A PILOT STUDY OF METABOLIC EFFECT OF ANTIPSYCHOTICS IN CHILDREN

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。超重和肥胖、胰岛素抵抗和2型糖尿病（T2DM）在儿童中的患病率正在上升，这些疾病在美国儿童中流行。肥胖增加和相关的胰岛素敏感性降低，也称为胰岛素抵抗，是发生2型糖尿病、心血管疾病（CVD，例如心肌梗死和中风风险）、其他不良健康结果和社会心理功能下降的主要危险因素。肥胖导致的寿命缩短对年轻、高危人群的影响最为显著，严重肥胖的20岁非裔美国男性预计将减少20年寿命。随着使用非典型抗精神病药物治疗品行障碍和其他攻击性行为障碍的情况越来越多，人们对抗精神病药物（包括体重增加）对血糖、血脂和肥胖的影响的担忧也在增加，人们关注的焦点是广泛使用的新药物氯氮平和奥氮平。腹部肥胖增加可继发降低胰岛素敏感性，抗精神病药物可增加肥胖。然而，药物对血糖控制和胰岛素作用的影响也可能独立于肥胖的差异而发生。本项目旨在a)评估选定的抗精神病药物对骨骼肌（葡萄糖处理）、肝脏（葡萄糖产生）和脂肪组织（脂肪分解）中胰岛素作用的影响，b)评估选定的抗精神病药物对胰岛素分泌的影响c)评估选定的抗精神病药物对腹部脂肪量的影响。总体脂和总无脂质量d)评估所选抗精神病药物对静息代谢率（碳水化合物和脂肪氧化）的影响e)评估所选抗精神病药物对攻击症状疗效的影响。这些假设将通过测量1)使用“金标准”稳定同位素示踪方法的全身葡萄糖和脂质动力学，2)使用双能x射线吸收仪和磁共振成像的身体成分，以及3)葡萄糖耐量和脂质谱的纵向变化来评估。目的是解决非糖尿病儿童和青少年患者诊断为品行障碍，从未接受过抗精神病药物治疗。相关数据对于基础研究、确定长期心血管后果和制定治疗干预计划至关重要。

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. 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 infraction and stroke), other adverse health outcomes, and reduced psychosocial function. Reductions in lifespan attributable to obesity impact younger, at-risk individuals most measurably, with severely obese 20 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 project aims to a) evaluate effects of selected antipsychotic treatments 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 methodology, 2) body composition using dual energy x-ray absorptiometry and magnetic resonance imaging, and 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.