GLUCOSE AND LIPID METABOLISM ON ANTIPSYCHOTIC MEDICATION

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。高血糖和2型糖尿病在精神分裂症中比普通人群更常见。2型糖尿病的特征是胰岛素对骨骼肌、肝脏和脂肪组织的作用紊乱。由于急性并发症(如糖尿病酮症酸中毒)和长期并发症(如心血管疾病)，糖尿病导致发病率和死亡率增加。高血糖、血脂异常和腹部肥胖症的组合与心血管发病率和死亡率的增加甚至更密切相关。在引入抗精神病药物之前，人们首次注意到2型糖尿病和高血糖与精神分裂症的关联，这表明这些患者可能面临更高的风险。然而，从那时起，额外的糖调节异常(例如，新发糖尿病)、血脂异常、体重增加和肥胖都与抗精神病药物有关。最近，人们对抗精神病药物对血糖、血脂和肥胖症的影响的担忧有所增加，主要集中在广泛使用的新药氯氮平和奥氮平上。腹型肥胖症的增加会继而降低胰岛素敏感性，而营养减肥药则会增加肥胖症。然而，药物对血糖控制和胰岛素作用的影响也可能与肥胖程度的差异无关。本项目旨在a)评估部分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(全身脂肪分解)中胰岛素作用的影响，b)部分抗精神病药物对腹部脂肪组织质量、全身脂肪和总脱脂质量的影响，以及c)探索部分抗精神病药物治疗对糖耐量、脂谱、腹部脂肪组织质量、总脂肪和总脱脂质量的纵向影响。这些假说将通过1)使用“金标准”稳定同位素示踪方法测量全身葡萄糖和脂肪动力学，2)使用双能量X射线吸收和磁共振成像测量身体成分，以及3)糖耐量和脂肪分布的纵向变化来评估。这些目标将在长期接受利培酮、奥氮平、氯氮平或氟哌啶醇治疗的非糖尿病精神分裂症患者和未经治疗的健康对照组中解决。在接受奥氮平和利培酮(来自以上两组)治疗的患者中，也将进行重新评估，交叉使用另一种药物治疗6个月。迫切需要相关数据来瞄准基础研究，确定长期心血管后果，并计划治疗干预措施。

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. Hyperglycemia and type 2 diabetes mellitus are more common in schizophrenia than in the general population. Type 2 diabetes mellitus is characterized by disturbances in insulin action on skeletal muscle, liver and adipose tissue. Diabetes causes increased morbidity and mortality due to acute (e.g., diabetic ketacidosis) and long-term (e.g., cardiovascular disease) complications. The combination of hyperglycemia, dyslipidemia and abdominal adiposity is even more strongly associated with increased cardiovascular morbidity and mortality. The association of type 2 diabetes and hyperglycemia with schizophrenia was first noted prior to the introduction of antipsychotic medications, suggesting that these patients may be at increased risk. Since then, however, additional glucoregulatory abnormalities (e.g., new onset diabetes), dyslipidemia, and increased weight and adiposity have all been associated with antipsychotic medications. Concern about antipsychotic effects on glucose, lipids and adiposity has increased recently, focusing on the widely-used newer medications, clozapine and olanzapine. Increased abdominal adiposity can secondarily decrease insulin sensitivity and anipsychotics can increase adiposity. However, medication effects on glucose control and insulin action may alos occur independent of differences in adiposity. This project aims to a) evaluate the effects of selected antipsychoitc medications on insulin action in skeletal muscle (glucose disposal), liver (glucose production) and adipose tissue (whole-body lipolysis), b) the effects of selected antipsychotic medications on abdominal adipose tissue mass, total body fat and total fat-free mass, and c) explore the longitudinal effects of treatment with selected antipsychotics on glucose tolerance, lipid profiles, abdominal adipose tissue mass, total bady fat and total fat-free mass. 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 schizophrenia patients chronically treated with risperidone, olanzapine, clozapine, or haloperidol, and untreated healthy controls. Re-evaluations will also be performed in patients treated with olanzapine and risperidone (from groups above), crossed over to treatment with the other agent for 6 months. Relevant data is critically needed to target basic research, identify long-term cardiovascular consequences, and plan therapeutic interventions.