This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The prevalence of overweight and obesity, insulin resistance, and type 2 diabetes mellitus (T2DM) are increasing in children, with epidemic rates of these conditions in children in the United States (US). Increased adiposity and related reductions in insulin sensitivity, also referred to as insulin resistance, are major risk factors for the development of T2DM, cardiovascular disease (CVD, e.g., risk of myocardial infarction and stroke), other adverse health outcomes, and reduced psychosocial function. Reductions in lifespan attributale to obesity impact younger, at-risk individuals most measurably, with severly obese20-year old African American males expected to lose 20 years of life. With the use of atypical antipsychotics for treatment of conduct disorder and other aggressive behavior disorders on the rise, concerns about antipsychotic effects, including weight gain, on glucose, lipids and adiposity have also increased, focusing on the widely-used newer medications, clozapine and olanzapine. Increased abdominal adiposity can secondarily decrease insulin sensitivity and antipsychotics can increase adiposity. However, medication effects on glucose control and insulin action may also occur independent of differences in adiposity. This projects aims to a) evaluate effects of selected antipsyochotic treatment on insulin action in skeletal muscle (glucose disposal), liver (glucose production) and adipose tissue (lipolysis), b) evaluate effects of selected antipsychotic treatments on insulin secretion, c) evaluate effects of selected antipsychotic treatments on abdominal fat mass, total body fat and total fat-free mass, d) evaluate effects of selected antipsychotic treatments on resting metabolic rates (carbohydrate and fat oxidation) e) evaluate effects of selected antipsychotic treatments on efficacy for symptoms of aggression. These hypotheses will be evaluated by measuring 1) whole-body glucose and lipid kinetics with the use of 'gold standard' stable isotope tracer methodoloby, 2) body composition using dual energy x-ray absorptiometry and magnetic resonance imaging, adn 3) longitudinal changes in glucose tolerance and lipid profiles.
The aims will be addressed in non-diabetic child and adolescent patients diagnosed with conduct disorder who have never been treated with an antipsychotic medication. Relevant data is critically needed to target basic research, identify long-term cardiovascular consequences, and plan therapeutic interventions.
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