槲皮素对2型糖尿病大鼠胰岛素抵抗的改善作用及FGF21/MAPK信号通路的影响
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摘要
目的:探讨槲皮素对2型糖尿病大鼠胰岛素抵抗的改善作用及成纤维细胞生长因子21(fibroblast growth factor21,FGF21)/腺苷酸活化蛋白激酶(MAP-activated protein kinase,MAPK)信号通路的影响。方法:SD大鼠随机分为正常对照组(5只)和糖尿病模型组(20只)。正常对照组给予普通饲料,糖尿病模型组给予高脂饲料喂养。4周后根据造模结果将糖尿病模型组分为模型对照组、二甲双胍组和槲皮素组。二甲双胍组灌胃给予二甲双胍(125 mg·kg~(-1)),槲皮素组灌胃给予槲皮素(100 mg·kg~(-1)),正常对照组和模型对照组灌胃给予等量生理盐水。连续给予4周。检测血清中血糖、空腹胰岛素、胰岛素C肽,计算胰岛素抵抗指数,检测胰腺组织中FGF21、MAPK mRNA的表达及FGF21、MAPK和磷酸化-MAPK(p-MAPK)蛋白表达水平。结果:与正常对照组比较,模型对照组胰岛素C肽、FGF21mRNA相对量、MAPK mRNA相对量、FGF21蛋白表达量、MAPK蛋白表达量和p-MAPK蛋白表达量均降低,血糖、胰岛素、胰岛素抵抗指数增加(P<0.05)。与模型对照组比较,二甲双胍组和槲皮素组胰岛素C肽、FGF21mRNA相对量、MAPK mRNA相对量、FGF21蛋白表达量、MAPK蛋白表达量和p-MAPK蛋白表达量均增加,血糖、胰岛素、胰岛素抵抗指数降低(P<0.05)。二甲双胍组与槲皮素组各指标比较,差异均无统计学意义(P>0.05)。结论:槲皮素能降低血糖,其治疗效果与二甲双胍一致,可有效减轻大鼠外周胰岛素抵抗,其作用机制可以是激活了胰腺组织中FGF21/AMPK信号通路有关。
Objective: To investigate the effect of quercetin on insulin resistance and fibroblast growth factor 21 (FGF21)/MAPactivated protein kinase (MAPK) signaling pathway in type 2 diabetic rats. Methods: Female SD rats were randomly divided into the normal control group (n = 5,normal diet) and the diabetic model group (n = 20,high-fat diet) according to the different feeding methods. Four weeks later,the diabetic model group was further divided into the model control group (normal saline),metformin group (125 mg·kg~(-1) metformin) and quercetin group (100 mg·kg~(-1) quercetin). Various indices after the 4-week treatment were detected,including serum blood glucose,fasting insulin,insulin C-peptide,insulin resistance index,and the expressions of FGF21,MAPK mRNA,FGF21,MAPK and p-MAPK protein. Results: The levels of insulin C-peptide,FGF21 mRNA,MAPK mRNA,as well as the expression levels of FGF21 protein,MAPK protein and p-MAPK protein among the four groups were ranked as metformin group,quercetin group > the model control group > the normal groups (P<0.05). The levels of blood glucose,insulin and insulin resistance index were ranked as metformin group,quercetin group < the model control group < the normal groups (P<0.05). No difference was found between metformin group and quercetin group (P>0.05).Conclusion: Quercetin can reduce serum blood glucose,and its effect is similar to that of metformin,which can effectively alleviate peripheral insulin resistance in rats. The action mechanism is related to the activation of FGF21/MAPK signaling pathway in pancreatic tissue.
Objective: To investigate the effect of quercetin on insulin resistance and fibroblast growth factor 21 (FGF21)/MAPactivated protein kinase (MAPK) signaling pathway in type 2 diabetic rats. Methods: Female SD rats were randomly divided into the normal control group (n = 5,normal diet) and the diabetic model group (n = 20,high-fat diet) according to the different feeding methods. Four weeks later,the diabetic model group was further divided into the model control group (normal saline),metformin group (125 mg·kg~(-1) metformin) and quercetin group (100 mg·kg~(-1) quercetin). Various indices after the 4-week treatment were detected,including serum blood glucose,fasting insulin,insulin C-peptide,insulin resistance index,and the expressions of FGF21,MAPK mRNA,FGF21,MAPK and p-MAPK protein. Results: The levels of insulin C-peptide,FGF21 mRNA,MAPK mRNA,as well as the expression levels of FGF21 protein,MAPK protein and p-MAPK protein among the four groups were ranked as metformin group,quercetin group > the model control group > the normal groups (P<0.05). The levels of blood glucose,insulin and insulin resistance index were ranked as metformin group,quercetin group < the model control group < the normal groups (P<0.05). No difference was found between metformin group and quercetin group (P>0.05).Conclusion: Quercetin can reduce serum blood glucose,and its effect is similar to that of metformin,which can effectively alleviate peripheral insulin resistance in rats. The action mechanism is related to the activation of FGF21/MAPK signaling pathway in pancreatic tissue.
引文
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2侯清涛,李芸,李舍予,等.全球糖尿病疾病负担现状[J].中国糖尿病杂志,2016,24(1):92-96
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8洪天配,郭晓蕙.2型糖尿病合并慢性肾脏病患者口服降糖药治疗的新进展[J].中国糖尿病杂志,2016,24(9):769-772
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10 Wang Z,Zhai D,Zhang D,et al.Quercetin decreases insulin resistance in a polycystic ovary syndrome rat model by improving inflammatory microenvironment[J].Reproductive Sciences,2016,24(5):682-290
11张灵枝,邓旭铭,潘顺顺,等.EGCG防治糖尿病作用及机制研究进展[J].华南农业大学学报,2017,38(5):50-55
12 Belwal T,Nabavi S F,Nabavi SM,et al.Dietary anthocyanins and insulin resistance:when food becomes a medicine[J].Nutrients,2017,9(10):1111-1119
13 Yan X,Chen J,Zhang C,et al.FGF21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation[J].Journal of Cellular&Molecular Medicine,2015,19(7):1557-1568
14付坤,伍熙,吕媛,等.成纤维生长因子21对载脂蛋白E基因敲除小鼠脂质代谢的影响及机制[J].中华老年心脑血管病杂志,2015,17(4):402-406
15 Cheng Y,Zhang J,Guo W,et al.Up-regulation of Nrf2 is involved in FGF21-mediated fenofibrate protection against type 1 diabetic nephropathy[J].Free Radical Biology&Medicine,2016,93(11):94-109
16陈海峰,吴峰,卢楠,等.血清成纤维细胞生长因子21、脂联素与冠状动脉性心脏病的相关性[J].中华高血压杂志,2016,12(8):758-762
17薄亮,蒋硕,龚长义,等.细颗粒物暴露对小鼠糖代谢及炎症反应的影响及机制研究[J].卫生研究,2016,45(4):653-657
18 Vonholstein-Rathlou S,Bondurant L,Peltekian L,et al.FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver[J].Cell Metabolism,2016,23(2):335-343
19王超.氧化苦参碱抑制p38MAPK通路减轻高脂喂养胰岛素抵抗小鼠氧化应激[J].中国中药杂志,2016,41(15):2872-2876
20 Jeanson Y,Ribas F,Galinier A,et al.Lactate induces FGF21 expression in adipocytes through a p38-MAPK pathway[J].Biochemical Journal,2016,473(6):42-56
2侯清涛,李芸,李舍予,等.全球糖尿病疾病负担现状[J].中国糖尿病杂志,2016,24(1):92-96
3王建华,郑昊林,刘淼,等.社区老年人群糖代谢异常、糖尿病患病率与糖尿病控制情况及影响因素分析[J].中华流行病学杂志,2016,37(9):1220-1222
4杨茜,邹大进.肥胖与2型糖尿病的共同起源:能量过剩引发肝脏胰岛素抵抗[J].中国糖尿病杂志,2016,11(2):116-119
5杨婷玉,刘亚妮,师少军.槲皮素对药物代谢酶调控作用的研究进展[J].中国药师,2016,19(3):555-559
6 Singhal G,Fisher FM,Chee MJ,et al.Fibroblast growth factor 21(FGF21)protects against high fat diet induced inflammation and islet hyperplasia in pancreas[J].Plos One,2016,11(2):148-159
7 Lee H,Min K,Yi JS,et al.A phosphoproteomic screen identifies a guanine nucleotide exchange factor for Rab3A protein as a mitogenactivated protein(MAP)kinase phosphatase-5-regulated MAP kinase target in interleukin 6(IL-6)secretion and myogenesis[J].Journal of Biological Chemistry,2017,292(9):3581-3590
8洪天配,郭晓蕙.2型糖尿病合并慢性肾脏病患者口服降糖药治疗的新进展[J].中国糖尿病杂志,2016,24(9):769-772
9刘一杰,薛永常.植物黄酮类化合物的研究进展[J].中国生物工程杂志,2016,36(9):81-86
10 Wang Z,Zhai D,Zhang D,et al.Quercetin decreases insulin resistance in a polycystic ovary syndrome rat model by improving inflammatory microenvironment[J].Reproductive Sciences,2016,24(5):682-290
11张灵枝,邓旭铭,潘顺顺,等.EGCG防治糖尿病作用及机制研究进展[J].华南农业大学学报,2017,38(5):50-55
12 Belwal T,Nabavi S F,Nabavi SM,et al.Dietary anthocyanins and insulin resistance:when food becomes a medicine[J].Nutrients,2017,9(10):1111-1119
13 Yan X,Chen J,Zhang C,et al.FGF21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation[J].Journal of Cellular&Molecular Medicine,2015,19(7):1557-1568
14付坤,伍熙,吕媛,等.成纤维生长因子21对载脂蛋白E基因敲除小鼠脂质代谢的影响及机制[J].中华老年心脑血管病杂志,2015,17(4):402-406
15 Cheng Y,Zhang J,Guo W,et al.Up-regulation of Nrf2 is involved in FGF21-mediated fenofibrate protection against type 1 diabetic nephropathy[J].Free Radical Biology&Medicine,2016,93(11):94-109
16陈海峰,吴峰,卢楠,等.血清成纤维细胞生长因子21、脂联素与冠状动脉性心脏病的相关性[J].中华高血压杂志,2016,12(8):758-762
17薄亮,蒋硕,龚长义,等.细颗粒物暴露对小鼠糖代谢及炎症反应的影响及机制研究[J].卫生研究,2016,45(4):653-657
18 Vonholstein-Rathlou S,Bondurant L,Peltekian L,et al.FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver[J].Cell Metabolism,2016,23(2):335-343
19王超.氧化苦参碱抑制p38MAPK通路减轻高脂喂养胰岛素抵抗小鼠氧化应激[J].中国中药杂志,2016,41(15):2872-2876
20 Jeanson Y,Ribas F,Galinier A,et al.Lactate induces FGF21 expression in adipocytes through a p38-MAPK pathway[J].Biochemical Journal,2016,473(6):42-56