This research application will use an already established cohort to investigate the early development of obesity, insulin resistance, and their interaction with associated cardiovascular (CV) risk factors in a cross- generational study between parents (generation 1), on whom we have long-term repeated observations from age 7 to 40, and their children (generation 2). The underlying hypotheses are that early adiposity and insulin resistance drive the development of CV risk and that children, by sharing genetic and environmental factors with their parents, exhibit a similar risk profile for development of type 2 diabetes and atherosclerotic CV disease. Our access to a cohort of individuals who were initially recruited in early childhood, followed through adolescence and young adulthood and currently have children equivalent in age to their own age when they were first recruited, offers a unique opportunity to test this hypothesis. The major objective of this application is to relate individual CV risk factors (hyperinsulinemia, blood pressure, obesity, lipids), lifestyle behaviors, visceral fat (abdominal CT), measures of inflammation, adipocytokines, oxidative stress, vascular studies, and specific measures of insulin resistance (euglycemic hyperinsulinemic clamps) between generations by comparing findings in the parents (generation 1, when they were children and at their current adult age) with their children (generation 2). Overt cardiovascular disease is rare in children, but the factors associated with its development are present early in life. Thus, this study will document the importance, in this current era of epidemic obesity and type 2 diabetes mellitus (T2DM), of identifying high-risk families and children in order to introduce effective intervention strategies prior to disease development. Delineation of similarities in the elements of CV risk between parents and their children and identification of markers that predict which children are at risk for metabolic and cardiovascular complications are the initial steps to achieve this clinical scientific goal.
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