Exendin-4对自发性Ⅱ型糖尿病KKAy小鼠的治疗作用

研究Exendin-4对自发性Ⅱ型糖尿病KKAY小鼠的治疗作用.以胰岛素为阳性对照,给自发性Ⅱ型糖尿病KKAy小鼠皮下注射Exendin-4(0.2,0.6,1.8μg/kg),每天给药1次,连续给药4周,分别于首次给药后0,1,2,3,4 h及1,2,3,4周取血,测定小鼠空腹血糖浓度;末次给药后1 h取血,测定空腹血清胰岛素、甘油三酯、总胆固醇浓度.给自发性Ⅱ型糖尿病KKAy小鼠皮下注射1.0 IU/kg剂量胰岛素,在给药后1,2,3 h及1,2,3,4周,其空腹血糖浓度与空白对照组比,均显著降低.自发性Ⅱ型糖尿病KKAy小鼠给Exendin-4后1,2,3 h及1,2,3,4周,空腹血糖浓度显著降低(P<0.05 VS对照);连续给药4周后,其血清胰岛素浓度显著增加,0.6 μg/kg组和1.8 big/kg组血清甘油三酯浓度下降(P<0.05 VS对照).Exendin-4对自发性Ⅱ型糖尿病KKAy小鼠有治疗作用.     

CW7213对STZ致糖尿病大鼠血糖及糖耐量的影响

目的:研究CW7213对链脲佐菌素(STZ)糖尿病大鼠血糖及糖耐量的影响.方法:以胰岛素为阳性对照,给STZ所致的Wistar糖尿病大鼠皮下注射CW7213(10、30、60 μg· kg-1),每天给药1次,连续4周,分别于给药后0、1、2、3h及2、4周取血,测定大鼠空腹血糖浓度;在第3天,给药15 min后灌胃给予2.5 g·kg-1葡萄糖,负荷0.5、1、2h后取血,测定血糖浓度.结果:单次给药后,CW7213高、中剂量组均可降低糖尿病大鼠的血糖浓度(P＜0.01,与模型组);连续给药后,CW7213高、中剂量组均可降低STZ所致糖尿病大鼠的血糖浓度(P＜0.01、P＜0.05,与模型组);负荷葡萄糖后,CW7213高、中剂量组可显著抑制血糖的升高(P＜0.05、P＜0.01,与模型组).结论:CW7213剂量相关性地降低了STZ糖尿病大鼠的血糖浓度,抑制了糖尿病大鼠在葡萄糖负荷后的血糖升高,改善了糖尿病症状下的高血糖状况.     

CW7213对自发性2型糖尿病KKAy小鼠的治疗作用

目的:研究CW7213对自发性2型糖尿病KKAy小鼠的治疗作用.方法:以胰岛素为阳性对照,给自发性2型糖尿病KKAy小鼠皮下注射CW7213(20、60、120 μg·kg-1),每天给药1次,连续4周,分别于首次给药后0、1、2、3h及1、2、3、4周取血,测定小鼠的空腹血糖浓度;给药第3周,对小鼠给药15 min后灌胃给予2.5g·kg-1葡萄糖,负荷0.5、1、2、3h后取血,测定血糖浓度;末次给药1h后,测定小鼠空腹血清胰岛素、甘油三酯和总胆固醇浓度.结果:CW7213各剂量组在给药后不同时间段其小鼠空腹血糖浓度与空白对照组相比,呈剂量相关性降低且有显著差异(P＜0.01,P＜0.05);CW7213连续给药4周后,与空白对照组相比,小鼠的血清胰岛素浓度显著增加,高、中剂量组的甘油三酯浓度下降( P＜0.01,P＜0.05),对血清总胆固醇未见明显影响.结论:CW7213单次或连续给药对自发性2型糖尿病KKAy小鼠有治疗作用.     

胰岛素和降钙素宫内给药新途径

1胰岛素将切除卵巢的雌性大鼠分为三组，宫内、皮下注射和宫内对照组。第一组系按0．4或4U／kg剂量将其溶液滴入大鼠子宫内；第二组，皮下注入同剂量胰岛素溶液；第三组为对照组，子宫滴入生理盐水。试验表明：胰岛素经皮下注射和宫内给药后，得到相似的药物浓度一时间曲线，吸收程度相同，AUC值差异不大，都可显著降低血清葡萄糖水平。给药后0．5～2小时内，血清胰岛素浓度达到最大值；给药后2到刎。时内，血中葡萄糖浓度达到最小值，而对照组血糖水平无变化。本试验还采用控释胰岛素制剂植入用链少霉素致糖尿病的雌性大鼠的子宫内。同时…     

胰岛素不同给药途径对糖尿病小鼠葡萄糖代谢的影响

目的：观察胰岛素治疗对糖尿病小鼠口服葡萄糖代谢的影响。方法：四氧嘧啶诱导小鼠糖尿病模型。糖尿病小鼠[^14C]-葡萄糖灌胃，同时腹腔或皮下注射胰岛素。每隔一定时间取尾静脉血测血糖和放射性，2h后处死小鼠，取心、肝、肾组织测放射性。结果：糖尿病小鼠口服[^14C]-葡萄糖后血糖迅速上升，但其血液放射性水平与正常小鼠和胰岛素给药小鼠无差异。糖尿病小鼠皮下注射胰岛素50％出现低血糖。口服[^14C]-葡萄糖后2h，糖尿病小鼠肝、肾放射性水平分别是正常小鼠的4倍和1．5倍，心脏放射性水平降低为正常小鼠的30％。腹腔注射胰岛素的糖尿病小鼠肝、肾和心脏的放射性水平与正常小鼠无统计学差异。皮下注射胰岛素使50％小鼠血糖降至正常，但其肝、肾的放射性水平仍显著高于正常小鼠。对于因皮下注射胰岛素而处于严重低血糖的糖尿病小鼠，肝、肾的放射性水平与正常小鼠无统计学差异，心脏的放射性水平仍显著低于正常小鼠。结论：皮下胰岛素给药可以纠正血糖．但不能纠正糖代谢异常。     

活性糖元保降血糖作用实验研究

目的：观察活性糖元保对糖尿病小鼠或大鼠模型的降血糖作用。方法：ICR小鼠皮下注射四氧嘧啶复制糖尿病小鼠模型，灌胃给予活性糖元保1．0、2．0、4．0g／kg剂量（均折算成生药量，下同），每2周检测一次体重以及空腹血糖，连续8周；SD大鼠以小剂量链脲霉素合并高脂饮食诱发2型糖尿病模型，灌胃给予活性糖元保0．75、1．50、3．00g／kg剂量，每2周检测一次体重以及空腹血糖，连续8周；另采用四氧嘧啶诱发的糖尿病小鼠观察其对糖耐量影响。结果：活性糖元保1．0、2．0、4．0g／kg剂量可降低四氧嘧啶所致糖尿病模型小鼠血糖值，并明显改善该模型小鼠糖耐量，减少其血糖曲线下面积；3．00g／kg剂量对小剂量链脲霉素合并高脂饮食诱发的2型糖尿病大鼠血糖也有一定的降低作用。结论：活性糖元保具有一定的调节血糖和改善糖耐量的作用。     

乌拉坦对大鼠胰岛素水平的影响(英文)

目的　观察麻醉剂量的乌拉坦对空腹大鼠、葡萄糖负荷大鼠和肾上腺素诱发高血糖大鼠血浆胰岛素水平的影响。方法　采用放射免疫测定法测定血浆胰岛素活性。结果　麻醉剂量的乌拉坦 (1 .5g·kg-1 ,sc ,ip各半 )给药后 2 0min显著升高空腹大鼠及葡萄糖负荷大鼠血浆胰岛素水平 ,给药后 50min血浆胰岛素水平分别从 (1 1± 4)及 (1 1± 4)mU·L-1 升至 (2 5±1 1 )及 (47± 6)mU·L-1 ;相同剂量的乌拉坦给药后 1 4 0min使肾上腺素诱发的高血糖大鼠血浆胰岛素水平从 (1 0± 3)升至 (51± 1 8)mU·L-1 。与血浆胰岛素水平的变化相比 ,乌拉坦给药后 50min显著升高空腹大鼠和葡萄糖负荷大鼠的血糖水平 ,但对肾上腺素诱发的高血糖大鼠的血糖水平无明显影响。结论　乌拉坦显著升高空腹大鼠、葡萄糖负荷大鼠及肾上腺素诱发的高血糖大鼠血浆胰岛素水平。乌拉坦促进胰岛素分泌的机制包括高血糖依赖性促分泌和非血糖依赖性促分泌两种     

口服胰岛素微粒剂降血糖有效性及大鼠胃肠道有效吸收部位的研究

分别以葡萄糖氧化酶法、放射免疫分析法对服用微粒剂后的四氧嘧啶致糖尿病小鼠与狗的血糖、血清胰岛素进行测定 ,验证确有外源性胰岛素进入动物体内 ,在给药后 1h动物血清胰岛素增至最高 ,约 2h动物血糖降至最低 ,且作用强度、时间与血清胰岛素变化相对应。给药剂量在 4 0～35 0u/kg范围 ,存在量效关系 :Y(% ) =13 2 1- 1 70 7X(u/kg) ,r =0 9788。给小鼠腹腔注射葡萄糖 (2 g/kg)可见 ,微粒剂 (17u/kg)能对抗并减缓因注射外源还原性单糖引起的动物血糖升高 ,0 5h可抵抗百分率达 86 % (P <0 0 0 5 )。经四氧嘧啶糖尿病大鼠胃肠道不同部位给药发现 :给药部位不同 ,微粒剂降血糖程度有显著差别 ,其中经回肠部位给药效果最好 ,降血糖百分率达 5 6 %(P <0 0 1)。     

国产齐拉西酮的急性毒性作用的实验研究

目的：研究国产齐拉西酮灌胃(ig)给予和腹腔(ip)给药对NIH小鼠的急性毒性反应。方法：以0．5％羧甲基纤维素钠配制齐拉西酮悬液，小鼠灌胃给予和腹腔给予，观察指标包括给药后立即和连续14天观察小鼠的一般情况和计算半数致死量(LD50)。结果：齐拉西酮小鼠灌胃的LD50大于2．0g／kg。腹腔注射给药的LD50为1．407g/kg，95％可信限为1．167～1．697g／kg。结论：对于NIH小鼠，齐拉西酮灌胃给药、腹腔给药的LD50与国外产齐拉西酮的急性毒性相似。     

何首乌有效成分二苯乙烯苷对少半乳糖致脑老化小鼠脑组织神经营养因子表达的影响

目的：观察何首乌有效成分二苯乙烯苷（2，3，5，4’-四羟基-二苯乙烯-β-葡萄糖苷TSG）对D-半乳糖致脑老化小鼠海马组织神经营养因子的影响，方法：1）实验分组：将三月龄Balb／c雌性小鼠随机分为正常对照组、模型组（D-半乳糖注射组）、D-半乳糖＋TSG大剂量组（0．3g／kg／d）、中剂量组（0．1g／kg／d）、小剂量组（0．03g／kg／d）；除正常对照组注射等量的生理盐水外，其余各组用D-半乳糖（生理盐水溶解后），每日颈后皮下注射50mg／kg，连续60天，建立脑老化小鼠模型。同时各组分别灌胃给药（除正常对照及模型组给予溶剂外）其余各组给予TSG每日一次，连续60d后，断头取脑分离皮层海马迅速液氮冷冻，-70℃保存。2）样品处理：将各组小鼠的海马组织匀浆离心取上清，Follin法测定蛋白浓度，调整蛋白浓度一致后并加上样缓冲液，煮沸5分钟。     

The intravenous glucose tolerance test in cannulated Wistar rats: a robust method for the in vivo assessment of glucose-stimulated insulin secretion

INTRODUCTION: Glucose-stimulated insulin secretion (GSIS) is critical in mammalian fuel homeostasis and is diminished early in the evolution of beta-cell dysfunction, ultimately contributing to the development of Type 2 diabetes. We sought to standardise and validate the intravenous glucose tolerance test (IVGTT), a commonly used technique to assess GSIS, in anaesthetised and conscious cannulated male Han Wistar rats. METHODS: Male Han Wistar rats were cannulated via the right jugular vein and left carotid artery. Anaesthetised and chronically cannulated conscious models underwent IVGTT using increasing doses of glucose (0.2, 0.5 and 1.0 g glucose/kg LBM) or following pre-treatment with Exendin-4 (EX-4) before receiving a 0.5 g glucose/kg LBM bolus dose. Blood glucose, plasma insulin and plasma C-peptide were measured at time-points throughout the experiments. RESULTS: Dose-dependent increases in blood glucose, insulin and C-peptide (where measured) were observed following administration of increasing doses of an intravenous glucose bolus in both the anaesthetised and conscious cannulated rats. The 0.5 g glucose/kg LBM bolus resulted in an intermediate response and was used in the second part of the study. EX-4 pre-treatment in combination with glucose resulted in GSIS potentiation, as assessed by plasma insulin measurement alone (anaesthetised model) or insulin and C-peptide measurements (conscious model). DISCUSSION: The IVGTT was standardised in anaesthetised and conscious cannulated male Han Wistar rats by performing a glucose dose response study and validated by examining GSIS potentiation using EX-4. Based on these results, the 0.5 g glucose/kg LBM bolus dose is recommended as the dose to use to assess GSIS in any standardised screening phase of new compounds with the potential to enhance glucose-sensitive pancreatic function. The experimental conditions described in these studies could be transferred to disease models for more detailed assessment of novel compound efficacy.     

Therapeutic effects of berberine in impaired glucose tolerance rats and its influence on insulin secretion

AIM: To explore the anti-diabetic effects of berberine and its influence on insulin secretion. METHODS: Impaired glucose tolerance rats induced by iv injection of streptozotocin 30 mg/kgwere treated with berberine 187.5 and 562.5 mg/kg while fed with high fat laboratory chow. After rats were treated for 4 weeks, oral glucose tolerance was determined, and for 8 weeks, the fasting blood glucose, insulin, lipid series were determined. In insulin secretion experiments, berberine 93.75, 187…     

Effect of caesalpina bonducella seeds on blood glucose in rabbits

The seeds of Caesalpinia bonducella (L.) Flem. (Caesalpiniaceae) are sold in shops in Dar es Salaam, Tanzania, for the treatment of diabetes mellitus. A suspension of the powdered seed kernel in 0.5% carboxymethylcellulose (CMC) was tested for ability to lower blood glucose in fasted and glucose-fed normal albino rabbits. Following administration of 0.2, 0.4 and 0.8 g/kg body weight of the powder there was no difference in areas under the fasting blood glucose and oral glucose tolerance test (OGTT) curves as compared to controls given CMC (P > 0.05). Similarly, 0.2 g/kg body weight of the powder administered for 7 consecutive days had no effect on either fasting blood glucose or the clearance of a glucose load from the blood. However, 0.1 g/kg body weight chlorpropamide significantly decreased the area under the fasting blood glucose and OGTT curves as compared to controls given CMC (P = 0.05). Thus, contrary to a previous report, we could not detect any hypoglycaemic activity in the seeds of Caesalpinia bonducella growing in Dar es Salaam.     

Effects of nifedipine on insulin secretion and glucose metabolism in rats and in hypertensive type 2 (non-insulin dependent) diabetics

The effects of nifedipine (Adalat) on glucose metabolism and insulin release were studied in rats and in patients with type 2 diabetes mellitus complicated with hypertension. 1. In rats, 2.5-50 micrograms/kg of intravenous nifedipine reduced glucose tolerance and insulin release after intravenous glucose in a dose related fashion, although fasting blood sugar and insulin were not affected at 50 micrograms/kg of nifedipine. 2. Daily 20 to 60 mg of oral nifedipine for 12-75 weeks to 14 type 2 diabetics with hypertension did not affect their fasting blood glucose or hemoglobin A1. Mean glucose tolerance curve after the treatment was significantly ameliorated, although insulin response during the oral glucose loading did not show any significant change. Those results suggest firstly that there may be a difference in insulinopenic effect of nifedipine between the species, and secondly that long-term administration of nifedipine produced no adverse influence on glucose metabolism in type 2 diabetics.     

异搏定对大鼠四氧嘧啶引起的糖耐量和胰岛素改变的影响

本实验以糖耐量为背景,观察四氧嘧啶(allxan,AXN)对大鼠胰岛B细胞的破坏作用以及异搏定(verapamil,VAP)的预防作用。尾静脉注射AXN(50mg/kg,iv)后的第48h经口灌注葡萄糖(5g/kg),则血糖急剧升高,并在120min时仍然持续上升,这51.05±3.18mmol/L。血清胰岛素在葡萄糖刺激后无明显升高,未出现正常的分泌高峰。在AXN注射前30min,预先注射VAP(40mg/kg,ip)则给药48h台的糖耐量曲线和血清胰岛素反应均与正常对照组相类似:在第60min时,血糖呈现高峰,并在灌糖后的120min逐渐趋于基础水平。在口服葡萄糖负荷后第30min,异搏定预防组大鼠血清胰岛素分泌显著增多,出现了正常的胰岛素分泌峰。本实验结果提示异搏定具有防止有害物质损伤胰岛B细胞的作用。     

二甲双胍联合运动疗法对抗精神病药致糖脂代谢紊乱患者血抵抗素和脂联素水平的影响

目的 探讨二甲双胍联合运动疗法对抗精神病药致糖脂代谢紊乱患者血抵抗素和脂联素水平的影响.方法 选择山东省滨州市人民医院诊治的200例精神分裂症患者,完全随机分对照组（100例）和研究组（100例）.对照组在持续使用抗精神病药物的同时采用二甲双胍治疗,研究组在对照组治疗基础上联合运动疗法,比较2组患者治疗前及治疗12周后体质量、腰围、空腹及餐后2h血糖、血脂谱、血抵抗素、胰岛素抵抗指数、糖化血红蛋白以及脂联素水平.结果 对照组治疗前体质量、腰围、空腹血糖、餐后2h血糖、糖化血红蛋白、胰岛素抵抗指数、三酰甘油、总胆固醇、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇分别为（65 ±8）kg、（84 ±5） cm、（7.2±1.5） mmol/L、（10.8±2.2） mmol/L、（7.8±0.6）％、（6.3±2.6）、（2.5±0.3）mmol/L、（6.2±1.0） mmol/L、（0.7±0.2）mmol/L、（3.4±0.4）mmol/L,治疗后分别为（63±6）kg、（83 ±4）cm、（6.5 ± 1.3） mmol/L、（7.8±0.6）mmol/L、（6.5±0.4）％、（3.5±0.7）、（2.2±0.3）mmol/L、（5.6±0.9）mmol/L、（1.0±0.3）mmol/L、（2.6±0.3）mmol/L.研究组治疗前体质量、腰围、空腹血糖、餐后2h血糖、糖化血红蛋白、胰岛素抵抗指数、三酰甘油、总胆固醇、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇分别为（65 ±8） kg、（84 ±5）cm、（7.3±1.6） mmol/L、（10.6±2.3） mmol/L、（7.9±0.6）％、（6.4±2.5）、（2.6 ±0.3） mmol/L、（6.3±1.1） mmol/L、（0.7±0.2）mmol/L、（3.3±0.4）mmol/L,治疗后分别为（58±6）kg、（80 ±4）cm、（5.7±1.2） mmol/L、（7.3±0.5）mmol/L、（6.1±0.4）％、（2.9±0.6）、（1.8±0.3）mmol/L、（4.9±0.8）mmol/L、（1.3±0.3）mmol/L、（2.3±0.3）mmol/L,研究组治疗12周后,体质量、腰围、空腹血糖、餐后2h血糖、糖化血红蛋白、胰岛素抵抗指数、总胆固醇、三酰甘油、低密度脂蛋白胆固醇明显低于对照组治疗后和本组治疗前,高密度脂蛋白胆固醇高于对照组治疗后和本组治疗前,差异均有统计学意义（均P＜0.05）.2组患者治疗前血抵抗素、脂联素等指标比较差异无统计学意义[对照组分别为（45±13）、（30±10）μg/L,研究组分别为（45±13）、（30±10） μg/L,均P＞0.05].治疗12周后,研究组患者血抵抗数、脂联素等脂肪细胞因子明显低于对照组治疗后[分别为（35±8）μg/L比（43±8）μg/L、（22 ±9） μg/L比（28±9） μg/L,均P＜0.05].结论 二甲双胍在影响糖代谢和胰岛素分泌、减轻胰岛素抵抗的同时,可通过降低血抵抗素、脂联素等脂肪细胞因子而产生的作用,运动疗法可减轻体质量,缓解胰岛素抵抗,联合治疗的效果优于单用二甲双胍.     

重组Exendin-4-胰高血糖素样肽1/IgG4(Fc)融合蛋白的表达和活性研究

目的  构建表达长效胰高血糖素样肽1（glucagon-like peptide 1,GLP-1）受体激动剂重组Exendin-4-GLP-1/IgG4(Fc)融合蛋白的质粒载体,并研究该融合蛋白的活性。方法  将编码Exendin-4-GLP-1/IgG4(Fc)的重组基因插入表达载体pOptiVEC™-TOPO^®来构建重组质粒Exendin-4-GLP-1/IgG4(Fc)-pOptiVEC™-TOPO^®。将构建的重组质粒转染CHO/DG44细胞并收获表达产物后,分别用亲和层析法和免疫印迹法对表达产物进行纯化和检测。通过胰岛素释放实验确认重组融合蛋白对INS-1细胞胰岛素分泌的影响,同时在CD1小鼠中研究该融合蛋白对血糖的调节作用。结果  转染重组质粒的CHO/DG44细胞可成功表达Exendin-4-GLP-1/IgG4(Fc)。蛋白质印迹法检测显示,纯化的表达产物的相对分子质量（M_r）与预期相符（重组融合蛋白单体和二聚体的M_r分别约为35 000和70 000）。胰岛素释放实验表明,在葡萄糖浓度恒定的情况下INS-1细胞分泌的胰岛素量随重组融合蛋白浓度的升高而增加。CD1小鼠实验显示,重组融合蛋白对链脲佐菌素诱导的糖尿病小鼠的血糖具有调节作用,Exendin-4-GLP-1/IgG4(Fc)处理的糖尿病小鼠的血糖明显低于对照糖尿病小鼠（F=3194,P＜0.01）。结论  Exendin-4-GLP-1/IgG4(Fc)具有天然GLP-1的活性,可作为GLP-1受体激动剂用于2型糖尿病的治疗。     

Hypoglycemic agent YM440 ameliorates the impaired hepatic glycogenesis after glucose loading by increasing glycogen synthase activity in obese Zucker rats

We studied the role of hepatic glycogenesis in glucose intolerance after glucose loading in obese Zucker rats and the effects of YM440 ((Z)-1,4-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]but-2-ene) on it. Lean and obese Zucker rats were treated with YM440 (300 mg/kg) for 14 days and then fasted for 20 h. Thirty percent glucose (0.6 g/kg) or saline was administered intravenously followed by NaH14CO3. Gluconeogenesis was evaluated based on the incorporation of 14C-bicarbonate into blood glucose and hepatic glycogen. Obese rats showed an increase in the incorporation of 14C into blood glucose of 2.5-fold compared to lean rats. The glucose loading decreased the 14C-blood glucose release by 18% in obese rats and 43% in lean rats at 45 min. Glucose loading increased the hepatic glycogen content and 14C incorporation into glycogen in lean but not obese rats. YM440 decreased levels of fasting plasma insulin and blood glucose and the hepatic glycogen content by 50% compared with values for untreated obese rats. After glucose loading, YM440 promoted the incorporation of 14C into glycogen and glycogen synthase activity, leading to an improvement in glucose tolerance. These results indicate that glucose intolerance in obese rats was associated with decreased hepatic glycogenesis and YM440 improved the intolerance by normalizing glycogen metabolism.