改良胆胰转流术对GK大鼠的长期降糖效果

目的:观察改良胆胰转流术(new billiopancreatic diversion,NBPD)和十二指肠改道术(duodenaljejunal bypss,DJB)对GK大鼠的血糖、血脂的长期影响,并探讨其可能的降糖机制.方法:将30只12周龄♂SPF级GK大鼠随机分为3组,每组10只,分别行DJB、NBPD组和假手术.检测手术前后体质量、血糖、血脂等水平,观察术后48 wk胰岛细胞形态.结果:与本组术前1 wk随机血糖相比,术后1 wk NBPD和DJB组大鼠随机血糖下降(9.729 mmol/L±0.652 mmol/L vs 17.743mmol/L±3.734 mmol/L,9.367 mmol/L±1.118 mmol/L vs 16.500 mmol/L±3.272mmol/L).术后24 wk,NBPD组大鼠血糖升至18.043 mmol/L±6.970mmol/L,与假手术组相比差异无统计学意义,而DJB组大鼠随机血糖14.233 mmol/L±2.759 mmol/L,明显低于假手术组及NPBD组.术后48 wk,DJB组大鼠胰岛细胞数量较NBPD组和假手术组明显增多.结论:NBPD及DJB术后早期均能明显降低GK大鼠血糖,但NBPD术后长期降糖效果不佳.这可能是术后早期胆胰液转流影响了GK大鼠消化吸收功能,造成血糖降低.远期肠道功能代偿,而NBPD并无肠道旷置,从而造成血糖回升.     

胃旁路手术治疗2型糖尿病模型大鼠的机制

目的 探讨胃旁路术(GBP)对2型糖尿病(非胰岛素依赖型糖尿病,NIDDM)大鼠模型治疗作用的可能机制.方法 将60只已成功建模的SD成年雄性2型糖尿病大鼠随机分为胃旁路术组(A组)和假手术组(Sham-A组),每组30只.观察、记录所有SD大鼠手术前后体重、空腹血糖(FPG)水平、胰岛素(FINS)水平,计算胰岛素敏感指数(IAI)=1/FPG×FINS);ELISA法检测手术前后血浆胰高血糖素样肽-1(GLP-1)、葡萄糖依赖性促胰岛素激素(GIP)的水平,RT-PCR检测胰腺组织胰高血糖素样肽-1受体(GLP-1R)mRNA、葡萄糖依赖性促胰岛素激素受体(GIPR) mRNA表达变化.结果 GBP术后8wA组糖尿病大鼠的空腹血糖由术前的(20.05±3.50) mmol/L下降至(5.85±0.72) mmol/L(P ＜0.05),且长期维持在较低水平;GBP术后8wA组糖尿病大鼠的空腹胰岛素水平由术前的(7.55±3.15)μU/ml升高至(14.85±2.52)μU/ml(P＜0.05);GBP术后8wA组糖尿病大鼠的空腹胰岛素敏感指数由术前的(0.32±0.12)下降至(0.12±0.06)(P＜0.05).空腹血清GLP-1由术前的(16.86±0.85) pmol/L上升至(35.58±2.15) pmol/L(P ＜0.05),经25％葡萄糖灌胃30 min后更加明显;空腹血清GIP由术前的(7.65±0.75)pmoL/L下降至(4.28±0.08) pmol/L(P＜0.05),经25％葡萄糖灌胃30 min后更加明显.胰腺GLP-1R mRNA表达由术前的(1.01±0.02)倍上升至(5.38±0.65)倍(P＜0.05);胰腺GIP mRNA术前术后无明显变化.结论 GBP对SD大鼠2型糖尿病模型具有明显的治疗作用;其可能机制是过早进入空肠下段的食物,促进GLP-1分泌、减少GIP分泌,同时促进GLP-1R高表达,进而促进胰岛素分泌和(或)增加胰岛素敏感性.     

慢性氯化钴处理对Caspase-3凋亡基因在糖尿病大鼠心肌梗死区表达的影响

目的:探讨慢性氯化钴处理对GK糖尿病大鼠血糖及心肌细胞凋亡的影响。方法:应用体重200~250g的雄性GK糖尿病大鼠及其对照雄性Wistar大鼠,制作大鼠在体心梗模型,制作前测量血糖,手术成功后大鼠被分为六组:Wistar假手术组、Wistar心梗组、Wistar心梗+氯化钴组、GK假手术组、GK心梗组和GK心梗+氯化钴组,每组至少存活6只。3周后,测量血糖,剪取心脏,检测缺血坏死区Caspase-3凋亡基因的表达。结果:(1)术后3周,与GK假手术组及心梗组相比,GK心梗+氯化钴处理组血糖降低[(27.73±2.58)mmol/L、(27.87±3.18)mmol/L比(16.3±2.15)mmol/L],P均<0.05;(2)与GK心梗组相比,GK心梗+氯化钴处理组Caspase-3光密度值[(0.84±0.03)比(0.70±0.03)]及mRNA表达[(0.64±0.03)比(0.52±0.03)]显著减少,P均<0.05;(3)Wistar心梗组和Wistar心梗+氯化钴组血糖、Caspase-3光密度值及mRNA表达未见明显差异(P均>0.05)。结论:慢性氯化钴处理可降低GK糖尿病大鼠血糖,减少Caspase-3凋亡基因在缺血坏死区的表达。     

十二指肠空肠旁路术对非肥胖2型糖尿病GK大鼠的疗效及机制初探

雄性GK和Wistar大鼠各18只,随机分为GK大鼠手术组(A组)和假手术组(B组)、Wistar大鼠手术组(C组)和假手术组(D组),每组9只。检测术前及术后第1、4、8周各组体重、空腹血糖、血浆胰高血糖素样肽-1(glucagon-likepeptide-1 GLP-1)水平,同时测术后第8周小肠组织中GLP-1水平。结果:A组术后8周空腹血糖由(7.69±0.74)pmol/L下降到(5.95±0.78)mmol/L(P<0.01),空腹GLP-1由(7.69±0.74)pmol/L上升到(29.00±3.94)pmol/L(P<0.01),空腹血糖与血浆及组织GLP-1水平均成负相关(P<0.01),组织GLP-1水平与血浆GLP-1水平成正相关(P<0.01)。B组手术前后空腹血糖与GLP-1无明显变化。结论:DJB能显著改善非肥胖2型糖尿病大鼠的血糖,且不依赖体重下降,提示临床上非肥胖的2型糖尿病患者也可能通过手术达到降糖效果。DJB的降糖作用可能与术后血浆及肠道组织中GLP-1分泌增多起作用。     

胃旁路术与胆胰转流术治疗2型糖尿病机制的研究

目的 比较胃旁路术(GBP)与胆胰转流术(BPD)对非胰岛素依赖性糖尿病大鼠的治疗效果,探讨其机制.方法 40只糖尿病GK大鼠按数字表法随机分为GBP组、BPD组、饮食控制组和对照组,每组10只.GBP组、BPD组分别行GBP及BPD手术;饮食控制组大鼠每天给予基础饲料15 g,自由进水;对照组不限食量.记录手术时间、死亡率.每周测空腹体重.检测治疗前及治疗后1、2、3、4、8、16周的空腹血糖、瘦素、胰岛素样生长因子-1(IGF-1)水平.结果 GBP组平均手术时间为(25±4)min,BPD组为(35±6)min;GBP组大鼠死亡1只,BPD组死亡3只,两组差异均有统计学意义(P值均＜0.01).治疗前各组大鼠血糖、瘦素及IGF-1水平无统计学差异.治疗后对照组大鼠血糖及瘦素均无明显变化.饮食控制组大鼠治疗后2周起血糖及瘦素水平开始下降,第4周时显著降低,并持续至16周(P＜0.05),但血IGF-1水平无明显变化.GBP组与BPD组大鼠治疗后2周起血糖及瘦素水平开始下降,而血IGF-1水平开始升高,并持续至16周[血糖:(6.8±1.0)、(6.3±0.8)mmol/L比(13.9±2.6)、(14.1±2.4)mmol/L;瘦素:(16.1±3.3)、(17.2±3.2)pg/ml比(29.4±3.9)、(29.4±3.9) pg/ml;IGF-1:( 166.1±8.3)、(142.2±8.2) ng/L比(119.4±8.8)、(109.8±7.9)ng/L,P值均＜0.01],但这两组的血糖及瘦素水平无统计学差异;而GBP组大鼠血IGF-1水平较BPD组升高更显著(P＜0.05).结论 GBP和BPD均能较好地控制糖尿病大鼠的血糖水平,其机制可能与瘦素的降低及IGF-1的升高有关.GBP在手术时间、死亡率及增加血IGF-1水平等方面优于BPD.     

回肠转位术对GK大鼠血糖及GLP-1分泌影响的研究

目的 观察回肠转位术对GK大鼠血糖及胰升血糖素样肽-l（GLP-1）变化的影响,研究手术对GK大鼠的降糖作用及其可能机制. 方法 随机数字表法分别将雄性SD、GK大鼠（SD、GK组）各分为假手术（A、C）组和手术（B、D）组.观察并测定手术前后各组血糖、胰岛素及GLP-1水平的变化.采用免疫组化检测末段回肠组织GLP-1表达水平. 结果 D组术后血糖降低,术后第2周由术前（8.25±0.52） mmol/L降至（6.62±0.54） mmol/L（P＜0.05）,术后第8周降至（4.78±0.48） mmol/L（P＜0.05）.术后第1周GLP-1由（6.56±0.90） pmol/L升至（12.35±1.43） pmol/L（P＜0.05）,术后第4周升至（26.1±2.64）pmol/L（P＜0.05）. 结论 回肠转位术对GK大鼠有降糖作用,其机制可能是食物快速进入回肠,刺激黏膜细胞,使GLP-1分泌增多,导致胰岛素分泌增加作为主要途径.     

缺血型胆道纤维化狭窄大鼠模型的建立

目的:探索建立大鼠缺血型胆道纤维化狭窄动物模型的方法.方法:选取48只成年SD大鼠,随机分为假手术组、胆总管夹闭60、120和180min组共4组,每组12只.假手术组只游离暴露胆总管,其他各组分别用两枚微血管夹夹闭游离的胆总管两端60、120和180min后取出微血管夹,恢复夹闭处胆管的血供.4个实验组分别于术后4wk随机选取8只大鼠行下腔静脉取血,分离血清进行肝功能测定.取胆总管及肝组织石蜡包埋,HE染色,观察组织病理变化并观察各组动物的存活率、体质量改变情况.剩余大鼠于术后8wk处死,行肝功能的测定及组织病理学检查.结果:假手术组、60min组和120min大鼠的存活率为100,180min组大鼠的存活率为75(9/12).术后4wk,60、120和180min组大鼠体质量明显低于较假手术组(240.4g±11.5g,212.7g±13.6g,200.6g±11.8gvs260.6g±15.7g,均P<0.05).各组大鼠肝功能指标存在明显差异,60、120、180min组与假手术组相比显著增高(ALT:55.3IU/L±5.3IU/L,215.6IU/L±26.8IU/L,245.5IU/L±38.5...     

乙型肝炎肝硬化患者血清胃促生长素和瘦素水平变化

目的检测乙型肝炎肝硬化患者血清胃促生长素(Ghrelin)和瘦素(Leptin)水平变化,并探讨其与胰岛素抵抗的关系。方法在Child A级(n=33)、B级(n=32)和C级(n=32)乙型肝炎肝硬化患者和35例健康人,常规检测血清空腹血糖(FPG)和空腹胰岛素(FINS)水平,并计算胰岛素抵抗指数(IRS);采用酶联免疫吸附法检测Ghrelin和Leptin。结果 Child A级、B级和C级乙型肝炎肝硬化患者血清FPG[分别为(5.55±0.47)mmol/L、(6.62±0.58)mmol/L和(7.37±0.73)mmol/L]、FINS[分别为(14.31±2.12)m IU/L、(15.56±2.21)m IU/L、(16.78±2.32)m IU/L]水平和IRS[分别为(3.63±0.47)、(4.72±0.56)和(5.48±0.77)]均明显高于健康人[分别为(4.74±0.36)mmol/L、(13.17±2.02)m IU/L和(2.85±0.39),P0.05),且与病情严重程度呈正相关(r1=0.627,r2=0.671,r3=0.714,P0.05);各组乙型肝炎肝硬化患者血清Ghrelin[分别为(170.81±37.15)ng/L、(131.90±28.66)ng/L和(94.74±25.38)ng/L)水平较健康人[(208.14±40.36)ng/L]明显降低,且随着Child分级变差而逐级下降(P0.05),与IRS呈负相关(r4=-0.617,P0.05);各组乙型肝炎肝硬化患者血清Leptin水平[分别为(12.17±3.57)μg/L、(15.26±3.81)μg/L和(18.09±4.10)μg/L]较健康人[(9.54±3.32)μg/L]明显升高,且随着Child分级变差而逐级升高(P0.05),与IRS呈正相关(r5=0.642,P0.05)。结论乙型肝炎肝硬化患者血清Ghrelin和Leptin水平与胰岛素抵抗密切相关,临床检测血清Ghrelin和Leptin水平对判断病情严重程度具有重要的临床价值。     

A型肉毒毒素对大鼠胃排空及血浆胃动素、血清瘦素的影响

目的: 探讨A型肉毒毒素(botulinum A,BTA)对大鼠胃排空及某些激素的影响.方法:选用♂Wistar大鼠40只,随机分为4组:对照组、BTA小剂量(10U)组、中剂量(20U)组及大剂量(40U)组.给药方法均为剖腹胃窦部肌层注射.观察12wk,记录进食量及体质量变化.12wk末,测定胃半排空时间,放免法测定血浆胃动素和血清瘦素含量.结果:12wk与对照组相比,中、高剂量组大鼠进食量及体质量明显降低(24.25±1.33g,25.02±1.81g vs 30.61±2.07g;441.54±14.64g,437.33±20.73g vs 517.98±24.11g ,均P<0.05),胃半排时间显著延长(161.67±23.53min, 200.33±44.37min vs 86.83±22.98min, P<0.05),血浆胃动素含量减少,差别有统计学意义(80.56±10.43ng/L, 65.99±10.50ng/L vs 123.65±31.10ng/L, P<0.05);小、中、大剂量组血清瘦素均显著低于对照组(0.99±0.13μg/L,0.97±0.18μg/L,0.83±0.23μg/L vs 1.28±0.25μg/L),差别有统计学意义 P<0.05).结论:大鼠注射BTA后体内胃动素、瘦素含量减少,其可能影响体内某些激素的分泌.     

高尿酸血症对缺血性脑卒中的影响

目的:探讨高尿酸血症对缺血性脑卒中的影响。方法:175只Wistar大鼠,分为空白对照组(35只,不做任何处理)和大脑中动脉闭塞(MCAO)组(140只),MCAO组又根据是否给予及给予抗高尿酸药物别嘌呤醇(All)浓度不同分为:MCAO对照组(35只)、MCAO+All(10mg)组(35只)、MCAO+All(20mg)组(35只)和MCAO+All(30mg)组(35只);测定比较各组大鼠血清及脑组织中尿酸、IL-6和TNF-α水平及蛋白表达,以及脑梗死面积。结果:MCAO组血清尿酸水平显著高于空白对照组[(90.38±31.27)mmol/L比(56.26±8.82)mmol/L],P=0.001。与MCAO对照组比较,MCAO+All 10mg,20mg和30mg组中血清及脑组织中IL-6[血清:(25.63±0.7)ng/L比(23.52±0.6)ng/L、(18.33±0.9)ng/L、(20.11±0.8)ng/L,脑组织:(1.20±0.32)ng/L比(0.98±0.26)ng/L、(0.64±0.34)ng/L、(0.87±0.16)ng/L]和TNF-α[血清:(200.42±8.2)ng/L比(184.37±6.2)ng/L、(165.75±6.8)ng/L、(171.25±7.5)ng/L,脑组织:(2.41±0.6)ng/L比(2.12±0.2)ng/L、(1.62±0.8)ng/L、(1.77±0.5)ng/L]水平和蛋白表达均明显降低,脑梗死面积[(48.42±6.2)%比(40.25±3.1)%、(10.48±4.2)%、(22.42±5.2)%]均明显缩小;且MCAO+All(20mg)组的血清及脑组织中IL-6和TNF-α水平及蛋白表达最低,脑梗死面积最小(P<0.05或<0.01)。结论:缺血性脑卒中大鼠尿酸水平明显升高,抑制尿酸水平可改善炎症及梗死面积,这可能是通过炎症分子通路对其发挥作用。     

Lack of compensatory increase in islet blood flow and islet mass in GK rats following 60% partial pancreatectomy

The effects of a 60% partial pancreatectomy were studied in hyperglycemic GK (Goto-Kakizaki) rats. Partial pancreatectomy or a sham operation was performed on 12-week-old female Wistar rats, GK rats or hybrids between male GK rats and female Wistar rats. Measurements of pancreatic blood flow and islet blood flow were performed by a microsphere technique 2 weeks after surgery. Glucose tolerance was decreased in hybrid compared with Wistar rats, and in GK rats compared with both hybrid and Wistar rats before surgery. Partial pancreatectomy induced minor changes in glucose tolerance. Wistar rats had a decreased islet mass following partial pancreatectomy. Both hybrid and GK rats showed a significant decrease in relative islet volume, but only GK rats in total islet mass, compared with Wistar rats 2 weeks after surgery. Pancreatic blood flow and islet blood flow did not significantly differ between sham-operated Wistar, hybrid or GK rats. After partial pancreatectomy, islet blood flow in relation to islet mass increased 3-fold in Wistar rats and 2-fold in hybrid rats. In contrast, GK rats showed no increase in islet blood flow following partial pancreatectomy. It is concluded that compensatory mechanisms after partial pancreatectomy are operating less efficiently in hybrid and GK rats.     

胃旁路术后IRS-1和IRS-2的表达变化对糖尿病大鼠空腹血糖和胰岛素抵抗的影响及作用机制

目的探讨Roux-en-Y胃旁路术（RYGB）后胰岛素受体底物（IRS）-1和IRS-2的表达变化对糖尿病大鼠空腹血糖和胰岛素抵抗的影响及其作用机制。 方法用随机数字表法将30只糖尿病模型的Wistar大鼠分为RYGB组、假手术组和饮食对照组。另选取10只同周龄的正常Wistar大鼠为对照组。RYGB组接受RYGB,假手术组在相同位置处切开胃壁和空肠后行原位缝合,饮食对照组的进食量为RYGB组前1天的进食量,空白对照组自由进食普通饲料。于术前和术后1、2、3、4周检测空腹血糖（FPG）和空腹胰岛素（FIns）水平,并计算胰岛素抵抗指数（HOMA-IR）。其后处死大鼠,取骨骼肌、肝脏和胰腺组织。采用Western blot技术检测各组大鼠骨骼肌和肝脏中IRS-1和IRS-2的表达情况,采用免疫组化方法检测胰腺IRS-2的表达情况。4组数据的比较采用单因素方差分析,组间两两比较采用LSD-t检验;组内两组数据的比较采用配对t检验;4组胰腺组织IRS-2阳性表达率的比较采用χ²检验。 结果术后第4周,RYGB组大鼠的FPG水平较术前明显降低（t=30.617,P<0.05）,低于同期的假手术组和饮食对照组（LSD-t_假手术组=12.112,LSD-t_{饮食对照组}=10.095,P值均<0.05),与空白对照组比较差异无统计学意义（LSD-t=0.347,P>0.05）;RYGB组大鼠的HOMA-IR值也较术前明显下降（t=8.631,P<0.05）,低于同期假手术组和饮食对照组（LSD-t_假手术组=7.713,LSD-t_{饮食对照组}=7.931,P值均<0.05）,与空白对照组比较差异无统计学意义（LSD-t=0.822,P>0.05）。手术4周后,RYGB组大鼠肌肉组织中IRS-1和其磷酸化的p-IRS-1表达水平明显高于假手术组和饮食对照组（P<0.05）;RYGB组大鼠肝脏组织中IRS-2的表达水平明显低于假手术组和饮食对照组（P<0.05）,稍高于空白对照组;RYGB组大鼠胰腺细胞中IRS-2的阳性表达率为76%,明显高于饮食对照组的2%,假手术组的3%和空白对照组的44%（χ²_{饮食对照组}=230.181,χ²_假手术组=222.994,χ²_{空白对照组}=42.667,P值均<0.05）。 结论RYGB能引起相应靶器官内IRS-1和IRS-2的表达变化,这可能是改善2型糖尿病胰岛素抵抗和降低空腹血糖水平的机制之一。     

Altered glucose and insulin responses to brain medullary thyrotropin-releasing hormone (TRH)-induced autonomic activation in type 2 diabetic Goto-Kakizaki rats

Insulin secretion is impaired in type 2 diabetes (T2D). The insulin and glucose responses to central autonomic activation induced by excitation of brain medullary TRH receptors were studied in T2D Goto-Kakizaki (GK) rats. Blood glucose levels in normally fed, pentobarbital-anesthetized GK and nondiabetic Wistar rats were 193 and 119 mg/100 ml in males and 214 and 131 mg/100 ml in females. Intracisternal injection (ic) of the stable TRH analog RX 77368 (10 ng) induced significantly higher insulin response in both genders of overnight-fasted GK rats compared with Wistar rats and slightly increased blood glucose in female Wistar rats but significantly decreased it from 193 to 145 mg/100 ml in female GK rats. RX 77368 (50 ng) ic induced markedly greater glucose and relatively weaker insulin responses in male GK rats than Wistar rats. Bilateral vagotomy blocked ic RX 77368-induced insulin secretion, whereas adrenalectomy abolished its hyperglycemic effect. In adrenalectomized male GK but not Wistar rats, ic RX 77368 (50 ng) dramatically increased serum insulin levels by 6.5-fold and decreased blood glucose levels from 154 to 98 mg/100 ml; these changes were prevented by vagotomy. GK rats had higher basal pancreatic insulin II mRNA levels but a lower response to ic RX 77368 (50 ng) compared with Wistar rats. These results indicate that central-vagal activation-induced insulin secretion is susceptible in T2D GK rats. However, the dominant sympathetic-adrenal response to medullary TRH plays a suppressing role on vagal-mediated insulin secretion. This unbalanced vago-sympathetic activation by medullary TRH may contribute to the impaired insulin secretion in T2D.     

Is human Type 2 diabetes maternally inherited? Insights from an animal model

AIMS: Patients with Type 2 diabetes mellitus more often report a history of an affected mother than father. However, in the few studies where both parents and offspring have been directly tested, this apparent maternal excess has not been confirmed. Rodent models of diabetes have the advantage that all parents and offspring can undergo glucose tolerance testing at a specific age in adult life. The aim of this study was to gain insights into the inheritance of human Type 2 diabetes by using a rat model. METHODS: Goto Kakizaki (GK) rats (a model of Type 2 diabetes) were mated with non-diabetic Wistar rats. Offspring were produced from 20 GK female vs. Wistar male and 20 Wistar female vs. GK male crosses. Fasting blood glucose was measured at 6 weeks and 3 months of age and an intravenous glucose tolerance test (0.8 g/kg) performed at 6 months of age. RESULTS: Wistar mothers produced litters with almost twice as many viable offspring as GK mothers (14.1 vs. 7.4, P < 0.001). Despite the larger litter size, offspring in the two groups were of comparable weight at 6 weeks and 6 months of age. At 3 months of age, male offspring of Wistar mothers were heavier than offspring of GK mothers (415.7 g vs. 379.5 g, P = 0.016) but this difference was not sustained at 6 months of age. Fasting blood glucose at all ages and average blood glucose during the glucose tolerance test were similar in both groups. CONCLUSIONS: We therefore conclude that there is no evidence for maternal transmission of diabetes in the GK rat. Mothers were able to adjust their supply of milk so that offspring attained similar weights independent of litter size. The weight of the offspring remained independent of litter size into adult life.     

心力衰竭大鼠肾脏血管紧张素Ⅱ受体各亚型表达的改变

目的:探讨大鼠心力衰竭(心衰)时肾脏血管紧张素Ⅱ受体(angiotensinⅡreceptor ATR)各亚型表达水平的变化。方法:选择雄性Wistar大鼠35只,随机分为对照组(10只)、假手术组(10只)、其余15只制作心肌梗死后心衰模型成功9只为模型组。取大鼠肾脏皮质,采用反转录聚合酶链反应(RT-PCR)法分别测定各组大鼠ATR各亚型mRNA表达水平。结果:假手术组与对照组AT1R、AT2R比较,差异无统计学意义(P>0.05);与假手术组比较,模型组大鼠AT1R表达明显上调,差异有统计学意义(P<0.05),模型组大鼠AT2R表达明显下调,差异有统计学意义(P<0.01)。结论:心衰时肾脏AT1R明显上调,可能与此时RAS激活、血管紧张素Ⅱ(AngⅡ)生成增多有关;而AT2R明显下调,提示肾脏代偿能力不足,最终会导致心衰肾脏的功能明显减退。     

Augmented reduction of islet β‐cell mass in Goto‐Kakizaki rats fed high‐fat diet and its suppression by pitavastatin treatment

Aims/Introduction: High fat diet (HFD) is known to be a risk for development of type 2 diabetes. It is unclear, however, how it affects the glucose tolerance or the islet structure in type 2 diabetes. The aim of this study is: (i) to examine the effects of HFD on the islet in GK rats, non‐obese type 2 diabetic model; and (ii) to explore if pitavastatin treatment influences the change. Materials and Methods: To see the effects of HFD on islet changes in type 2 diabetes, 4‐week old male GK and Wistar rats were fed HFD for 16 weeks and subjected to glucose tolerance tests and pathological studies of the islet. The effects of pitavastatin (3 mg/kg/day for 16 weeks, oral), one of the lipophilc statins, were also examined in both GK and Wistrar rats fed with or without HFD. Results: The HFD induced hyperlipidemia and aggravated glucose intolerance in both GK and Wistar rats. Pitavastatin treatment did not influence the glucose tolerance in HFD‐fed animals. HFD caused an increase in hepatic lipid contents in all the animals, which was partially suppressed by pitavastatin treatment. GK rats showed reduced β‐cell mass, and fibrosis and macrophage migration in the islets. HFD feeding in GK rats augmented these changes which were associated with enhanced expression of 8‐hydroxydeoxyguanosine and an increase in apoptotic cells. Pitavastatin treatment improved the HFD‐induced islet pathology, and pancreatic insulin contents paralleled the structural changes. Conclusions: HFD feeding worsened the islet pathology in GK rats which was suppressed by pitavastatin treatment. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00173.x, 2011)     

What are Arrhythmogenic Substrates in Diabetic Rat Atria?

INTRODUCTION: Diabetes mellitus is one of the significant independent risk factors for the development of atrial fibrillation (AF). However, the pathophysiological mechanisms of the relationship have not been fully elucidated. METHODS AND RESULTS: The genetic type II diabetes (GK) rats and their original (Wistar) ones were subjected to electrophysiological (n = 8 per group) and histological (n = 7 per group) studies. At 40 weeks old, when GK rats had significantly (P < 0.01) more increased plasma glucose and HbA(1c) values than Wistar rats, atrial electrical stimuli in the isolated-perfused hearts induced significantly greater number of repetitive atrial responses in GK rats than in Wistar rats (47.9 +/- 17.5 vs 3.1 +/- 1.3 beats, respectively, P < 0.01). GK rats showed significantly longer intra-atrial activation time than Wistar rats (18.3 +/- 0.4 ms vs 15.9 +/- 0.5 ms, P < 0.01) without any significant difference in the atrial refractoriness. The histological examination revealed significantly increased diffuse fibrotic deposition in GK rats atria compared with Wistar ones (P < 0.01). CONCLUSION: The present diabetic GK rat showed increased atrial arrhythmogenicity with intra-atrial conduction disturbance, and thus indicated that the structural remodeling of atrium characterized by diffuse interstitial fibrosis would be a major substrate for diabetes-related AF.     

Type 2 diabetes mellitus — genes or intrauterine environment? An embryo transfer paradigm in rats

Aims/hypothesis The familial predisposition to Type 2 diabetes mellitus is mediated by both genetic and intrauterine environmental factors. In the normal course of events, maternal genes always develop in the same uterus, thus restricting studies aimed at investigating the relative contribution of these factors. We have developed an embryo transfer paradigm in rats to overcome this difficulty.Methods Euglycaemic female Wistar rats were superovulated and mated with male Wistar rats. The following day, fertilised eggs were transferred into pseudo-pregnant female Wistar rats or hyperglycaemic Goto Kakizaki (GK) rats. Pregnancies were allowed to go to term. Offspring were weighed at 6 weeks, 3 months and 6 months of age and an intravenous glucose tolerance test was carried out at 6 months of age.Results Offspring from Wistar into Wistar embryo transfers (n=20) were not significantly hyperglycaemic compared to the non-manipulated Wistar stock colony (n=26). However, offspring from Wistar gametes reared in hyperglycaemic GK mothers (n=51) were significantly lighter at 6 weeks of age (156±4.1 g vs 180±6.1 g [mean ± SEM], p<0.01) and significantly more hyperglycaemic at 6 months of age (fasting glucose 6.6±0.18 mmol/l vs 4.8±0.21 mmol/l, mean blood glucose during glucose tolerance test 14.3±0.31 mmol/l vs 11.1±0.28 mmol/l, p<0.01) than Wistar gametes transferred back into euglycaemic Wistar mothers. When GK rats were superovulated and mated together, transfer of 1-day-old embryos into pseudo-pregnant Wistar dams did not alleviate hyperglycaemia in adult offspring.Conclusions/interpretation In GK rats, a euglycaemic intrauterine environment cannot overcome the strong genetic predisposition to diabetes. However, in Wistar rats with a low genetic risk of diabetes, exposure to hyperglycaemia in utero significantly increases the risk of diabetes in adult life.Abbreviations AvGTT weighted average blood glucose during glucose tolerance test - FG fasting blood glucose - GK Goto Kakizaki - W Wistar     

1型糖尿病对主动脉缩窄大鼠结构和功能的影响

目的探讨糖尿病是否能加重左心室超负荷引起的心力衰竭。方法 3周龄雄性Wistar大鼠54只,随机分为4组:假手术组14只,胸主动脉缩窄(TAC)组12只,假手术+链脲佐菌素(STZ)组15只(STZ组),TAC+STZ组(联合组)13只。记录大鼠的体质量演变,并分别于TAC术后15、50d对所有大鼠行超声心动图检查。在TAC术后66d处死大鼠,分离左心房、右心房、心室等,进行称重,天狼星红染色分析心肌纤维化。结果与假手术组比较,STZ组50d舒张末室间隔厚度(IVST)、左心室后壁舒张末厚度(PWT)、左心室质量、心率明显降低(P<0.01);TAC组15dIVST、PWT、LVM明显升高(P<0.01)。与15d比较,TAC组和联合组50d左心室肥厚百分比明显增高(P<0.01)。与假手术组比较,STZ组大鼠体质量、左心室质量、左心房质量、肺脏质量、左心室质量/胫骨长度明显降低,左心室质量/体质量明显升高;而TAC组大鼠左心室质量、左心房质量、肺脏质量、左心室质量/胫骨长度、左心室质量/体质量明显升高(P<0.05,P<0.01)。结论糖尿病明显增加了TAC诱导的左心室肥厚,但并没有加重TAC大鼠模型的心力衰竭指征,可能是因为糖基化终产物的聚集所致。