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（由申请人提供）：非典型抗精神病药（AAPS）药物的使用与肥胖发生率的急剧增加有关，2型糖尿病（T2DM）（T2DM）和心血管疾病（CVD）在精神分裂症人群中。 AAP会引起患者的巨大体重增加，迄今为止，代谢后果被认为是体育肥胖增加的继发性。但是，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独立于体重增加或精神病。我们发现内源性葡萄糖的产生，后葡萄糖的产生，后胰岛素血症和高甘油三酸酯血症以及胰岛素敏感性降低，仅在奥氮平对健康对照受试者进行9天后，胰岛素敏感性就会降低。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中肝葡萄糖和脂质代谢的影响。总体假设是奥氮平阻止了毒蕈碱对内源性葡萄糖产生的抑制作用，从而导致EGP和高胰岛素血症增加，从而促进脂肪生成。相比之下，阿立哌唑有预计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产生的增加是否是由于肝胰岛素敏感性降低所致。在研究1中，正常体重控制受试者将被随机分为三个实验条件之一。奥氮平，阿立哌唑或安慰剂。受试者将经历一个葡萄糖高胰岛素夹，并输注6,6- [2H2] - 葡萄糖，以确定内源性葡萄糖的产生。我们将在药物给药之前和之后通过高胰岛素血症抑制内源性葡萄糖的抑制程度。 SPA2：确定奥氮平是否可以防止毒蕈碱抑制内源性葡萄糖的产生。在研究2中，如上所述，在随机处理后，受试者将经历具有稳定同位素输注的胰岛夹具。我们将在AAP给药之前和之后确定毒蕈碱激动剂贝富诺对EGP的影响。 SPA3：确定奥氮平是否诱导从头脂肪生成和VLDL-APOB100产生的增加。在研究3中，在治疗随机分组后，受试者将接受17小时的[1-13C]标记的乙酸盐和15小时输注的[5,5,5,5，-2H3]标记为亮氨酸，以确定肝脏DE脂肪生成和VLDL APOBB100在施用AAPS或APSBOS或PLASSBO之前的肝APOBB100。这些研究的结果将解释为什么奥氮平和其他AAP与代谢疾病有关，有助于指导未来的临床人群机械研究，并洞悉神经系统在葡萄糖稳态中的作用和T2DM的病因。公共卫生相关性：用于治疗精神分裂症和双相情感疾病的非典型抗精神病药（AAP）与糖尿病的大量体重增加和增加有关。这些药物可能会直接损害胰腺和肝脏的功能，但研究人员无法将治疗效果与疾病和体重增加区分。为了将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AAPS，Olanzapine和Aripiprazole对健康对照受试者中葡萄糖和肝代谢的影响。这些研究的发现将与精神分裂症的治疗具有重要的临床相关性。