苯扎贝特对2型糖尿病大鼠胰岛β细胞半胱天冬蛋白酶-3表达的影响
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摘要
目的:观察苯扎贝特对2型糖尿病大鼠胰岛β细胞半胱天冬蛋白酶-3(caspase-3)表达的影响,探讨其对胰岛β细胞保护的作用机制。
方法:60只雄性SD大鼠随机分为常规饲料组(14只)和高糖高脂饲料组(46只),分别给予常规饲料和高糖高脂饲料喂养。8周后,测定所有大鼠甘油三酯(TG)、总胆固醇(TC)、空腹血糖(FBG)、空腹胰岛素(FINS)等水平,高糖高脂饲料组腹腔注射链脲佐菌素(STZ,30mg/kg)溶液建立2型糖尿病大鼠模型,常规饲料组则给予等体积的柠檬酸缓冲液腹腔注射。成模的28只2型糖尿病大鼠随机分为2组:糖尿病组(DM,n=14)和糖尿病+苯扎贝特干预组(DMB,n=14),常规饲料组大鼠全部作为正常对照组(NC,n=14),三组一同进入药物干预,DMB组每日给予苯扎贝特50mg/kg灌胃,NC组和DM组每日予相应容量的蒸馏水灌胃,连续灌胃12周。测定三组大鼠药物干预前后的TG、TC、FBG、FINS等水平。干预12周后处死所有大鼠,取胰腺组织HE染色镜下观察,原位末端核苷酸标记法(TUNEL)检测胰岛β细胞凋亡,免疫组化SP法观察胰岛β细胞caspase-3的表达。
结果:(1)与常规饲料组相比,高糖高脂饲料组大鼠血TG、TC水平明显升高(P<0.01),FINS水平也升高(P<0.05),FBG则无明显差异(P>0.05)。(2)成模后糖尿病大鼠合并糖脂代谢紊乱,经过苯扎贝特干预后,DMB组大鼠TG、TC较干预前明显下降(P<0.01),FBG也得到改善(P<0.05),FINS水平也得到恢复(P<0.05)。(3)与NC组相比,DM组、DMB组大鼠胰岛β细胞亡率、caspase-3阳性表达率均明显增多,与DM组相比,DMB组大鼠胰岛β细胞凋亡率、caspase-3阳性表达率下降(P<0.05),但均高于NC组(P<0.05)。
结论:苯扎贝特可以改善糖尿病大鼠糖脂代谢紊乱,进一步减轻胰岛素抵抗及改善胰岛分泌功能,其作用机制可能与下调胰岛caspase-3表达,减少胰岛β细胞凋亡有关。
Objective:To observe the influence of caspase-3 expression of isletβcell in type 2 diabetic rats and study the mechanism of protection toβcell by treatment of bezafibrate.
Method:60 Sprague-Dawley male rats were randomlized to normal diet group(n=14)and high sugar and fat diet group(n=46),then separately fed with normal diet and high sugar and fat diet.After 8 weeks, the levels of Triglyceride(TG),Total cholesterol(TC),Fasting blood glucose (FBG),Fasting insulin (FINS) et al were detected,then the high sugar and fat diet group were injected with STZ solution(30mg/kg),the other rats were injected with the same volume of citrate buffer solution.Type 2 diabetes rats models would be formed.Then 28 type 2 diabetes rats were randomly divided into two groups: diabetes group(DM,n=14) and diabetes with bezafibrate group (DMB,n=14),the normal diet group were all included as normal control group(NC,n=14).DMB group were treated with bezafibrate (50mg/kg) everday, NC and DM groups were given the same dose of distilled water. The levels of TG、TC、FBG、FINS in all groups were detected before and after the treatment of bezafibrate.After 12 weeks intervention,dyed with Hematoxylin-Eosin, the morphous of pancrease islet were observed by microscope,the apoptosis of isletβcell was detected by TUNEL,the expression of caspase-3 in islets was detected by immunohistochemistry.
Results:1.The levels of TG、TC in the high sugar and fat diet group were higher than in the normal diet group(P<0.01),the levels of FINS was also higher in high sugar and fat diet group(P<0.05),the levels of FBG had no dirfference in the two groups(P>0.05).2.The levels of TG、TC were decreased conspicuously in DMB group after intervention, the levels of FBG was also decreased(P<0.05),but the levels of FINS was improved(P<0.05).3.The apoptosis index of isletβcell and expression of caspase-3 were more in DM and DMB groups than in NC group, the apoptosis index of isletβcell and expression of caspase-3 in DMB group was decreased than DM group(P<0.05),but both higher than NC group.
Conclusion:Intervening hyperlipemia in diabetes rats with Bezafibrate could reduce the resistance of iusulin and improve the secretary function ofβcell,it was associated with downregulating expression of caspase-3 and decreasing apoptosis ofβcell to the protection ofβcell.
方法:60只雄性SD大鼠随机分为常规饲料组(14只)和高糖高脂饲料组(46只),分别给予常规饲料和高糖高脂饲料喂养。8周后,测定所有大鼠甘油三酯(TG)、总胆固醇(TC)、空腹血糖(FBG)、空腹胰岛素(FINS)等水平,高糖高脂饲料组腹腔注射链脲佐菌素(STZ,30mg/kg)溶液建立2型糖尿病大鼠模型,常规饲料组则给予等体积的柠檬酸缓冲液腹腔注射。成模的28只2型糖尿病大鼠随机分为2组:糖尿病组(DM,n=14)和糖尿病+苯扎贝特干预组(DMB,n=14),常规饲料组大鼠全部作为正常对照组(NC,n=14),三组一同进入药物干预,DMB组每日给予苯扎贝特50mg/kg灌胃,NC组和DM组每日予相应容量的蒸馏水灌胃,连续灌胃12周。测定三组大鼠药物干预前后的TG、TC、FBG、FINS等水平。干预12周后处死所有大鼠,取胰腺组织HE染色镜下观察,原位末端核苷酸标记法(TUNEL)检测胰岛β细胞凋亡,免疫组化SP法观察胰岛β细胞caspase-3的表达。
结果:(1)与常规饲料组相比,高糖高脂饲料组大鼠血TG、TC水平明显升高(P<0.01),FINS水平也升高(P<0.05),FBG则无明显差异(P>0.05)。(2)成模后糖尿病大鼠合并糖脂代谢紊乱,经过苯扎贝特干预后,DMB组大鼠TG、TC较干预前明显下降(P<0.01),FBG也得到改善(P<0.05),FINS水平也得到恢复(P<0.05)。(3)与NC组相比,DM组、DMB组大鼠胰岛β细胞亡率、caspase-3阳性表达率均明显增多,与DM组相比,DMB组大鼠胰岛β细胞凋亡率、caspase-3阳性表达率下降(P<0.05),但均高于NC组(P<0.05)。
结论:苯扎贝特可以改善糖尿病大鼠糖脂代谢紊乱,进一步减轻胰岛素抵抗及改善胰岛分泌功能,其作用机制可能与下调胰岛caspase-3表达,减少胰岛β细胞凋亡有关。
Objective:To observe the influence of caspase-3 expression of isletβcell in type 2 diabetic rats and study the mechanism of protection toβcell by treatment of bezafibrate.
Method:60 Sprague-Dawley male rats were randomlized to normal diet group(n=14)and high sugar and fat diet group(n=46),then separately fed with normal diet and high sugar and fat diet.After 8 weeks, the levels of Triglyceride(TG),Total cholesterol(TC),Fasting blood glucose (FBG),Fasting insulin (FINS) et al were detected,then the high sugar and fat diet group were injected with STZ solution(30mg/kg),the other rats were injected with the same volume of citrate buffer solution.Type 2 diabetes rats models would be formed.Then 28 type 2 diabetes rats were randomly divided into two groups: diabetes group(DM,n=14) and diabetes with bezafibrate group (DMB,n=14),the normal diet group were all included as normal control group(NC,n=14).DMB group were treated with bezafibrate (50mg/kg) everday, NC and DM groups were given the same dose of distilled water. The levels of TG、TC、FBG、FINS in all groups were detected before and after the treatment of bezafibrate.After 12 weeks intervention,dyed with Hematoxylin-Eosin, the morphous of pancrease islet were observed by microscope,the apoptosis of isletβcell was detected by TUNEL,the expression of caspase-3 in islets was detected by immunohistochemistry.
Results:1.The levels of TG、TC in the high sugar and fat diet group were higher than in the normal diet group(P<0.01),the levels of FINS was also higher in high sugar and fat diet group(P<0.05),the levels of FBG had no dirfference in the two groups(P>0.05).2.The levels of TG、TC were decreased conspicuously in DMB group after intervention, the levels of FBG was also decreased(P<0.05),but the levels of FINS was improved(P<0.05).3.The apoptosis index of isletβcell and expression of caspase-3 were more in DM and DMB groups than in NC group, the apoptosis index of isletβcell and expression of caspase-3 in DMB group was decreased than DM group(P<0.05),but both higher than NC group.
Conclusion:Intervening hyperlipemia in diabetes rats with Bezafibrate could reduce the resistance of iusulin and improve the secretary function ofβcell,it was associated with downregulating expression of caspase-3 and decreasing apoptosis ofβcell to the protection ofβcell.
引文
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[1]陈丽,陈青.肥胖与2型糖尿病.山东医药,2000,40(24).
[2]杨文英,邢小燕,林红等.高甘油三脂血症是非胰岛素依赖性糖尿病发病的独立危险因素.中华内科杂志,1995,34:583-6.
[3] Stofan N,Stumvoll M,Bogardus C,et al.Elevated Plasma nonesterificated fatty acids are associated with deterioration of acute insulin response in IGT but not NGT.Am J Physiol Endocnol Metab,2003,284(6):ll56-61.
[4] McGarry JD, Banting lecture 2001:dysregulation of fatty acid metabolism in the etiology of type 2 diabetes.Diabetes,2002,51(1):7-18.
[5] Girard J.Contribution of free fatty acids to impairment of insulin secretion and action mechanism of beta-cell lipotoxicity.Med Sci(Paris),2005,21 Spec:19-25.
[6] Randle PJ,Garland PB,Hales CN,et al.The glucose fatty-acid cycle:its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.Lancet,1963,1:785.
[7] Margaret E,Griffin,Melisssa J,et al.Free fatty acid induced insulin resistance is associated with activation of protein kinase C and alterations in the insulin signaling cascade.Diabetes,1999,48(6):1270-4.
[8] Haber EP,Procopio J,Carvalho CR,et al.New insights into fatty acids modulation of pancreatic beta-cell function. ELSERVIER,2006,248:1-41.
[9] Stein DT,Esser V,Stevenson BE,et al.Essentiality of circulating fatty acids for glucose- stimulated insulin secretion in the fasted rat.J Clin Invest,1996,97:2728-32.
[10] Unger RH,Zhou YT.Lipotoxicity of beta-cells in obesity and other causes of fatty acid spilover. Diabetes,2001,50(Suppl 1) :1l8一21.
[11] Milburn JL, Hirose H, Lee Y, et al. Pancreatic beta-cells in obesity. Evidence for induction of functional, morphologic, and metabolic abnormalities by increased long chain fatty acids. J Biol Chem,1995,270 (3):1295-9..
[12]卜石,杨文英,王昕等.脂毒性对大鼠胰岛细胞凋亡的作用.中华糖尿病杂志,2004, 12(6):433-6.
[13] Listenberger LL,Ory DS,Schaffer JE,et al.Palmitate induced apoptosis can occur through a cetamide independent pathway.J Biol Chem,2001,275(18):14890-5.
[14]李小明,孙志贤.细胞凋亡中的关键蛋白酶-Caspase-3.国外医学.分子生物学分册,1999, 21(1):6-9.
[15] Piro S,Anellom,Dipetro C,et al.Chronic exprosure to free fatty acids or high glucose induces apoptosis in rat pancreatic islets:possible role of oxidative stress.Metabolism,2002, 51(10):1340-7.
[16] Lupi R,Dotta F,Marselli L, et al.Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets:evidence that beta-cell death is caspase mediated partially dependent on ceramide pathway and Bcl-2 regulated.Diabetes,2002, 51(5):1437-42.
[17] Hirota N,Otabe S,Nakayama H,et al.Sequential activation of caspases and synergistic beta-cell cytotoxicity by palmitate and anti-Fas antibodies.Life Sci,2006,79(13):1312-6.
[18] Robertson RP,Harmon JS.Diabetes, glucose toxicity, and oxidative stress:a case of double jeopardy for the pancreatic islet beta cell.FreeRadic BiolMed,2006,41(2):177-84.
[19] Agata MR, Salvatore P, Marcello A, et al.Glucotoxicity and Lipotoxicity in the beta cell.International Congress Series,2003,1253:115-21.
[20]陆亚群,苏珂.脂毒性促进胰岛β细胞凋亡在2型糖尿病中的作用.上海医学,2009,30(9):399-401
[2]陈丽,陈青.肥胖与2型糖尿病.山东医药,2000,40(24).
[3]杨文英,邢小燕,林红等.高甘油三脂血症是非胰岛素依赖性糖尿病发病的独立危险因素.中华内科杂志,1995,34:583-6.
[4] Stofan N,Stumvoll M,Bogardus C,et al.Elevated Plasma nonesterificated fatty acids are associated with deterioration of acute insulin response in IGT but not NGT.Am J Physiol Endocnol Metab,2003,284(6):ll56-61.
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