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。我们更仔细地研究了胰岛素分泌（通过急性胰岛素反应测量）与血糖浓度的关系。我们发现，在西南部血统的美洲原住民中，急性胰岛素反应的下降与葡萄糖增加呈非线性关系，而白人则呈线性下降。然而，在两组中，急性胰岛素反应的下降先于目前确定的葡萄糖调节受损的截止值。 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。我们之前已经证实了相对于身体大小的较低能量消耗之间的这种关联，作为一个更大的队列中体重增加的预测因素，随访时间更长。此外，我们能够证明，较低的能量消耗也预示着脂肪量的增加。使用5岁和10岁时测量的静息能量消耗，我们还能够证明，10岁时（但不是5岁时）相对较低的静息能量消耗预测体重指数的增加，表明代谢率对儿童后期体重的影响。 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。 我们还研究了心肺功能与能量消耗的关系。我们发现，V02 max（心肺适能的量度）与24 hEE和AFT相关，表明运动诱导的能量消耗和饮食诱导的产热的生理学具有共同的潜在机制。然而，VO 2 max并不能预测体重变化。 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，我们发现较高的体外脂解与较高的全身脂质氧化和较少的体重增加相关。我们还发现，骨骼肌中的鞘脂浓度（这是细胞信号传导中重要的细胞膜成分）与能量消耗和体重增加有关。此外，骨骼肌中内源性大麻素浓度的增加也与较低的能量消耗有关。在中介分析中，内源性大麻素anandamide似乎是神经鞘氨醇对能量消耗影响的中介体。 遗传因素是肥胖症及其危险因素的基础。黑皮质素4受体基因的突变与人类体重指数增加和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。在对儿童期体重增加轨迹的分析中，我们证实了MC 4 R突变的儿童聚集在最高的体重增加轨迹中。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，一种更常见的单核苷酸多态性（SNP）已被确定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。 使用专门为西南遗产的美洲原住民设计的定制基因分型阵列，我们还确定了g蛋白偶联受体（GPR 158）的变体。GPR 158参与神经递质信号传导，但我们发现这种变体与较低的24小时EE和较低的静息代谢率有关。

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 examined more closely the relationship of insulin secretion (as measured by the acute insulin response) to plasma glucose concentrations. We found that in Native Americans of southwestern heritage that the decline in the acute insulin response was non-linear with increasing glucose while there was a linear decline in whites. However, in both groups, declines in the acute insulin response preceded currently established cut-offs for impaired glucose regulation. 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 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. 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 increase in body mass index indicating an effect of metabolic rate on weight in late 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. We have also examined the relationship of cardiorespiratory fitness to measures of energy expenditure. We found that V02 max, a measure of cardiorespiratory fitness, is associated with 24hEE and with AFT, indicating that the physiology of exercise induced energy expenditure and diet induced thermogenesis share common underlying mechanisms. V02 max does not however predict weight change. 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 also found that sphingolipid concentrations (which are cell membrane components important in cellular signaling) in skeletal muscle are associated with energy expenditure and weight gain. Furthermore, increased endocannabinoid concentrations in skeletal muscle are also associated with lower energy expenditure. In mediation analysis, the endocannabinoid anandamide appears to be the mediator of sphingomeylins effect on energy expenditure. 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 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 a custom genotyping array designed specifically for Native Americans of southwestern heritage, we have also identified a variant in g protein couple receptor (GPR158). GPR158 is involved in neurotransmitter signaling, but we found an association with this variant and lower 24 hour EE and lower resting metabolic rate.