Atypical Antipsychotics: Effects on Hepatic Glucose and Lipid Metabolism in Human

描述(申请人提供)：非典型抗精神病(AAPS)药物的使用与精神分裂症人群中肥胖症、2型糖尿病(T2 DM)和心血管疾病(CVD)的发病率急剧增加有关。AAPS会导致患者体重大幅增加，到目前为止，代谢后果被认为是身体肥胖增加的次要结果。然而，我们实验室的初步数据显示，对胰腺b细胞和肝脏的直接影响与体重增加或精神疾病无关。我们发现健康对照组服用奥氮平仅9天后，内源性葡萄糖生成增加，餐后高胰岛素血症和高甘油三酯血症增加，胰岛素敏感性降低。在拟议的住院研究中，我们将扩大这些发现，并检查奥氮平和阿立哌唑与安慰剂对正常体重控制受试者肝脏糖脂代谢的影响。总体假设是，奥氮平阻断了毒扁豆碱对内源性葡萄糖产生的抑制，导致EGP增加和高胰岛素血症，进而促进脂肪生成。相比之下，阿立哌唑预计对脂肪和葡萄糖代谢的影响有限。SPA1：确定奥氮平诱导的内源性葡萄糖产生增加是否由于肝脏胰岛素敏感性降低所致。在研究1中，体重控制正常的受试者将被随机分成三种实验条件之一：奥氮平、阿立哌唑或安慰剂。受试者将接受正常血糖、高胰岛素钳夹并输注6，6-[2H2]-葡萄糖以确定内源性葡萄糖的产生。我们将比较给药前后高胰岛素血症对内源性葡萄糖生成的抑制程度。SPA2：确定奥氮平是否能阻止毒鼠碱抑制内源性葡萄糖的产生。在研究2中，在如上所述的随机治疗后，受试者将接受稳定同位素输注的胰岛夹闭。我们将在AAP用药前和用药后确定M受体激动剂Be-ecol对EGP的影响。SPA3：确定奥氮平是否诱导肝脏新生脂肪生成和VLDL-apoB100产生增加。在研究3中，在随机治疗后，受试者将接受17小时注射[1-13C]标记醋酸酯和15小时注射[5，5，5，-2H3]标记亮氨酸，以确定在服用AAPS或安慰剂前后肝脏新生脂肪生成和极低密度脂蛋白apobB100的产生。这些研究的结果将解释为什么奥氮平和其他潜在的AAP与代谢性疾病有关，有助于指导未来临床人群的机制研究，并为神经系统在血糖稳态中的作用和T2 DM的病因提供洞察力。公共卫生相关性：用于治疗精神分裂症和躁郁症的非典型抗精神病药物(AAP)与体重大幅增加和糖尿病发病率增加有关。这些药物可能会直接损害胰腺和肝脏的功能，但研究人员还无法区分治疗的紧急效果与疾病和体重增加。为了将药物对组织功能的影响与体重增加或疾病区分开来，我们将研究两种AAP，奥氮平和阿立哌唑对健康对照组受试者葡萄糖和肝脏代谢的影响。这些研究的结果将对精神分裂症的治疗具有重要的临床意义。

DESCRIPTION (provided by applicant): The use of the atypical antipsychotic (AAPs) medications is associated with a dramatic increase in the incidence of obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) in the schizophrenic population. AAPs induce tremendous weight gain in patients and to date, metabolic consequences are thought to be secondary to increased body adiposity. However, preliminary data from our laboratory demonstrate direct effects on the pancreatic b-cell and the liver independent of weight gain or psychiatric disease. We have found increased endogenous glucose production, post-prandial hyperinsulinemia and hypertriglyceridemia as well as decreased insulin sensitivity after only 9 days of olanzapine administration to healthy control subjects. In the proposed inpatient studies, we will expand these findings and examine the effects of olanzapine and aripiprazole compared to placebo on hepatic glucose and lipid metabolism in normal weight control subjects. The overall hypothesis is that olanzapine blocks muscarinic inhibition of endogenous glucose production, resulting in increased EGP and hyperinsulinemia which in turn promote lipogenesis. In contrast, aripiprazole is expected to exhibit limited effects on lipid and glucose metabolism. SPA1: Determine if the olanzapine-induced increase in endogenous glucose production is due to decreased hepatic insulin sensitivity. In Study 1, normal weight control subjects will be randomized to one of three experimental conditions; olanzapine, aripiprazole or placebo. Subjects will undergo a euglycemic, hyperinsulinemic clamp with infusion of 6,6-[2H2]-glucose to determine endogenous glucose production. We will compare the magnitude of suppression of endogenous glucose production by hyperinsulinemia prior to and following drug administration. SPA2: Determine if olanzapine prevents muscarinic suppression of endogenous glucose production. In Study 2, after treatment randomization as described above, subjects will undergo a pancreatic islet clamp with a stable isotope infusion. We will determine the effect of the muscarinic agonist bethanechol on EGP prior to and following AAP administration. SPA3: Determine if olanzapine induces an increase in hepatic de novo lipogenesis and VLDL- apoB100 production. In Study 3, following treatment randomization, subjects will undergo an 17-h infusion of [1-13C] labeled acetate and 15-h infusion of [5,5,5,-2H3] labeled leucine to determine hepatic de novo lipogenesis and VLDL apobB100 production prior to and following administration of the AAPs or placebo. Findings from these studies will explain why olanzapine and potentially other AAPs are associated with metabolic disease, help direct future mechanistic studies in clinical populations and provide insight on the role of the nervous system in glucose homeostasis and the etiology of T2DM. PUBLIC HEALTH RELEVANCE: The atypical antipsychotics (AAPs) used for the treatment of schizophrenia and bipolar disease are associated with tremendous weight gain and increased incidence of diabetes. These drugs may directly impair functioning of the pancreas and the liver but investigators have not been able to differentiate treatment-emergent effects from disease and weight gain. To separate drug effects on tissue function from weight gain or disease, we will investigate the effects of two AAPs, olanzapine and aripiprazole on glucose and liver metabolism in healthy control subjects. Findings from these studies will have important clinical relevance to the treatment of schizophrenia.