EVALUATION OF THE STABLE LABELED ORAL GLUCOSE TOLERANCE TEST

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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.