EVALUATION OF THE STABLE LABELED ORAL GLUCOSE TOLERANCE TEST

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。在过去30年中，肥胖（BMI >第95百分位）儿童（6- 19岁）的患病率增加了三倍，1999年达到13-14%。伴随着肥胖的增加，儿童（0-19岁）2型糖尿病的发病率增加了四倍。肥胖本身与胰岛素敏感性降低（或胰岛素抵抗增加）和2型糖尿病有关。我们之前已经测量了一些葡萄糖代谢的参数，例如使用稳定的标记频繁采样静脉葡萄糖耐量试验（SLIVGTT）在非肥胖和肥胖儿童和青少年中的胰岛素敏感性。我们证明，肥胖青少年是胰岛素抵抗的（非肥胖青少年胰岛素敏感性的一半），但通过增加他们的胰岛素分泌（非肥胖受试者的两倍）来维持正常的胰岛素水平，从而增加对胰腺β细胞的需求。与非肥胖青少年相比，肥胖青少年并没有增加胰岛素敏感性，而是增加了胰岛素分泌，以应对高碳水化合物饮食。最近，布雷达等人描述了一种稳定的标记OGTT来测量成人的胰岛素敏感性。由于口服葡萄糖推注将模拟进餐，因此标记OGTT提供了比IVGTT更生理的测量胰岛素敏感性的方法。OGTT尚未在儿童中描述。 除了胰岛素敏感性，确定口服葡萄糖推注（模拟进餐）对总葡萄糖输入和肝葡萄糖产生的影响也很重要。Basu等人最近描述了一种三重示踪剂方法，该方法使用稳定同位素和放射性同位素标记的示踪剂分级输注，分别反映成年人的总葡萄糖进入速率和肝葡萄糖产生速率。目前还没有在儿童中进行的此类研究。由于儿童的葡萄糖周转率高于成人，因此必须调整成人使用的示踪剂输注速率。此外，出于道德原因，放射性示踪剂不能用于儿童。在青春期前儿童和青少年的一些初步研究中，我们1）采用了布雷达等人描述的稳定标记OGTT，2）采用了Basu等人描述的模型，仅使用稳定同位素标记的示踪剂。经过多次调整后，我们现在确信，稳定同位素标记的化合物的输注速率以及研究期的持续时间都得到了优化，我们建议将稳定标记的OGTT与两种额外葡萄糖示踪剂的分级静脉输注相结合，用于非肥胖和肥胖青春期前儿童和青少年的研究。这将使我们能够确定胰岛素敏感性以及葡萄糖推注对这些人群中总葡萄糖进入速率和肝脏葡萄糖产生速率的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Over the past 30 years, the prevalence of obese (BMI >95th percentile) children (6-19y) has increased threefold to reach 13-14% in 1999. Concomitant with this increase in obesity, the incidence of type 2 diabetes in children (0-19 y) has increased fourfold. Obesity per se has been associated with reduced insulin sensitivity (or increased insulin resistance) and type 2 diabetes. We have previously measured a number of parameters of glucose metabolism, e.g. insulin sensitivity in non-obese and obese children and adolescents using the stable labeled frequent sampled intravenous glucose tolerance test (SLIVGTT). We demonstrated that obese adolescents are insulin resistant (half the insulin sensitivity of non-obese adolescents) but maintain normoglycemia by increasing their insulin secretion (values twice those of the non-obese subjects), thus, increasing the demands on the pancreatic Beta-cells. In contrast to the non-obese adolescents, the obese adolescents did not increase insulin sensitivity, but rather insulin secretion in response to a high carbohydrate diet. Recently, Breda et al. described a stable labeled OGTT to measure insulin sensitivity in adults. Since an oral glucose bolus would mimic a meal, the labeled OGTT provides a more physiological approach to measure insulin sensitivity than the IVGTT. The OGTT has not been described in children. In addition to insulin sensitivity, it is also of importance to determine the impact of an oral glucose bolus (mimicking a meal) on total glucose entry and hepatic glucose production. Basu et al. have recently described a triple tracer approach using graded infusions of tracers labeled with stable and radioactive isotopes reflecting rates of total glucose entry and hepatic glucose production, respectively in adult humans. There are no such studies described in children. Since children have higher glucose turnover rates than adults, the tracer infusion rates used in adults must be adjusted. In addition, radioactive tracers cannot be used in children for ethical reasons. In some preliminary studies in pre-pubertal children and adolescents, we have 1) adapted the stable labeled OGTT described by Breda et al. and 2) the model described by Basu et al. to children using only tracers labeled with stable isotopes. After a number of adjustments, we are now confident that the infusion rates of the compounds labeled with stable isotopes as well as the duration of the study periods are optimized and we propose to apply the stable labeled OGTT combined with the graded intravenous infusions of two additional glucose tracers to studies of non-obese and obese pre-pubertal children and adolescents. This will enable us to determine insulin sensitivity as well as the effect of a glucose bolus on rates of total glucose entry and hepatic glucose production, respectively, in these populations.