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

非典型抗精神病药：对人体肝葡萄糖和脂质代谢的影响

• 批准号: 7714499
• 负责人: KAREN L TEFF
• 金额: $ 49.54万
• 依托单位: MONELL CHEMICAL SENSES CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7714499
• 关键词: Acetates; Acute; Address; Adult; Affinity; Aftercare; Attenuated; Bethanechol; Binding; Blood specimen; Cardiovascular Diseases; Clinical; Clozapine; Coupled; Data; Defect; Diabetes Mellitus; Disease; Etiology; Exhibits; Fasting; Fiber; Funding; Future; Glucose; Goals; Hepatic; Hepatocyte; Hour; Human; Hyperinsulinism; Hypertriglyceridemia; Impairment; Incidence; Infusion procedures; Ingestion; Inpatients; Insulin; Insulin Resistance; Intake; Islets of Langerhans; Label; Laboratories; Leucine; Light; Lipids; Liver; Longevity; Mental disorders; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Muscarinic Acetylcholine Receptor; Muscarinic Agonists; Muscarinics; Nervous system structure; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Pancreas; Patients; Pharmaceutical Preparations; Placebos; Population; Prevalence; Production; Public Health; Randomized; Relative (related person); Research Personnel; Risk; Role; Schizophrenia; Secondary to; Time; Tissues; Triglycerides; United States National Institutes of Health; Very low density lipoprotein; Weight Gain; Weight maintenance regimen; absorption; aripiprazole; atypical antipsychotic; blood glucose regulation; clinically relevant; design; glucose metabolism; glucose production; insight; insulin sensitivity; lipid biosynthesis; lipid metabolism; liver metabolism; olanzapine; patient population; prevent; public health relevance; receptor binding; relating to nervous system; response; stable isotope; treatment effect; treatment site

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.

描述（由申请方提供）：使用非典型抗精神病药物（AAP）与精神分裂症人群中肥胖、2型糖尿病（T2 DM）和心血管疾病（CVD）的发生率显著增加相关。AAP诱导患者体重大幅增加，迄今为止，代谢后果被认为是继发于身体肥胖增加。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，在健康对照受试者中，奥氮平给药仅9天后，内源性葡萄糖生成增加、餐后高胰岛素血症和高胰岛素血症以及胰岛素敏感性降低。在拟定的住院研究中，我们将扩展这些结果，并在正常体重控制受试者中检查奥氮平和阿立哌唑与安慰剂相比对肝脏葡萄糖和脂质代谢的影响。总体假设是奥氮平阻断了毒蕈碱对内源性葡萄糖生成的抑制，导致EGP增加和高胰岛素血症，进而促进脂肪生成。相比之下，阿立哌唑预计对脂质和葡萄糖代谢的影响有限。SPA 1：确定奥氮平诱导的内源性葡萄糖生成增加是否是由于肝脏胰岛素敏感性降低所致。在研究1中，正常体重对照受试者将被随机分配至三种实验条件之一：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，输注6，6-[2 H2]-葡萄糖，以测定内源性葡萄糖生成。我们将比较给药前后高胰岛素血症对内源性葡萄糖产生的抑制程度。SPA 2：确定奥氮平是否可预防内源性葡萄糖生成的毒蕈碱抑制。在研究2中，在如上所述的治疗随机化后，受试者将接受稳定同位素输注的胰岛钳夹。我们将确定毒蕈碱激动剂氨甲酰胆碱对EGP的影响之前和之后AAP管理。SPA 3：确定奥氮平是否诱导肝脏新生脂肪生成和VLDL-apoB 100生成增加。在研究3中，治疗随机化后，受试者将接受17小时[1- 13 C]标记醋酸盐输注和15小时[5，5，5，-2 H3]标记亮氨酸输注，以确定AAP或安慰剂给药前后肝脏新生脂肪生成和VLDL apobB 100生成。这些研究的结果将解释奥氮平和其他潜在AAP与代谢疾病相关的原因，有助于指导临床人群的未来机制研究，并提供神经系统在葡萄糖稳态和T2 DM病因中的作用的见解。公共卫生关系：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（AAP）与体重的巨大增加和糖尿病发病率的增加有关。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后出现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，我们将研究两种AAP奥氮平和阿立哌唑对健康对照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。