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

描述（由申请人提供）：非典型抗精神病药物（AAPs）的使用与精神分裂症人群中肥胖、2型糖尿病（T2DM）和心血管疾病（CVD）发病率的急剧增加有关。AAPs会导致患者体重急剧增加，迄今为止，代谢后果被认为是继发于体脂增加。然而，我们实验室的初步数据表明，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以及胰岛素敏感性降低，仅在给予健康对照者奥氮平9天后。在拟议的住院研究中，我们将扩展这些发现，并将奥氮平和阿立哌唑与安慰剂相比，对正常体重控制受试者的肝糖脂代谢的影响。总体假设是奥氮平阻断毒菌碱对内源性葡萄糖生成的抑制，导致EGP升高和高胰岛素血症，进而促进脂肪生成。相比之下，阿立哌唑对脂质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生成的增加是否由于肝脏胰岛素敏感性的降低。在研究1中，体重正常的受试者将被随机分为三种实验条件；奥氮平，阿立哌唑或安慰剂。受试者将接受正血糖、高胰岛素钳夹，并输注6,6-[2H2]-葡萄糖，以测定内源性葡萄糖的产生。我们将比较高胰岛素血症在给药前后对内源性葡萄糖产生的抑制程度。SPA2：测定奥氮平是否阻止毒蕈碱抑制内源性葡萄糖生成。在研究2中，如上所述的随机化治疗后，受试者将接受胰岛钳夹和稳定同位素输注。我们将确定毒蕈碱激动剂比萘酚在AAP给药前后对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生成的增加。在研究3中，治疗随机化后，受试者将接受17小时的[1-13C]标记醋酸酯输注和15小时的[5,5,5，-2H3]标记亮氨酸输注，以测定给药AAPs或安慰剂前后肝脏新生脂肪生成和VLDL载脂蛋白100生成。这些研究的发现将解释为什么奥氮平和潜在的其他AAPs与代谢性疾病相关，有助于指导未来临床人群的机制研究，并为神经系统在葡萄糖稳态和2型糖尿病病因中的作用提供见解。公共卫生相关性：用于治疗精神分裂症和双相情感障碍的非典型抗精神病药物（AAPs）与体重增加和糖尿病发病率增加有关。这些药物可能直接损害胰腺和肝脏的功能，但研究人员还不能区分治疗产生的影响与疾病和体重增加。为了将药物对组织功能的影响与体重增加或疾病分开，我们将研究奥氮平和阿立哌唑两种AAPs对健康对照者葡萄糖和肝脏代谢的影响。这些研究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.