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PhD Thesis: Jaime Rosa

Dissertation Abstract:
Inflammatory, immunologic and oxidative status in children with type 1 diabetes and obesity: altered molecular patterns at rest and in response to exercise 

By Jaime Sou Rosa
Doctor of Philosophy in Pharmacology and Toxicology
University of California, Irvine, 2009
Professor Pietro R. Galassetti, Chair

In diabetes and obesity, increased inflammation and oxidative stress are associated with multiple disease complications, including micro/macro-vascular damage and progressing insulin resistance. While these concepts are established in adults, it is unclear to what extent they apply to children, who often display drastically different immunologic and physiologic mechanisms.

Importantly, inflammatory and oxidative processes are markedly modulated by physical exercise, which is also known to protect against long-term cardiovascular morbidity in healthy, obese and diabetic populations. Whether and to what degree inflammatory and oxidative stress responses to exercise are altered in obese and diabetic children are still poorly understood. This dissertation project therefore targeted key aspects of inflammatory and oxidative homeostasis in these populations, by measuring, at rest and during exercise, key inflammatory and oxidative stress markers in a large cohort of healthy, obese and type 1 diabetic children.

At rest, obese and diabetic children displayed significant elevations in interleukin-6 (IL-6), F2-isoprostanes (F2-IsoP), myeloperoxidase (MPO), and other biomarkers compared to controls; in diabetic children, this was regulated by the intensity of recent hyperglycemia. When challenged with exercise (30-min intermittent cycling at ~80% VO2max), obese and diabetic children also displayed exaggerated inflammatory and oxidative stress adaptation (increased post-exercise biomarker plasma concentrations, as well as accelerated kinetics during the exercise bouts).

Specific alterations were condition-specific: IL-6 increased more in obese versus diabetic children; F2-IsoP increased proportionally to the degree of obesity, while MPO was particularly elevated in children with diabetes.

These alterations may reduce the long-term cardioprotective efficacy of physical activity in these children. With the downstream, overall goal to reduce the development of cardiovascular complications in these patients, our data may help provide the rationale for pharmacologic inhibitors specifically targeting individual molecular alterations, and to optimize the development of tailored exercise strategies, currently still largely based on empirical, relatively nonscientific bases.