Clinical research has long been a central component in the career of the candidate. UCI's strong interest in developing metabolic research and its solid history of exercise and pediatric research, well match the candidate's research interest and offers a unique potential for career development. The candidate's long-term plan is to establish an independent line of studies focused on altered mechanisms of stress responses; gradually become an independently funded investigator; and eventually coordinate, alongside his own research, a broad -range of metabolic clinical studies by UCI investigators with a variety of research interests. Initial studies, proposed in this application, are designed to identify novel physiological mechanisms causing the alarmingly high incidence of hypoglycemia in children with Type 1 diabetes. High levels of spontaneous physical activity in these children induce rapidly changing patterns of metabolic demand, contribute to glucose instability, and often result in exercise-associated hypoglycemia. Exercise is important in diabetic children, preventing cardiovascular disease, improving glycemic control/insulin sensitivity, and exerting beneficial effects on development and growth. We hypothesize that the neuroendocrine and metabolic responses which prevent hypoglycemia during exercise in the healthy child, acutely fail in the diabetic. In adult patients, exercise responses are acutely reduced by antecedent stress; it is unknown whether this also occurs in children, who are metabolically very different from adults. In addition, based on the new observation made in the candidate's mentor's laboratory that in healthy children exercise acutely increases levels of inflammatory cytokines and growth factors, we will test the novel hypothesis that in diabetic children altered secretion of these mediators may contribute to glucose instability. IL-6, the most abundantly secreted cytokine during exercise, is most likely to impact glucose homeostasis due to recently discovered yet still unclear glucoregulatory properties. This comprehensive approach will be used to define whether adaptive responses to exercise are altered in diabetic children, as compared to controls, and if alterations correlate with gender and/or physical fitness. We will also investigate how the presence and characteristics of antecedent hypoglycemia, with emphasis on nocturnal hypoglycemia, affect children's adaptive response to exercise. Techniques will include maximal/intermittent exercise testing, euglycemic glucose clamping, indirect calorimetry, continuous glucose monitoring, stable isotope glucose and lipid turnover assessment, and hormonal, cytokine, and intermediate metabolite analysis. The results from our studies will hopefully provide the conceptual basis for new therapeutic strategies aimed at correcting the high incidence of hypoglycemia in children with diabetes.
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