人肝癌细胞胰岛素抵抗模型建立及有效中药成分的筛选

背景：目前,复方中药、单味中药在体内降糖作用及其降糖机制研究较多,但体外尤其是中药单体成分对胰岛素抵抗细胞有何影响尚不清楚。 目的：体外建立人肝癌细胞(HepG2)胰岛素抵抗模型,并初步筛选可有效改善胰岛素抵抗的中药有效成分。 方法：用不同浓度的胰岛素对HepG2细胞进行不同时间的诱导,通过MTT法对细胞活性评价及葡萄糖氧化酶法对HepG2细胞葡萄糖消耗量测定,明确建立稳定的HepG2胰岛素抵抗模型的胰岛素诱导浓度及诱导时间。模型建立后,应用不同浓度的齐墩果酸、药根碱、阿魏酸、大黄酸、马钱苷、葛根素、大豆苷分别作用于胰岛素抵抗细胞24 h,用葡萄糖氧化酶法分别观察不同浓度的上述中药成分对胰岛素抵抗模型HepG2细胞葡萄糖消耗的影响,MTT法对各组细胞活性进行评价。 结果与结论：HepG2细胞在10-6 mol/L浓度的胰岛素中作用24 h,葡萄糖消耗量明显减少(P < 0.01),说明实验成功诱导出稳定人肝癌细胞胰岛素抵抗模型。10-5 mol/L浓度胰岛素组的胰岛素抵抗更明显(P < 0.01)。各时间点10-5 mol/L浓度胰岛素作用的细胞成活率逐渐降低,死亡细胞增多(P < 0.05)。齐墩果酸、药根碱、阿魏酸、大黄酸、马钱苷、葛根素、大豆苷均有改善细胞胰岛素抵抗的作用。其中,质量浓度2×10-1 g/L药根碱、大黄酸、葛根素和齐墩果酸,2×10-5 g/L马钱苷和阿魏酸对改善人肝癌细胞胰岛素抵抗效果较好(P < 0.01)。     

利培酮与氯氮平对正常及胰岛素抵抗大鼠糖代谢的影响

目的:观察利培酮与氯氮平对正常大鼠及胰岛素抵抗大鼠糖代谢的影响. 方法:雄性Wistar大鼠60只,随机分为A组(正常对照组)、B组(利培酮组)、C组(氯氮平组)、D组(胰岛素抵抗组)、E组(胰岛素抵抗+利培酮组)和F组(胰岛素抵抗+氯氮平组),每组各12只.以高糖、高脂饲料诱导法建立大鼠胰岛素抵抗模型.12周后以口服糖耐量实验葡萄糖曲线下面积(AUC)、早期相胰岛素分泌指数(△I30/△G30)、正糖钳夹实验葡萄糖输注率(GIR)及免疫组化法检测利培酮、氯氮平对正常及胰岛素抵抗大鼠血糖、胰岛素抵抗及胰岛素分泌的影响. 结果:利培酮及氯氮平对正常大鼠糖耐量AUC无明显影响(t=0.638,1.021;P均＞0.05);利培酮及氯氮平分别上调胰岛素抵抗大鼠糖耐量AUC(t=2.029,3.305;P＜0.05或P＜0.01).利培酮对正常大鼠胰岛素抵抗无明显影响(t=1.832,P=0.072),利培酮、氯氮平分别下调胰岛素抵抗大鼠GIR(t=2.061,3.568;P ＜0.05或P＜0.001).利培酮对正常大鼠△I30/△G30无明显影响(t=1.972,P=0.058),利培酮及氯氮平明显下调胰岛素抵抗大鼠△I30/△G30(t=2.721,3.696;P＜0.01或P＜0.001).利培酮对正常及胰岛素抵抗大鼠胰岛素染色积分下光密度均无明显影响(t=0.086,0.685;P均＞0.05),氯氮平下调胰岛素抵抗大鼠胰岛素染色积分下光密度(=3.728,P＜0.001). 结论:利培酮对正常大鼠葡萄糖敏感性及胰岛功能影响较小,氯氮平、利培酮对胰岛素抵抗大鼠的胰岛素敏感性及胰岛素分泌有一定影响.     

奥氮平对谷氨酸功能低下的精神分裂症小鼠模型的作用

目的 观察奥氮平对谷氨酸功能低下小鼠模型表现出的高活动性及前脉冲抑制(PPI)缺失的作用.方法 昆明种小鼠165只.(1)取36只小鼠分为4组:溶媒空白对照组(腹腔注射溶媒,以下简称对照组),3种奥氮平剂量(0.1 mg/kg体质量,0.2 mg/kg体质量,0.3 mg/kg体质量,腹腔注射)组,每组8～10只;观察奥氮平对小鼠探究行为和自主活动的影响.(2)取49只小鼠分为5组:对照组,地卓西平马来酸盐(MK-801)模型组(溶媒+MK-801,0.25 mg/kg体质量,腹腔注射),3种剂量(同上)奥氮平干预组(奥氮平+MK-801 0.25 mg/kg体质量,腹腔注射),每组9～10只;观察奥氮平对MK-801致小鼠自主活动增加的影响.(3)取80只小鼠分为8组:对照组,MK-801模型组(溶媒+MK-801,0.5 mg/kg体质量,腹腔注射),3种奥氮平剂量给药组(奥氮平+生理盐水,奥氮平剂量分别为0.3 mg/kg体质量,1 mg/kg体质量,3 mg/kg体质量),3种奥氮平剂量(同上)干预组(奥氮平+MK-801 0.5 mg/kg体质量,腹腔注射),每组10只;观察奥氮平对基线前脉冲抑制(PPI)及MK-801引起的PPI缺失的影响.结果 (1)与对照组比较,奥氮平剂量为0.2 mg/kg体质量和0.3mg/kg体质量时,小鼠的探究行为及自主活动总路程减少(P均＜0.05);但剂量为0.1 mg/kg时,对小鼠的探究行为(P=0.363)及自主活动(P=0.196)无影响.(2)奥氮平剂量为0.1～0.3 mg/kg体质量时,呈剂量依赖性抑制MK-801引起的自主活动增加(P均＜0.05).(3)奥氮平剂量为0.3～3mg/kg体质量时,对基线的PPI无影响(P均＞0.05),剂量为1～3 mg/kg时呈剂量依赖性修复了MK-801引起的PPI缺失(P均＜0.05).结论 奥氮平能够特异性地抑制谷氨酸功能低下小鼠模型表现出的高活动性和PPI缺失,与奥氮平的临床药理作用一致.     

盐酸小檗碱对奥氮平所致精神分裂症患者体质量增加的影响

目的:探讨盐酸小檗碱对奥氮平所致精神分裂症患者体质量增加的干预效果,以及与胰岛素抵抗的关系。方法:选取70例接受奥氮平单药治疗后出现体质量增加≥7%的精神分裂症患者,采用随机数字表法分为研究组35例(最终完成33例)和对照组35例(最终完成32例),在原奥氮平治疗基础上研究组合并盐酸小檗碱900 mg/d,对照组合并安慰剂900 mg/d,观察8周。分别在治疗前和治疗8周末测量两组体质量、体质量指数(BMI)、腰围(WC)、空腹血糖(FBG)、空腹胰岛素(Fins)水平及胰岛素抵抗指数(HOMA-IR);采用治疗中出现的症状量表(TESS)评估药物安全性。结果:以奥氮平使用剂量、使用时间为协变量的重复测量方差分析结果显示,体质量(F=4.569,F=78.784)、BMI(F=4.052,F=65.422)、WC(F=5.146,F=45.068)及HOMA-IR(F=9.171,F=21.342)的组间效应显著(P均0.05);体质量(F=78.784)、BMI(F=65.422)、WC(F=45.068)及HOMA-IR(F=21.342)的组间和治疗的交互效应显著(P均0.01);而时间效应不显著(P0.05)。研究组治疗前后体质量变化值及BMI变化值与HOMI-IR变化值呈正相关(r1=0.423,r2=0.403;P0.05);与WC变化值无明显相关(P0.05)。两组药物不良反应差异无统计学意义(P0.05)。结论:盐酸小檗碱可降低奥氮平所致精神分裂症患者的体质量增加,这可能与其改善胰岛素抵抗有关。     

胰岛素抵抗小鼠脂肪组织肿瘤坏死因子α和脂联素mRNA表达与有氧运动的影响**★

背景：有研究表明有氧运动可通过调节脂肪组织过氧化物酶体激活物增殖受体γ及其相关脂肪因子进而影响胰岛素敏感性，但其影响结果及作用机制至今少有报道。 目的：观察有氧运动后，胰岛素抵抗C57BL/6小鼠脂肪组织过氧化物酶体激活物增殖受体γ、肿瘤坏死因子α和脂联素 mRNA及蛋白表达水平的变化，分析有氧运动对胰岛素抵抗小鼠影响的作用机制。 方法：C57BL /6 小鼠经高脂饮食喂养10周后建立胰岛素抵抗动物模型，建模后将小鼠随机分为安静组与运动组。运动组进行为期6周，75% VO2max强度跑台运动；安静组同等条件下饲养不运动。使用RT-PCR 和Western blot法检测两组脂肪组织过氧化物酶体激活物增殖受体γ，脂联素、肿瘤坏死因子α mRNA和蛋白表达。 结果与结论：6周有氧跑台运动对小鼠脂肪组织过氧化物酶体激活物增殖受体γ表达差异无显著性意义(P > 0.05)，但可显著增加小鼠脂肪组织脂联素的表达(P < 0.01)，降低肿瘤坏死因子α的表达(P < 0.05)；并且可显著降低血液中三酰甘油、游离脂肪酸水平(P < 0.05, P < 0.01)。结果提示有氧运动可能通过调节过氧化物酶体激活物增殖受体γ相关脂肪因子-脂联素和肿瘤坏死因子α的表达来间接调节脂肪组织对胰岛素的敏感性。有氧运动可以显著增加机体组织对胰岛素的敏感性，从而改善C57BL/6 小鼠胰岛素抵抗的症状。     

托吡酯抗癫痫治疗对糖代谢的影响

目的观察癫痫患者服用托吡酯后血糖、胰岛素、胰岛素抵抗指数等变化,评估托吡酯对于抗癫痫治疗的临床意义及局限性。方法回顾性分析2014-06—2016-05我院神经内科门诊及住院的78例癫痫患者临床资料,随机分成2组,托吡酯组40例给予托吡酯治疗,丙戊酸钠组38例给予常规的丙戊酸钠治疗,分别于治疗前和治疗后3个月、6个月检测2组糖代谢指标差异及不良反应发生情况。结果 2组治疗后体质量、胰岛素、IR、瘦素及脂联素比较差异有统计学意义(P0.05)。托吡酯不良反应发生率为12.5%,显著低于丙戊酸钠组的23.7%,差异有统计学意义(P0.05)。结论 (1)癫痫患者葡萄糖代谢存在异常,抗癫痫药物对癫痫患者糖代谢存在影响;(2)托吡酯与丙戌酸钠均会导致癫痫患者糖代谢指标出现不同程度的下降或升高,故两种药物是否可作为理想药物尚待进一步研究,建议临床合理选用抗癫痫药物,尽可能减少药物不良反应。     

奥氮平诱导性肥胖大鼠血清和纹状体TNF—α表达变化

目的观察奥氮平诱导性肥胖大鼠血清和大脑纹状体肿瘤坏死因子-α（TNF-α）含量的影响。方法40只SD雄性大鼠随机分为对照组和奥氮平组,各20只,前者采用普通饲料喂养,后者在普通饲粮喂养基础上灌胃奥氮平（1．2mg·kg^-1）4周建立奥氮平诱导肥胖大鼠。采用酶联免疫测定法测定血清中TNF-α的含量,生化比色法测定血清葡萄糖（FBS）含量,对脑组织采用HE染色观察形态学变化,采用免疫组织化学方法观察两组大鼠脑组织中TNF-α的表达。结果与对照组比较,奥氮平组大鼠的体重、血糖、血脂和血清TNF-α水平和纹状体TNF-α蛋白表达均有不同程度的升高,差异有统计学意义（P〈0．01）。结论奥氮平可以导致大鼠体重增加,糖脂代谢紊乱,血清及纹状体TNF-α升高,通过调节TNF-α异常变化可能改善奥氮平诱导肥胖大鼠中枢摄食活动。     

中枢性睡眠呼吸暂停综合征与糖代谢异常的相关性研究

目的探讨中枢性呼吸睡眠暂停综合征与糖代谢异常的相关性。方法选择睡眠呼吸暂停综合征(SAHS)肥胖患者36例为观察组,无SAHS 36例正常体质量人群为对照组。根据多导睡眠图监测结果计算呼吸暂停低通气指数;测量空腹血糖、胰岛素、血氧饱和度、口服糖耐量(DGTT)等,采用IR稳定状态模式评估方法(HOMA-IR)指数评估IR。结果 SAHS的糖代谢异常明显高于对照组;SAHS组HOMA-IR明显高于对照组;SAHS组最低脉搏、血氧饱和度低于对照组。结论SAHS与2型糖尿病高发和糖耐量受损有关,是胰岛素抵抗的独立危险因素,睡眠呼吸暂停与空腹胰岛素水平有一定的相关性,睡眠呼吸暂停的严重程度与胰岛素抵抗有关。     

四种抗精神病药对糖代谢及脂代谢的不良影响

目的研究4种抗精神病药对糖代谢、脂代谢的不良影响。方法112例精神分裂症患者根据临床治疗需要分为氯氮平组（30例）、奥氮平组（24例）、利培酮组（29例）和舒必利组（29例），均治疗观察4周。每组患者于治疗前后测空腹血糖、甘油三酯、胆固醇、胰岛素、C肽，量身高、体质量、腰围、臀围，并计算体质量指数（BMI）及胰岛素抵抗指数（IR）。结果（1）治疗后4组患者的空腹胰岛素、C肽及IR均升高，与治疗前的差异有统计学意义（P〈0．05）；治疗后氯氮平组和奥氮平组患者的甘油三酯及胆固醇均明显高于治疗前（P〈0．05）。（2）治疗后BMI的升高程度为：氯氮平〉奥氮平〉舒必利〉利培酮，差异均有统计学意义（P〈0．05）。空腹胰岛素、C肽、甘油三酯、胆固醇及IR的升高程度为：氯氮平和奥氮平〉舒必利和利培酮，差异均有统计学意义（P〈0．05）。（3）氯氮平组、奥氮平组的甘油三酯及IR升高程度均为男性大于女性，胆固醇升高程度为女性大于男性；舒必利组的变化则相反。结论氯氮平和奥氮平对糖代谢及脂代谢的影响大于利培酮和舒必利，并存在性别差异。     

奥氮平诱导的小鼠肥胖模型MCP-1水平分析

目的 探讨脂肪因子和重要的炎症趋化刺激因子——单核细胞趋化蛋白1 (MCP-1)的血清水平在奥氮平诱导的肥胖中的作用.方法 20只雄性小鼠随机分为两组:实验组和对照组,实验组训练小鼠每天自主摄入奥氮平3 mg/kg体重.7周后取小鼠血浆并检测血浆MCP-1水平.解剖小鼠并留取附睾脂肪垫及肾周脂肪,计算小鼠腹腔脂肪指数及肥胖指数.结果 实验组体重、附睾脂肪垫及肾周脂肪湿重均高于对照组.经计算,腹腔脂肪指数及肥胖指数均高于对照组,可判断为建模成功.实验组血浆MCP-1水平显著高于对照组.结论 在奥氮平诱导的肥胖小鼠模型血浆MCP-1水平升高提示炎症可能参与奥氮平诱导的肥胖.     

Differential effects of 3 classes of antidiabetic drugs on olanzapine-induced glucose dysregulation and insulin resistance in female rats

Background

The second-generation antipsychotic drug olanzapine is an effective pharmacological treatment for psychosis. However, use of the drug is commonly associated with a range of metabolic side effects, including glucose intolerance and insulin resistance. These symptoms have been accurately modelled in rodents.

Methods

We compared the effects of 3 distinct classes of antidiabetic drugs, metformin (100 and 500 mg/kg, oral), rosiglitazone (6 and 30 mg/kg, oral) and glyburide (2 and 10 mg/kg, oral), on olanzapine-induced metabolic dysregulation. After acutely treating female rats with lower (7.5 mg/kg) or higher (15 mg/kg) doses of olanzapine, we assessed glucose intolerance using the glucose tolerance test and measured insulin resistance using the homeostatic model assessment of insulin resistance equation.

Results

Both doses of olanzapine caused pronounced glucose dysregulation and insulin resistance, which were significantly reduced by treatment with metformin and rosiglitazone; however, glucose tolerance did not fully return to control levels. In contrast, glyburide failed to reverse the glucose intolerance caused by olanzapine despite increasing insulin levels.

Limitations

We evaluated a single antipsychotic drug, and it is unknown whether other antipsychotic drugs are similarly affected by antidiabetic treatments.

Conclusion

The present study indicates that oral hypoglycemic drugs that influence hepatic glucose metabolism, such as metformin and rosiglitazone, are more effective in regulating olanzapine-induced glucose dysregulation than drugs primarily affecting insulin release, such as glyburide. The current model may be used to better understand the biological basis of glucose dysregulation caused by olanzapine and how it can be reversed.     

Differential effects of 3 classes of antidiabetic drugs on olanzapine-induced glucose dysregulation and insulin resistance in female rats

Background: The second-generation antipsychotic drug olanzapine is an effective pharmacological treatment for psychosis. However, use of the drug is commonly associated with a range of metabolic side effects, including glucose intolerance and insulin resistance. These symptoms have been accurately modelled in rodents. Methods: We compared the effects of 3 distinct classes of antidiabetic drugs, metformin (100 and 500 mg/kg, oral), rosiglitazone (6 and 30 mg/kg, oral) and glyburide (2 and 10 mg/kg, oral), on olanzapineinduced metabolic dysregulation. After acutely treating female rats with lower (7.5 mg/kg) or higher (15 mg/kg) doses of olanzapine, we assessed glucose intolerance using the glucose tolerance test and measured insulin resistance using the homeostatic model assessment of insulin resistance equation. Results: Both doses of olanzapine caused pronounced glucose dysregulation and insulin resistance, which were significantly reduced by treatment with metformin and rosiglitazone; however, glucose tolerance did not fully return to control levels. In contrast, glyburide failed to reverse the glucose intolerance caused by olanzapine despite increasing insulin levels. Limitations: We evaluated a single antipsychotic drug, and it is unknown whether other antipsychotic drugs are similarly affected by antidiabetic treatments. Conclusion: The present study indicates that oral hypoglycemic drugs that influence hepatic glucose metabolism, such as metformin and rosiglitazone, are more effective in regulating olanzapine-induced glucose dysregulation than drugs primarily affecting insulin release, such as glyburide. The current model may be used to better understand the biological basis of glucose dysregulation caused by olanzapine and how it can be reversed.     

Olanzapine-induced diabetes mellitus

A potential side-effect in the treatment with olanzapine is hyperglycemia or new onset diabetes mellitus. There are possible mechanisms by which olanzapine could interfere with glucose metabolism but decreased insulin sensitivity due to weight gain is of most relevance.     

Insulin resistance following continuous, chronic olanzapine treatment: an animal model

Some atypical antipsychotics have been linked to an increased propensity for weight gain and metabolic disturbances, including type II diabetes. The objective of this study was to investigate an animal model to help understand the mechanisms underlying this phenomenon. Female, Sprague-Dawley rats were treated with olanzapine (2.0 or 7.5 mg/kg, via osmotic mini-pump) for 4 weeks, followed by the hyperinsulinemic/euglycemic and hyperglycemic clamp procedures to assess insulin sensitivity and secretion in vivo. Changes in body weight, visceral fat, food intake and locomotor activity were also assessed. Hepatic glucose production (R(A)) was increased in the hyperinsulinemic/euglycemic clamp for both treatment groups compared to control rats, while the high-dose olanzapine group had decreased peripheral glucose utilization (R(D)). No changes in insulin secretion were detected in the hyperglycemic clamp. Olanzapine did not change body weight or food intake, but did result in significant accumulation of visceral fat and decreases in locomotor activity. Like others, we found that a rodent model for antipsychotic-related weight gain per se is not tenable. However, chronic treatment with olanzapine was found to confer both hepatic and peripheral insulin resistance independent of weight gain, indicating a direct effect on glucose dysregulation.     

氯氮平对雄性小鼠血糖和胰岛素的影响

目的：探讨氯氮平对雄性C57BL／6小鼠血糖和胰岛素的影响。方法：63只雄性C57BL／6小鼠随机分为3大组,空白组、氯氮平4mg／kg组、氯氮平20mg／kg组,于灌药后的3h、1周、4周测定空腹血糖、糖耐量、胰岛素。结果：灌药后3h、l周空腹血糖、血胰岛素、血糖曲线下面积都无显著升高;灌药4周后空腹血糖值显著升高。腹腔注射高糖后60min的氯氮平20mg/kg组的血糖值及血胰岛素显著升高,结诊：氯氮可以慢性升高小鼠的空腹血糖和胰岛素,影响糖耐量,但急性期无明显影响。     

Glucose metabolism in patients with schizophrenia treated with atypical antipsychotic agents: a frequently sampled intravenous glucose tolerance test and minimal model analysis

BACKGROUND: While the incidence of new-onset diabetes mellitus may be increasing in patients with schizophrenia treated with certain atypical antipsychotic agents, it remains unclear whether atypical agents are directly affecting glucose metabolism or simply increasing known risk factors for diabetes. OBJECTIVE: To study the 2 drugs most clearly implicated (clozapine and olanzapine) and risperidone using a frequently sampled intravenous glucose tolerance test. DESIGN: A cross-sectional design in stable, treated patients with schizophrenia evaluated using a frequently sampled intravenous glucose tolerance test and the Bergman minimal model analysis. SETTING: Subjects were recruited from an urban community mental health clinic and were studied at a general clinical research center.Patients Fifty subjects signed informed consent and 41 underwent the frequently sampled intravenous glucose tolerance test. Thirty-six nonobese subjects with schizophrenia or schizoaffective disorder, matched by body mass index and treated with either clozapine, olanzapine, or risperidone, were included in the analysis. MAIN OUTCOME MEASURES: Fasting plasma glucose and fasting serum insulin levels, insulin sensitivity index, homeostasis model assessment of insulin resistance, and glucose effectiveness. RESULTS: The mean +/- SD duration of treatment with the identified atypical antipsychotic agent was 68.3 +/- 28.9 months (clozapine), 29.5 +/- 17.5 months (olanzapine), and 40.9 +/- 33.7 (risperidone). Fasting serum insulin concentrations differed among groups (F(33) = 3.35; P = .047) (clozapine>olanzapine>risperidone) with significant differences between clozapine and risperidone (t(33) = 2.32; P = .03) and olanzapine and risperidone (t(33) = 2.15; P = .04). There was a significant difference in insulin sensitivity index among groups (F(33) = 10.66; P<.001) (clozapineolanzapine>risperidone) (clozapine vs risperidone, t(33) = 2.94; P = .006; olanzapine vs risperidone, t(33) = 2.42; P = .02). There was a significant difference among groups in glucose effectiveness (F(30) = 4.18; P = .02) (clozapine相似文献   

Effect of olanzapine on body composition and energy expenditure in adults with first-episode psychosis

OBJECTIVE: Weight gain is a commonly observed adverse effect of atypical antipsychotic medications, but associated changes in energy balance and body composition are not well defined. The authors report here the effect of olanzapine on body weight, body composition, resting energy expenditure, and substrate oxidation as well as leptin, insulin, glucose, and lipid levels in a group of outpatient volunteers with first-episode psychosis. METHOD: Nine adults (six men and three women) experiencing their first psychotic episode who had no previous history of antipsychotic drug therapy began a regimen of olanzapine and were studied within 7 weeks and approximately 12 weeks after olanzapine initiation. RESULTS: After approximately 12 weeks of olanzapine therapy, the median increase in body weight was 4.7 kg, a significant increase of 7.3% from first observation. Body fat, measured by dual-energy x-ray absorptiometry, increased significantly, with a propensity for central fat deposition. Lean body mass and bone mineral content did not change. Resting energy expenditure, measured by indirect calorimetry, did not change. Respiratory quotient significantly increased 0.12 with olanzapine and was greatest in those who gained >5% of their initial weight. Fasting insulin, C-peptide, and triglyceride levels significantly increased, but there were no changes in glucose levels; total, high density lipoprotein, or low density lipoprotein cholesterol levels; or leptin levels. CONCLUSIONS: Olanzapine appears to have induced an increase in central body fat deposition, insulin, and triglyceride levels, suggesting the possible development of insulin resistance. The decrease in fat oxidation may be secondary or predispose patients to olanzapine-induced weight gain.     

5-羟色胺与氯氮平致糖脂代谢紊乱的相关性探讨

目的 通过研究非典型性抗精神病药氯氮平单用及与5-羟色胺合用对小鼠糖脂代谢的影响,探讨氯氮平致糖脂紊乱与5-羟色胺之间的关系.方法 42只雄性小鼠随机分为6组,分别为空白组、氯氮平4 mg/kg组、氯氮平20 mg/kg组、5-HT 20 mg/kg组、氯氮平4 mg/kg+5-HT 20mg/kg组和氯氮平20 mg/kg+5-HT 20 mg/kg组,分别于给药1周和4周时测定小鼠的空腹血糖和糖耐量,4周后测定小鼠血清甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白(HDL-C)、低密度脂蛋白(LDL-C)、血清胰岛素(Ins)和空腹血糖(FBG).结果 (1)单用氯氮平20 mg/kg可使小鼠糖耐量、TG、LDL-C、TC和HO-MA-IR水平升高,降低HDL-C水平.(2)5-羟色胺与氯氮平联用可改善糖耐量,显著降低单用氯氮平导致的TG、LDL-C、TC和HOMA-1R水平,同时升高HDL-C水平.结论 氯氮平导致的小鼠糖脂代谢紊乱可能与其抑制5-羟色胺受体有关.     

Ethnic heterogeneity in glucoregulatory function during treatment with atypical antipsychotics in patients with schizophrenia

OBJECTIVE: Atypical antipsychotics induce weight gain and are linked to increased diabetes risk, but their relative impact on factors that elevate disease risk are unknown. METHODS: We performed a 6-month, randomized, double-blind study to evaluate the effects of risperidone and olanzapine in patients with schizophrenia. At baseline and weeks 6 and 24, we quantified: (1) total adiposity by DEXA, (2) visceral adiposity by abdominal CT, and (3) insulin sensitivity (S(I)) and (4) pancreatic function ("disposition index", DI) by intravenous glucose tolerance test. RESULTS: At baseline, groups (risperidone: n=28; olanzapine: n=31) were overweight or obese by body mass index (risperidone: 28.4+/-5.4, olanzapine: 30.6+/-7.0kg/m(2)). Both drugs induced weight gain (p<0.004). Total adiposity was increased by olanzapine at 6 weeks (p=0.0006) and by both treatments at 24 weeks (p<0.003). Visceral adiposity was increased by olanzapine and risperidone by 24 weeks (p<0.003). S(I) did not deteriorate appreciably, although a downward trend was observed with risperidone. Given known ethnic differences in adiposity and S(I), we performed secondary analysis in African American and Hispanic subjects. In this subset, olanzapine expanded both total and visceral adiposity (p<0.02); no increase was observed with risperidone. There were modest downward trends for S(I) with both treatments. By week 24, olanzapine-treated subjects exhibited diminished DI (p=0.033), indicating inadequate pancreatic compensation for insulin resistance. CONCLUSIONS: This is the first prospective study in psychiatric patients that quantified antipsychotic effects on the multiple metabolic processes that increase diabetes risk. Results indicate that ethnic minorities may have greater susceptibility to antipsychotic-induced glucoregulatory complications.