R突变。最近，在MC 4 R中发现了一种更常见的单核苷酸多态性（SNP），它与西南遗产的美洲原住民的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增加的随意食物摄入有关。 利用全基因组测序，我们还发现D-氨基酸氧化酶基因中的终止密码子，一种参与多巴胺合成的酶与较低的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.