利拉鲁肽通过下调iNOS改善糖尿病前期小鼠胰岛功能
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摘要
目的:研究胰高血糖素样肽-1(GLP-1)类似物利拉鲁肽对糖尿病前期小鼠胰岛功能的影响。方法:30只雄性C57BL/6J小鼠随机均分为正常饮食(WT)组、高脂饮食(WH)组、利拉鲁肽(LH)干预组,以RT-PCR检测胰岛素mRNA的表达,以TUNEL法检测胰岛细胞凋亡,以免疫组化法检测胰岛局部诱导型NO合酶(i NOS)及细胞内胰岛素水平等。结果:与WT组相比,WH组胰岛素表达减少,单位面积胰岛细胞凋亡计数明显增加,局部i NOS相对浓度增加(均P<0.01);与WH组比较,LH组胰岛素表达增加,胰岛凋亡细胞计数降低,局部i NOS相对浓度下降(均P<0.05)。结论:GLP-1类似物利拉鲁肽可以改善糖尿病前期小鼠胰岛功能,其机制可能与下调胰岛局部i NOS表达,减弱氧化应激对胰岛的损伤有关。
Objective To study the effect of glucagon-like peptide-1( GLP-1) analogue liraglutide on islet function in pre-diabetic mice. Methods Thirty male C57 BL/6 J mice were randomly divided into control( WT) group,high-fat diet( WH) group and high-fat diet plus liraglutide( LH) group. The expression of insulin mRNA was detected by RT-PCR,the apoptosis of islet cells was detected by TUNEL,and immunohistochemistry was used to determine local inducible NO synthase( i NOS) and intracellular insulin level. Results Compared with WT group,the expression of insulin in the islets of WH group was decreased,the amount of apoptotic cells in unit of islet was increased,and the relative of i NOS was increased( all P<0.01). Compared with WH group,the expression of insulin in LH group increased,the number of apoptotic cells decreased,and the relative concentration of i NOS decreased( P < 0. 05). Conclusion GLP-1 analogue liraglutide plays an important role in improving islet function in pre-diabetes mice.The mechanism may be related to down-regulation of islet local i NOS expression and attenuation of oxidative stress of islet.
Objective To study the effect of glucagon-like peptide-1( GLP-1) analogue liraglutide on islet function in pre-diabetic mice. Methods Thirty male C57 BL/6 J mice were randomly divided into control( WT) group,high-fat diet( WH) group and high-fat diet plus liraglutide( LH) group. The expression of insulin mRNA was detected by RT-PCR,the apoptosis of islet cells was detected by TUNEL,and immunohistochemistry was used to determine local inducible NO synthase( i NOS) and intracellular insulin level. Results Compared with WT group,the expression of insulin in the islets of WH group was decreased,the amount of apoptotic cells in unit of islet was increased,and the relative of i NOS was increased( all P<0.01). Compared with WH group,the expression of insulin in LH group increased,the number of apoptotic cells decreased,and the relative concentration of i NOS decreased( P < 0. 05). Conclusion GLP-1 analogue liraglutide plays an important role in improving islet function in pre-diabetes mice.The mechanism may be related to down-regulation of islet local i NOS expression and attenuation of oxidative stress of islet.
引文
[1] Tuduri E,Lopez M,Diequez C,et al. Glucagon-Like Peptide 1 Analogs and their Effects on Pancreatic Islets[J].Trends Endocrinol Metab,2016,27(5):304-318.
[2] Chen C,Chmelova H,Cohrs CM,et al.Alterations in beta-Cell Calcium Dynamics and Efficacy Outweigh Islet Mass Adaptation in Compensation of Insulin Resistance and Prediabetes Onset[J].Diabetes,2016,65(9):2676-85.
[3]陆春丽,胡东辉,褚加成,等.利拉鲁肽对糖尿病前期小鼠胰岛功能及胰岛微血管内皮细胞作用的研究[J].中国糖尿病杂志,2018,26(5):412-416.
[4] Lu CL,Wang Y,Yuan L,et al.The angiotensin-converting enzyme 2/angiotensin(1-7)/Mas axisprotects the function of pancreatic beta cells by improving the function of islet microvascular endothelial cells[J]. Int J Mol Med,2014,34(5):1 293-1 300.
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[6]叶林秀,郭昆全,朱梅,等.胰高血糖素样肽-1类似物对2型糖尿病患者体质量及胰岛细胞的影响[J].湖北医药学院学报,2013,32(3):213-216.
[7] Oyadomari S,Takeda K,Takiquchi M,et al.Nitric oxide-induced apoptosis in pancreatic beta cells is mediated by the endoplasmic reticulum stress pathway[J]. Proc Natl Acad Sci U S A,2001,98(19):10 845-10 850.
[8] Bucris E,Beck A,Boura-Halfon S,et al.Prolonged insulin treatment sensitizes apoptosis pathways inpancreatic beta cells[J]. J Endocrinol,2016,230(3):291-307.
[9] Plaisance V,Brajkovic S,Tenenbaum M,et al. Endoplasmic Reticulum Stress Links Oxidative Stress to Impaired Pancreatic Beta-Cell Function Caused by Human Oxidized LDL[J]. PLo S One,2016,11(9):e0163046.
[10] Jia L,Xing J,Ding Y,et al.Hyperuricemia causes pancreaticβ-cell death and dysfunction through NF-κB signaling pathway[J].PLo S One,2013,8(10):e78284.
[1] Ortis F,Miani M,Colli ML,et al. Differential usage of NF-κB activating signals by IL-1βand TNF-αin pancreatic beta cells[J].FEBS Lett,2012,586(7):984-989.
[12] Kim MJ,Ryu GR,Kang JH,et al. Inhibitory effects of epicatechin on interleukin-1beta-induced inducible nitric oxide synthase expression in RINm5F cells and rat pancreatic islets by down-regulation of NF-kappa B activation[J].Biochem Pharmacol,2004,68(9):1 775-1785.
[13] Matsubara J,Sugiyama S,Sugamura K,et al.A dipeptidyl peptidase-4 inhibitor,des-fluoro-sitagliptin,improves endothelial function and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice[J].J Am Coll Cardiol,2012,59(3):265-276.
[14] Yu Z,Kuncewicz T,Dubinsky WP,et al.Nitric Oxidedependent Negative Feedback of PARP-1trans-Activation of the Inducible Nitric-oxide Synthase Gene[J]. J Biol Chem,2006,281(14):9 101-9 109.
[2] Chen C,Chmelova H,Cohrs CM,et al.Alterations in beta-Cell Calcium Dynamics and Efficacy Outweigh Islet Mass Adaptation in Compensation of Insulin Resistance and Prediabetes Onset[J].Diabetes,2016,65(9):2676-85.
[3]陆春丽,胡东辉,褚加成,等.利拉鲁肽对糖尿病前期小鼠胰岛功能及胰岛微血管内皮细胞作用的研究[J].中国糖尿病杂志,2018,26(5):412-416.
[4] Lu CL,Wang Y,Yuan L,et al.The angiotensin-converting enzyme 2/angiotensin(1-7)/Mas axisprotects the function of pancreatic beta cells by improving the function of islet microvascular endothelial cells[J]. Int J Mol Med,2014,34(5):1 293-1 300.
[5] Marathe CS,Rayner CK,Jones KL,et al.Glucagon-like peptides 1 and 2 in health and disease:a review[J].Peptides,2013(44):75-86.
[6]叶林秀,郭昆全,朱梅,等.胰高血糖素样肽-1类似物对2型糖尿病患者体质量及胰岛细胞的影响[J].湖北医药学院学报,2013,32(3):213-216.
[7] Oyadomari S,Takeda K,Takiquchi M,et al.Nitric oxide-induced apoptosis in pancreatic beta cells is mediated by the endoplasmic reticulum stress pathway[J]. Proc Natl Acad Sci U S A,2001,98(19):10 845-10 850.
[8] Bucris E,Beck A,Boura-Halfon S,et al.Prolonged insulin treatment sensitizes apoptosis pathways inpancreatic beta cells[J]. J Endocrinol,2016,230(3):291-307.
[9] Plaisance V,Brajkovic S,Tenenbaum M,et al. Endoplasmic Reticulum Stress Links Oxidative Stress to Impaired Pancreatic Beta-Cell Function Caused by Human Oxidized LDL[J]. PLo S One,2016,11(9):e0163046.
[10] Jia L,Xing J,Ding Y,et al.Hyperuricemia causes pancreaticβ-cell death and dysfunction through NF-κB signaling pathway[J].PLo S One,2013,8(10):e78284.
[1] Ortis F,Miani M,Colli ML,et al. Differential usage of NF-κB activating signals by IL-1βand TNF-αin pancreatic beta cells[J].FEBS Lett,2012,586(7):984-989.
[12] Kim MJ,Ryu GR,Kang JH,et al. Inhibitory effects of epicatechin on interleukin-1beta-induced inducible nitric oxide synthase expression in RINm5F cells and rat pancreatic islets by down-regulation of NF-kappa B activation[J].Biochem Pharmacol,2004,68(9):1 775-1785.
[13] Matsubara J,Sugiyama S,Sugamura K,et al.A dipeptidyl peptidase-4 inhibitor,des-fluoro-sitagliptin,improves endothelial function and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice[J].J Am Coll Cardiol,2012,59(3):265-276.
[14] Yu Z,Kuncewicz T,Dubinsky WP,et al.Nitric Oxidedependent Negative Feedback of PARP-1trans-Activation of the Inducible Nitric-oxide Synthase Gene[J]. J Biol Chem,2006,281(14):9 101-9 109.