高脂饮食和地塞米松联合诱导胰岛素抵抗大鼠模型

目的用高脂饲料＋地塞米松（dexamethasone,DEX）隔日腹腔注射建立实验性胰岛素抵抗大鼠模型,研究该模型糖代谢、脂代谢和激素水平等方面的变化。方法采用Wistar雄性大鼠,分为正常对照组、高脂组、DEX组（1mg/kg,i.p.）和高脂＋DEX组（1mg/kg,i.p.）,连续观察8周,每周测定大鼠空腹血糖,分别于造模第2周和第8周测糖耐量,8周后处死大鼠,测定胸腺、脾脏、肝脏等脏器重量。结果高脂饲料能加重腹腔注射DEX造成的空腹血糖升高,造模第8周空腹血糖（7.7±0.7）较空白组（6.5±0.6）显著升高。使模型动物糖耐量明显异常,肝糖原、肌糖原含量显著增加,血浆胰岛素及游离脂肪酸水平显著升高,各脏器指数明显增加。结论高脂＋DEX隔日腹腔注射能成功诱导胰岛素抵抗大鼠模型,这种造模方法较单纯注射DEX或单纯高脂饲养成模率高,造模周期短。     

不同性别大鼠在2型糖尿病造模过程中的稳定性

目的研究不同性别大鼠在2型糖尿病造模过程中的成功率及模型的稳定性。方法高糖高脂饮食联合腹腔注射小剂量链脲佐菌素诱导建立雄、雌性大鼠2型糖尿病模型。成模后所有大鼠每周固定时间测血糖和体重。观察24周后,心脏穿刺取血,测定空腹血糖（FPG）、血清胰岛素（FINS）、HbA1c、甘油三脂（TG）、胆固醇（TC）、高密度脂蛋白-胆固醇（HDL-C）、低密度脂蛋白-胆固醇（LDL-C）。结果单纯高糖高脂饮食喂养,雄、雌性大鼠血糖与正常组无显著差异;STZ注射后,雄性大鼠血糖升高并逐渐平稳,而雌性需两次STZ注射,模型才比较稳定。实验结束时,雄、雌性糖尿病大鼠FPG、FINS、HOMA-IR以及TG、TC、LDL-C均显著升高,说明模型存在胰岛素抵抗和脂代谢紊乱。结论高糖高脂饲料加一次性小剂量链脲佐菌素腹腔注射,可成功建立雄性大鼠2型糖尿病模型,而同等剂量,雌性模型需两次STZ。雄、雌性糖尿病大鼠模型具有高血糖、脂质代谢紊乱和胰岛素抵抗特点。造模成功率及稳定性与性别有关,雄性大鼠较雌性大鼠成模率高,稳定性好,且耗时更短。     

黄连素对糖尿病大鼠胰岛素抵抗的治疗作用*

目的:探讨黄连素对链脲佐菌素所致糖尿病大鼠胰岛素抵抗的治疗作用。方法:采用链脲佐菌素腹腔注射的方式建立大鼠糖尿病模型,将实验大鼠分为5组:分别为模型组、黄连素低(100 mg/kg)、黄连素中(200 mg/kg)、黄连素高(300 mg/kg)剂量组和阳性对照组(二甲双胍:50 mg/kg),每组10只。另取10只正常大鼠作为正常组。黄连素低、中、高剂量组小鼠每天分别灌胃100、200和300 mg/kg黄连素;对照组每天灌胃二甲双胍50 mg/kg;正常组和模型组每天给予相同体积的生理盐水进行灌胃;1次/天,连续灌胃4周。通过测定大鼠血FBG、果糖胺水平,OGTT实验,胰岛素(FINS)水平,并计算大鼠胰岛素抵抗指数(HOMA-IR)来评价黄连素对糖尿病大鼠胰岛素抵抗作用。结果:与正常组相比,给药前模型组大鼠静脉血FBG含量显著升高(P＜0.05);与模型组比较,给药2周及以后给药4周后阳性对照组、黄连素中剂量组和高剂量组大鼠静脉血FBG含量均显著下降(P＜0.05);给药4周后,阳性对照组、黄连素低、中、高剂量组OGTT实验结果显示在不同时间节点的血糖值均显著低于模型组(P＜ 0.05),阳性对照组、黄连素低、中、高剂量组FBG、果糖胺水平和HOMA-IR指标均低于模型组(P＜0.05);而胰岛素水平水平较模型组显著升高(P＜0.05)。结论:黄连素可明显降低大鼠的空腹血糖、果糖胺含量,提高胰岛素含量,对链脲佐菌素所致糖尿病大鼠的胰岛素抵抗有明显治疗作用。且一定范围内,黄连素剂量越高,对糖尿病大鼠胰岛素抵抗作用越明显。     

妊娠期高果糖膳食对子代胰岛素抵抗的影响

目的：探讨大鼠妊娠期高果糖膳食对子代胰岛素抵抗的影响。方法：正常饮食的成年雄性Wistar大鼠与雌性大鼠进行合笼,孕鼠随机分为5组,分别为正常对照组、正常剂量果糖组、高剂量果糖组、超高剂量果糖组和超高剂量蔗糖组,孕期每日分别给予2mL蒸馏水、2g/kg、6g/kg、18g/kg的果糖溶液以及18g/kg的蔗糖溶液灌胃,连续干预直至分娩,娩出仔鼠基础饲料喂养,并称量仔鼠体质量、检测空腹血糖。于第8周末检测空腹血糖、进行OGTT试验。于次日禁食12h后处死子代大鼠,麻醉、取血,测量血清胰岛素水平,计算胰岛素抵抗指数。结果：孕期连续干预后,娩出仔鼠出生体重：高剂量果糖组、超高剂量果糖组显著低于对照组（P＜0.05）;超高剂量果糖组娩出仔鼠空腹血糖显著高于对照组（P＜0.05）;OGTT试验：在30min处,高剂量果糖组、超高剂量果糖组以及超高剂量蔗糖组血糖值显著高于正常对照组及正常剂量果糖组（P＜0.05）,在120min处,高剂量果糖组、超高剂量果糖组及超高剂量蔗糖组血糖值显著高于正常对照组（P＜0.05）。高剂量果糖组、超高剂量果糖组及超高剂量蔗糖组的血清胰岛素含量和胰岛素抵抗指数都显著高于正常对照组和正常剂量果糖组（P＜0.05）。结论：妊娠期高果糖膳食会增加子代胰岛素抵抗及糖代谢的患病风险。     

天麦消渴片通过miRNA改善糖尿病大鼠血糖的机制

目的探讨天麦消渴片对糖尿病大鼠体重、血糖、血脂和胰岛素等相关代谢指标的影响,并且利用miRNA表达谱芯片和实时定量RT-PCR探讨天麦消渴片降血糖的机制。方法 SD大鼠通过高脂饮食/注射STZ法构建糖尿病大鼠模型。将SD大鼠分为小剂量天麦消渴片组[8只,给予50 mg/(kg·d)的天麦消渴片粉末悬浊液]、大剂量天麦消渴片组[8只,给予100 mg/(kg·d)的天麦消渴片粉末悬浊液]、糖尿病模型组(8只,给予等体积生理盐水)和正常对照组(8只,给予等体积生理盐水),均连续灌胃8周。每2周测定SD大鼠空腹血糖(FBG)和体重。7周末进行口服糖耐量实验(OGTT),测空腹和葡萄糖负荷后血糖。8周末测定大鼠空腹血糖、血清胰岛素和血脂水平,观察天麦消渴片对糖尿病大鼠血糖和血脂的改善作用。取大鼠胰腺组织进行miRNA表达谱芯片实验,并运用实时定量RT-PCR验证芯片结果,以期探讨天麦消渴片对糖尿病大鼠降血糖的机制。结果干预后,大剂量天麦消渴片组大鼠较糖尿病模型组空腹血糖和OGTT曲线下面积(AUC)显著下降。干预8周后,大剂量天麦消渴片组空腹血清胰岛素(FINS)和胰岛素抵抗指数(HOMA-IR)较糖尿病模型组显著降低(P0.01)。干预8周后,大剂量天麦消渴片组血总胆固醇(TC)和甘油三酯(TG)较糖尿病模型组显著降低(P0.05)。大剂量天麦消渴片组胰腺较糖尿病模型组有18个miRNA上调,3个miRNA下调。结论天麦消渴片不仅能有效降低糖尿病大鼠FBG,改善胰岛素敏感性,还能调节脂代谢。天麦消渴片可能是通过上调胰腺miR-375和miR-30d水平,刺激胰岛β细胞增殖,抑制胰岛α细胞增殖,增加胰岛素基因表达;上调胰腺let-7b、let-7e、miR-142-5p和miR-375,抑制细胞因子及受体相互作用通路和MAPK通路的功能,从而改善糖尿病大鼠血糖和胰岛素抵抗状态。     

槟榔碱对2型糖尿病大鼠肝脏胰岛素抵抗的作用

目的：探讨槟榔碱对2型糖尿病大鼠肝脏胰岛素抵抗的影响及其机制。方法：采用高果糖饲料饲养Wistar大鼠12周制备2型糖尿病大鼠模型,实验动物随机分为5组（n=8）：对照组、模型组、模型＋不同浓度的槟榔碱（0,0．5,1,5mg／kg）组。4周后通过检测血糖、血脂、胰岛素、RT-PCR检测肝脏组成型雄甾烷受体（CAR）、孕甾烷x受体（PXR）、糖代谢相关基因：葡萄糖-6-磷酸酶（G6Pase）、磷酸烯醇式丙酮酸羧激酶（PEPCK）和炎症相关因子：白细胞介素-6（IL-6）、肿瘤坏死因子α（TNF-α）mRNA表达,Western blot检测大鼠肝内p-AKT和葡萄糖转运体4（GLUT4）蛋白表达。结果：1,5mg／kg槟榔碱显著降低糖尿病大鼠体重、空腹血糖、空腹胰岛素、血脂和糖代谢相关基因及炎症相关因子mRNA水平,提高CAR、PXR mRNA水平及p-AKT、GLUT4蛋白水平。结论：槟榔碱可能通过提高CAR和PXR的表达,导致肝脏糖代谢关键酶PEPCK、G6Pase基因表达或者炎性因子肿瘤坏死因子-α（TNF-α）、白介素-6（n-6）表达降低,改善2型糖尿病大鼠肝脏胰岛素抵抗。     

骨钙素对高糖低脂饮食引起的糖尿病新西兰兔胰腺的影响

目的:基于一贯性高血糖症能导致胰岛素抵抗的假说,我们研究了高糖低脂饮食导致的非胰岛素依赖糖尿病大鼠的生理功能和组织学改变.方法:取正常新西兰兔24只,随机分为正常组、糖尿病(DM)组、糖尿病骨钙素干预(DM+OCGY)组.采用高唐低脂饮食喂养新西兰兔,建立非胰岛素依赖糖尿病模型.建立模型后,DM+OCGY组腹腔注射骨钙素(2.5 mg/kg·d),DM组腹腔注射相等量生理盐水.一个月后处死新西兰兔.用HE染色方法检测新西兰兔胰腺形态改变.结果:高糖低脂饮食能有效引起新西兰兔血糖的升高,尿糖阳性,HE染色表明胰腺细胞发生相应改变,DM+OCGY组空腹血糖的浓度明显降低,能逆转胰腺的相关改变.结论:高糖低脂饮食能诱导非胰岛素依赖糖尿病的发生,骨钙素对非胰岛素依赖型糖尿病血糖浓度有一定的调节作用.     

吉林人参低聚肽对糖尿病大鼠的降血糖作用研究

目的：研究吉林人参低聚肽（GOP）对正常大鼠和糖尿病大鼠的血糖调节作用及其机制。方法：正常大鼠降血糖实验：选取雄性SD大鼠30只,根据空腹血糖值随机分为空白对照组和GOP组,GOP组以灌胃的方式给予0.25g/kg bw的人参肽溶液、空白对照组给予等剂量的蒸馏水,连续灌胃30d,测定空腹血糖水平。糖尿病模型大鼠降血糖实验：采用高热能饲料联合小剂量四氧嘧啶建立实验性糖尿病大鼠模型,雄性SD大鼠135只,根据空腹血糖水平随机分为9组：空白对照组、糖尿病模型组（HGC）、乳清蛋白组（WPC）,0.0625、0.125、0.25、0.5、1.0、2.0 g/kg bw GOP组。GOP组以灌胃方式给予不同剂量的GOP溶液、WPC组给予0.25g/kg bw的乳清蛋白溶液、HGC和空白对照组给予等体积的蒸馏水。实验期间HGC组、WPC组和GOP各组饲喂高热能饲料,空白对照组使用基础鼠料。连续灌胃28d,HGC组、WPC组和GOP各组给予四氧嘧啶103~105mg/kg bw腹腔注射,空白对照组注射等体积生理盐水。5d后进行口服葡萄糖耐量试验（OGTT）,测定胰岛素水平、糖化血清蛋白、胆固醇等指标。结果：正常大鼠降血糖实验：空白对照组和GOP组空腹血糖水平没有显著差异。糖尿病大鼠降血糖实验：与HGC组比较,GOP 0.0625、0.125、0.25g/kg bw组和WPC组大鼠空腹胰岛素、糖化血清蛋白、总胆固醇、甘油三酯、OGTT实验0.5h血糖和血糖曲线下面积明显降低。结论：GOP对正常大鼠空腹血糖没有影响,而对高热能饲料联合小剂量四氧嘧啶诱导的糖尿病大鼠的糖脂代谢紊乱具有明显的改善作用。     

不同剂量链尿佐菌素诱导2型糖尿病大鼠模型的研究

目的:探讨不同剂量链脲佐菌素(Streptozotocin,STZ)联合高糖高脂饮食对2型糖尿病大鼠模型建立的影响。方法:90只8周龄SD雄性大鼠随机平均分为六组:普通饲料喂养+缓冲液组、高糖高脂饲料喂养+缓冲液(H.E组)、高糖高脂饲料喂养+35mg/kg链尿佐菌素组(H.E+35 mg/kg STZ组)、高糖高脂饲料喂养+45 mg/kg链尿佐菌素组(H.E+45 mg/kg STZ组)、高糖高脂饲料喂养+55 mg/kg链尿佐菌素组(H.E+55 mg/kg STZ组)及高糖高脂饲料喂养+65 mg/kg链尿佐菌素组(H.E+65 mg/kg STZ组),高糖高脂饲料喂养4周后诱导胰岛素抵抗,继之腹腔注射STZ,建立2型糖尿病大鼠模型。检测体重、胰岛素、空腹血糖、血脂、胰岛素敏感指数(ISI)。结果:与常规饮食组相比,高糖高脂饮食各组大鼠出现空腹血浆胰岛素(FINS)、空腹血糖(FBG)、血清甘油三脂(TG)、总胆固醇(TC)、游离脂肪酸(FFA)显著升高(P0.01),ISI显著下降(P0.01)。不同剂量STZ注射,H.E+45 mg/kg STZ组成模率最高且无自愈现象。结论:通过STZ腹腔注射联合高糖高脂饮食可成功复制出实验性2型糖尿病动物模型,45 mg/kg为STZ理想注射剂量。     

石榴皮多酚对妊娠期糖尿病大鼠胰岛素抵抗及氧化应激损伤的影响

摘要 目的：探讨石榴皮多酚（PPPs）对妊娠期糖尿病（GDM）大鼠胰岛素抵抗（IR）及氧化应激损伤的影响。方法：45只孕鼠随机分为对照组、模型组和PPPs组,各15只。模型组和PPPs组孕鼠经腹腔注射45 mg/kg链脲佐菌素制备GDM模型大鼠,对照组经腹腔注射生理盐水。模型制备成功后给予PPPs组大鼠按300 mg/kg PPPs灌胃,对照组和模型组灌胃等体积生理盐水。给药14 d后检测空腹尾静脉血中糖化血红蛋白（HbA1c）、空腹血糖（FBG）、空腹胰岛素（FINS）、肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、IL-6、超氧化物歧化酶（SOD）、超敏C反应蛋白（hs-CRP）、丙二醛（MDA）、过氧化氢酶（CAT）、尿酸（UA）、尿素氮（BUN）、血清肌酐（SCr）和尿液β-N-乙酰氨基葡萄糖苷酶（NAG）、肾损伤分子1（KIM-1）水平,计算稳态模型的胰岛素抵抗指数（HOMA-IR）。结果：模型组和PPPs组大鼠血清HbA1c、FBG、FINS、TNF-α、IL-1β、IL-6、hs-CRP、MDA、UA、BUN、SCr和尿液NAG、KIM-1水平以及HOMA-IR显著高于对照组,SOD和CAT活性显著低于对照组（P<0.05）。PPPs组大鼠血清HbA1c、FBG、FINS、TNF-α、IL-1β、IL-6、hs-CRP、MDA、UA、BUN、SCr和尿液NAG、KIM-1水平以及HOMA-IR均显著低于模型组,SOD和CAT活性显著高于对照组（P<0.05）。结论：PPPs能够显著减轻妊娠期糖尿病大鼠胰岛素抵抗、氧化应激水平,改善血糖和肾损伤。     

PPARalpha activation elevates blood pressure and does not correct glucocorticoid-induced insulin resistance in humans

Fibrates, activators of the nuclear receptor PPARalpha, improve dyslipidemia, but their effects on insulin resistance and vascular disease are unresolved. To test the hypothesis that PPARalpha activation improves insulin resistance and vascular function, we determined the effects of fenofibrate in healthy adults with insulin resistance induced by short-term glucocorticoid administration. Eighteen normal-weight subjects were studied in four stages: at baseline, after 21 days of fenofibrate (160 mg/day) alone, after 3 days of dexamethasone (8 mg/day) added to fenofibrate, and after 3 days of dexamethasone added to placebo (dexamethasone alone). Dexamethasone alone caused hyperinsulinemia, increased glucose, decreased glucose disposal, and reduced insulin-induced suppression of hepatic glucose production as determined by hyperinsulinemic euglycemic clamp and increased systolic blood pressure as determined by ambulatory monitoring, features associated with an insulin-resistant state. Fenofibrate improved fasting LDL and total cholesterol in the setting of dexamethasone treatment but had no significant effect on levels of insulin or glucose, insulin-stimulated glucose disposal, or insulin suppression of glucose production during clamps, or ambulatory monitored blood pressure. In the absence of dexamethasone, fenofibrate lowered fasting triglycerides and cholesterol but unexpectedly increased systolic blood pressure by ambulatory monitoring. These data suggest that PPARalpha activation in humans does not correct insulin resistance induced by glucocorticoids and may adversely affect blood pressure.     

Low-dose dexamethasone in the rat: a model to study insulin resistance

The main aim of this study was to set up a new animal model to study insulin resistance. Wistar rats (6 or 7 per group) received the following for 4 wk in experiment 1: 1) vehicle, 2) 2 microg/day subcutaneous dexamethasone, 3) metformin (400 mg x kg(-1) x day(-1) os), and 4) dexamethasone plus metformin. In experiment 2 the rats received the following: 1) vehicle, 2) dexamethasone, 3) dexamethasone plus arginine (2%; as substrate of the nitric oxide synthase for nitric oxide production) in tap water, and 4) dexamethasone plus isosorbide dinitrate (70 mg/kg; as direct nitric oxide donor) in tap water. Insulin sensitivity was significantly reduced by dexamethasone already at week 1, before the increase in blood pressure (day 15) and without significant changes in body weight compared with vehicle. Dexamethasone-treated rats had significantly higher triglycerides, hematocrit, and insulin, whereas serum total nitrates/ nitrites were lower compared with vehicle. The concomitant treatment with metformin minimized all the described effects of dexamethasone. In experiment 2, only isosorbide dinitrate was able to prevent the observed dexamethasone-induced metabolic, hemodynamic, and insulin sensitivity changes. Chronic low-dose subcutaneous dexamethasone (2 microg/day) is a useful model to study the relationships between insulin resistance and blood pressure in the rat, and dexamethasone might decrease insulin sensitivity and increase blood pressure through an endothelium-mediated mechanism.     

Oral salmon calcitonin improves fasting and postprandial glycemic control in lean healthy rats

A novel oral form of salmon calcitonin (sCT) was recently demonstrated to improve both fasting and postprandial glycemic control and induce weight loss in diet-induced obese and insulin-resistant rats. To further explore the glucoregulatory efficacy of oral sCT, irrespective of obesity and metabolic dysfunction, the present study investigated the effect of chronic oral sCT treatment on fasting and postprandial glycemic control in male lean healthy rats. 20 male rats were divided equally into a control group receiving oral vehicle or an oral sCT (2?mg/kg) group. All rats were treated twice daily for 5 weeks. Body weight and food intake were monitored during the study period and fasting blood glucose, plasma insulin and insulin sensitivity were determined and an oral glucose tolerance test (OGTT) performed at study end. Compared with the vehicle group, rats receiving oral sCT had improved fasting glucose homeostasis and insulin resistance, as measured by homeostatic model assessment of insulin resistance index (HOMA-IR), with no change in body weight or fasting plasma insulin. In addition, the rats receiving oral sCT had markedly reduced glycemia and insulinemia during OGTT. This is the first report showing that chronic oral sCT treatment exerts a glucoregulatory action in lean healthy rats, irrespective of influencing body weight. Importantly, oral sCT seems to exert a dual treatment effect by improving fasting and postprandial glycemic control and insulin sensitivity. This and previous studies suggest oral sCT is a promising agent for the treatment of obesity-related insulin resistance and type 2 diabetes.     

Effect of Dexamethasone on Insulin Secretion: Examination of Underlying Mechanisms

ObjectiveTo study the mechanism of increased insulin secretion in response to short-term administration of dexamethasone.MethodsMale Wistar rats were injected intraperitoneally with dexamethasone (dexamethasone; 200 mcg/kg body weight per day) or saline for 3 consecutive days. Insulin secretion in response to glucose, ionomycin, and KCl was quantified in islets isolated from the animals, and the amount of glucokinase was measured by Western blot.ResultsDexamethasone-treated animals had 1.18-fold higher fasting blood glucose concentration and 6.5-fold increase in fasting serum insulin concentration compared with findings from animals injected with saline. Compared with islets isolated from control rats, islets from dexamethasone-treated rats secreted more insulin at 60 minutes in response to 5.5 mM glucose (416.4 vs 115.6 fmoles/10 islets, P = .011) and in response to 16.6 mM glucose (985.5 vs 520.6 fmoles/10 islets, P = .014); no change in insulin secretion was observed at 10 minutes. Insulin secretion from islets of dexamethasone-treated rats and control rats was not differentially augmented in response to either ionomycin or potassium chloride. Glucokinase expression was not altered by treatment with dexamethasone.ConclusionsAugmentation of insulin secretion in response to glucose in the pancreatic islets from dexamethasone-treated rats is preserved in islets studied in vitro. The increase in glucose-stimulated insulin secretion appears to be mediated by steps upstream to β -cell membrane depolarization and the attended increase in intracellular calcium in the signaling pathway of insulin secretion. (Endocr Pract. 2010;16:763-769)     

Variation in Gene Expression of Inflammatory Cytokines in Leukocyte-Derived Cells of High-Fat-Diet-Induced Insulin-Resistant Rats

A high-fat diet is thought to enhance inflammation in various tissues by increasing insulin resistance. In this study, we determined the mRNA levels of inflammatory cytokines in leukocyte-derived cells in the blood of rats with high-fat-diet-induced insulin resistance. Feeding rats a high-fat diet for 77 d induced moderate insulin resistance, which was determined by increased plasma glucose and insulin concentrations, following an oral glucose tolerance test. The interleukin (IL)-1β mRNA level was higher in the insulin-resistant rats than in control rats at the fasting stage, whereas the tumor necrosis factor (TNF)-α mRNA level was greatly elevated at 180 min after glucose administration in the insulin-resistant rats. The results suggest that feeding rats a high-fat diet enhances the expression of fasting IL-1β and postprandial TNF-α genes in leukocyte-derived cells.     

Variation in gene expression of inflammatory cytokines in leukocyte-derived cells of high-fat-diet-induced insulin-resistant rats

A high-fat diet is thought to enhance inflammation in various tissues by increasing insulin resistance. In this study, we determined the mRNA levels of inflammatory cytokines in leukocyte-derived cells in the blood of rats with high-fat-diet-induced insulin resistance. Feeding rats a high-fat diet for 77 d induced moderate insulin resistance, which was determined by increased plasma glucose and insulin concentrations, following an oral glucose tolerance test. The interleukin (IL)-1beta mRNA level was higher in the insulin-resistant rats than in control rats at the fasting stage, whereas the tumor necrosis factor (TNF)-alpha mRNA level was greatly elevated at 180 min after glucose administration in the insulin-resistant rats. The results suggest that feeding rats a high-fat diet enhances the expression of fasting IL-1beta and postprandial TNF-alpha genes in leukocyte-derived cells.     

Regulation of insulin sensitivity,insulin production,and pancreatic β cell survival by angiotensin-(1-7) in a rat model of streptozotocin-induced diabetes mellitus

The aim of this study is to determine the antidiabetic activity of Ang-(1-7), an important component of the renin–angiotensin system, in a rat model of streptozotocin (STZ)-induced type 2 diabetes mellitus (DM). A total of 36 male Wistar rats were randomly divided into 3 groups: control group fed standard laboratory diet, DM group fed high-fat diet and injected with STZ, and Ang-(1-7) group receiving injection of STZ followed by Ang-(1-7) treatment. Body weight, blood glucose levels, fasting serum Ang II and insulin levels, and homeostasis model assessment of insulin resistance (HOMA-IR) were measured. The pancreas was collected for histological examination and gene expression analysis. Notably, the Ang-(1-7) group showed a significant decrease in fasting blood glucose and serum Ang II levels and HOMA-IR values and increase in fasting serum insulin levels. Pancreatic β cells in the control and Ang-(1-7) groups were normally distributed in the center of pancreatic islets with large clear nuclei. In contrast, pancreatic β cells in the DM group had a marked shrinkage of the cytoplasm and condensation of nuclear chromatin. Ang-(1-7) treatment significantly facilitated insulin production by β cells in diabetic rats. The DM-associated elevation of inducible nitric oxide synthase (iNOS), caspase-3, caspase-9, caspase-8, and Bax and reduction of Bcl-2 was significantly reversed by Ang-(1-7) treatment. Taken together, Ang-(1-7) protects against STZ-induced DM through improvement of insulin resistance, insulin secretion, and pancreatic β cell survival, which is associated with reduction of iNOS expression and alteration of the Bcl-2 family.     

Combined effect of ACE inhibitor and exercise training on insulin resistance in type 2 diabetic rats

The aim of this study was to investigate whether a combined treatment of ACE inhibitor and exercise training is more effective than either treatment alone in alleviating the insulin resistant states in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of type 2 diabetes. OLETF rats (25 weeks old) were randomly divided into 5 groups; sedentary control, exercise-trained, temocapril (ACE inhibitor; 2 mg/kg/day)-treated, with and without exercise, and losartan (AT1 receptor antagonist; 1 mg/kg/day)-treated. Long-Evans Tokushima Otsuka rats were used as a non-diabetic control. Body weight, the amount of abdominal fat and blood pressure were higher for OLETF rats than for control rats. However, glucose infusion rate (GIR), an index of insulin resistance, was decreased greatly in OLETF rats. The fasting levels of blood glucose, insulin and lipids were also increased in the diabetic strain. In OLETF rats, both temocapril and losartan reversed hypertensive states significantly, whereas GIR and hyperlipidemia were improved when rats were treated with ACE inhibitors, but not with the AT1 receptor antagonist. Exercise training decreased body weight and the amount of abdominal fat, and also increased GIR in parallel with improved dislipidemia. The combination of the ACE inhibitor with exercise training also improved obesity, hyperinsulinemia, dislipidemia and fasting level of blood glucose, and this combination resulted in the greatest improvement of insulin resistance. These results suggest that the combination of ACE inhibitor and exercise training may be a beneficial treatment for mixed diabetic and hypertensive conditions.