吉林大学学报(医学版)  2020, Vol. 46 Issue (01): 50-55     DOI: 10.13481/j.1671-587x.20200109

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杜兴旭, 乔子敬, 杨硕, 许智莹, 杨波, 李贺, 陈建光, 王春梅
DU Xingxu, QIAO Zijing, YANG Shuo, XU Zhiying, YANG Bo, LI He, CHEN Jianguang, WANG Chunmei
五味子多糖对2型糖尿病大鼠血清中炎症因子的影响及其作用机制
Effect of Schisandra chinensis polysaccharide on serum inflammatory factors in T2DM rats and its mechanism
吉林大学学报(医学版), 2020, 46(01): 50-55
Journal of Jilin University (Medicine Edition), 2020, 46(01): 50-55
10.13481/j.1671-587x.20200109

文章历史

收稿日期: 2019-03-05
五味子多糖对2型糖尿病大鼠血清中炎症因子的影响及其作用机制
杜兴旭1 , 乔子敬2 , 杨硕2 , 许智莹2 , 杨波2 , 李贺2 , 陈建光2 , 王春梅2     
1. 北华大学附属医院内分泌科, 吉林 吉林 132002;
2. 北华大学药学院药理学教研室, 吉林 吉林 132013
[摘要]: 目的 观察五味子多糖(SCP)对高脂饮食联合小剂量链脲佐菌素(STZ)诱导的2型糖尿病(T2DM)模型大鼠血清中炎症因子的影响,并探讨其治疗T2DM的可能机制。方法 雄性Wistar大鼠给予高脂饮食喂养,并一次性腹腔注射小剂量STZ(30 mg·kg-1)建立T2DM模型。将造模成功的大鼠随机分为模型组、低剂量(25 mg·kg-1)SCP组、中剂量(50 mg·kg-1)SCP组和高剂量(100 mg·kg-1)SCP组,每组10只,另取10只健康大鼠设为正常对照组。灌胃治疗8周后,各组大鼠行口服葡萄糖耐量试验(OGTT),采用葡萄糖氧化酶法检测空腹血糖(FBG),放射免疫分析法检测空腹血胰岛素(INS)水平并计算胰岛素敏感指数(ISI),采用酶联免疫吸附法(ELISA)检测大鼠血清中白细胞介素6(IL-6)、C反应蛋白(CRP)、白细胞介素1β(IL-1β)、肿瘤坏死因子α(TNF-α)和核因子-κB(NF-κB)水平,HE染色观察大鼠胰腺组织病理形态表现。结果 与正常对照组比较,模型组大鼠FBG明显升高(P < 0.01),血糖曲线下面积(AUC)明显增加,INS水平和ISI明显降低(P < 0.05或P < 0.01),血清中IL-6、CRP、IL-1β、TNF-α和NF-κB水平均明显升高(P < 0.05或P < 0.01)。与模型组比较,不同剂量SCP组大鼠FBG水平明显降低(P < 0.05),血糖AUC明显下降,INS水平和ISI明显升高(P < 0.05),血清中IL-6、CRP、IL-1β、TNF-α和NF-κB水平均明显降低(P < 0.05或P < 0.01)。与低剂量SCP组比较,中和高剂量SCP组大鼠FBG水平明显降低(P < 0.05),高剂量SCP组大鼠血清中INS水平明显升高(P < 0.05)。HE染色,与正常对照组比较,模型组大鼠胰岛萎缩,胰岛内细胞数目减少,边界不整;与模型组比较,不同剂量SCP组大鼠胰岛边界逐渐清晰,面积增大,细胞数目明显增加。结论 SCP可降低高脂饮食联合小剂量STZ诱导的T2DM大鼠FBG水平,升高INS水平,改善胰岛素抵抗(IR),其作用机制可能与抑制机体的炎症反应有关。
关键词: 五味子多糖    2型糖尿病    炎症因子    高脂饮食    链脲佐菌素    空腹血糖    
Effect of Schisandra chinensis polysaccharide on serum inflammatory factors in T2DM rats and its mechanism
DU Xingxu1 , QIAO Zijing2 , YANG Shuo2 , XU Zhiying2 , YANG Bo2 , LI He2 , CHEN Jianguang2 , WANG Chunmei2     
1. Department of Endocrinology, Affiliated Hospital, Beihua University, Jilin 132002, China;
2. Department of Pharmacology, College of Pharmacy, Beihua University, Jilin 132013, China
[ABSTRACT]: Objective To observe the effect of Schisandra Chinensis polysaccharide (SCP) on the serum inflammatory factors in the rats with type 2 diabetes mellitus (T2DM) induced by high-fat diet and lowdose of streptozotocin (STZ), and to explore its underlying mechanism in the treatment of T2DM. Methods The male Wistar rats were given high-fat diet and introperieoneally injected with low dose of STZ (30 mg·kg-1) in one time to establish the rat T2DM models. The successful model rats were randomly divided into model group, low dose (25 mg·kg-1) of SCP group, middle dose (50 mg·kg-1) of SCP group and high dose (100 mg·kg-1) of SCP group; there were 10 rats in each group. Another 10 healthy rats were used as normal control group. Eight weeks after the intragastric administration of SCP, oral glucose tolerance test (OGTT) was performed in the rats of various groups. The fasting blood glucose (FBG) and insulin (INS) levels were detected by glucose oxidase method and radioimmunoassay method, respectively, and the insulin sensitivity index (ISI) was calculated. The levels of interleukin-6 (IL-6), C-reactive protein (CRP), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and nuclear factor-κB (NF-κB) in serum of the rats were measured by enzyme linked immunosorbent assay (ELISA) method. HE staining was used to observe the pathomorphology of pancreas tissue of the rats. Results Compared with normal control group, the serum FBG level of the rats in model group was significantly increased (P < 0.01), and the area under the curve(AUC) of blood glucose of the rats was significantly increased, the serum INS level and the ISI were significantly decreased (P < 0.05 or P < 0.01); the levels of IL-6, CRP, IL-1β, TNF-α, and NF-κB in serum were all significantly increased (P < 0.05 or P < 0.01). Compared with model group, the serum FBG levels of the rats in different doses of SCP groups were markedly decreased (P < 0.05), the AUC of blood glucose of the rats were significantly decreased, the INS and the ISI levels were significantly elevated (P < 0.05); the levels of IL-6, CRP, IL-1β, TNF-α and NF-κB in serum were significantly decreased (P < 0.05 or P < 0.01). Compared with low dose of SCP group, the FBG levels of the rats in middle and high doses of SCP groups were significantly decreased(P < 0.05), the serum INS level of the rats in high dose of SCP group was significantly increased(P < 0.05). The HE staining results showed that compared with normal control group, the islets were atrophied, the number of cells in islets was decreased and the boundary was irregular in model group; compared with model group, the islet boundary in different doses of SCP groups became clear, the areas were increased, and the number cells was increased significantly. Conclusion: SCP can decrease the FBG level, increase the INS level and improve insulin resistance (IR) in the T2DM rats induced by high-fat diet combined with low dose of STZ, and its mechanism might be related to its inhibiting inflammation response.
KEYWORDS: Schisandra chinensis polysaccharide    type 2 diabetes mellieus    inflammatory factors    high-fat diet    streptozotocin    fasting blood glucose    

2型糖尿病(type 2 diabetic mellitus, T2DM)的主要病理特征是胰岛素抵抗(insulin resistance, IR)和胰岛β细胞功能衰竭。随着对T2DM和IR研究的不断深入,发现炎症反应已成为IR、胰岛β细胞功能减退、代谢综合征和心血管并发症的“共同土壤”[1]。2011年,DONATH等[2]研究表明:T2DM是一种炎症性疾病。大量研究[3-5]表明:炎症因子如白细胞介素类、肿瘤坏死因子α(tumor necrosis factor-α, TNF-α)、C反应蛋白(C-reactive protein, CRP)和核因子-κB (nuclear factor-κB, NF-κB)等可以通过血液和(或)旁分泌的作用影响胰岛素(insulin, INS)的敏感性和胰岛β细胞功能,因此抑制上述炎症因子能够起到改善IR、保护胰岛β细胞和降低血糖的作用[6-7]

五味子[Schisandra chinensis(Turcz.) Baill.]是著名的长白山道地药材,具有酸、苦、甘、辛和咸5种药性,且以酸味为主,能补益五脏,是治疗糖尿病之上品[8]。近年来研究[9-10]显示:五味子治疗糖尿病效果明显,不仅可以降低糖尿病大鼠血糖和血脂水平,还能提高靶组织对INS的敏感性,延缓胰岛β细胞凋亡,改善β细胞的功能。然而,五味子发挥抗糖尿病作用的具体成分和机制尚不清楚。多糖是五味子的主要活性成分之一,具有抗氧化、调节血脂和保护肝脏等功效[11-13]。本课题组前期研究[14]表明:五味子多糖(Schisandra chinensis polysaccharide, SCP)对链脲佐菌素(streptozotocin, STZ)和四氧嘧啶诱导的小鼠糖尿病均具有明显的降血糖作用,且能降低血清中TNF-α和白细胞介素1β(interleukin-1β,IL-1β)水平。为了进一步探讨SCP对T2DM的治疗作用及其与抗炎症反应的关系,本研究采用高脂饮食联合小剂量STZ建立T2DM大鼠模型,观察SCP对T2DM的治疗作用,并探讨SCP的降糖作用是否与其抑制炎症反应有关,为五味子的进一步开发和利用奠定理论基础。

1 材料与方法 1.1 实验动物、药物、主要试剂和仪器

雄性Wistar大鼠70只,体质量为180~230 g,由长春亿斯实验动物技术有限责任公司提供,动物许可证号:SCXK(吉)2016-0003。大鼠采取分笼饲养,自由摄食饮水,室温21℃~24℃,湿度40%~60%,适应环境5 d后用于实验。实验大鼠的普通饲料和高脂饲料均购于吉林省长春市亿斯实验动物技术有限责任公司,高脂饲料含碳水化合物53.3%、酪蛋白20.0%、猪油10.0%、蔗糖5.0%、胆固醇2.0%和其他9.7%。

SCP由东北师范大学生命科学中心制备[13]。STZ购自美国Sigma-Aldrich公司,葡萄糖试剂盒由中生北控生物科技股份有限公司提供,INS放射免疫分析试剂盒由上海朗顿生物科技有限公司提供,大鼠白细胞介素6(interleukin-6,IL-6)、CRP、IL-1β、TNF-α和NF-κB ELISA检测试剂盒均购于上海碧云天生物技术有限公司。S10手提式高速分散器(宁波新生生物科技股份有限公司),InfiniteM 200全自动酶标仪(瑞士TECAN集团公司),MH-1微量振荡器(海门市其林贝尔仪器制造有限公司)。

1.2 实验动物分组、造模和处理

Wistar大鼠70只,随机选取10只作为正常对照组,饲喂普通饲料;其余60只大鼠饲喂高脂饲料4周后一次性腹腔注射STZ 30 mg·kg-1,建立T2DM模型。正常对照组大鼠给予等体积枸橼酸缓冲液。1周后检测大鼠空腹血糖(fasting blood glucose,FBG),FBG≥7.0 mmol·L-1表示造模成功[15]。将糖尿病模型大鼠随机分为模型组及低、中和高剂量SCP组,每组10只。正常对照组和模型组大鼠给予等体积生理盐水,低、中和高剂量SCP组分别给予25、50和100 mg·kg-1 SCP灌胃,每天1次,连续8周。

1.3 口服葡萄糖耐量实验(oral glucose tolerance test, OGTT)

各组大鼠给药治疗8周后进行OGTT,实验前各组大鼠禁食12 h,灌胃给予葡萄糖2.5g·kg-1,分别于灌胃前(0 min)及灌胃后30、60和120 min采集大鼠眼内眦部血样,测定血糖水平,计算血糖曲线下面积(AUC)。公式为:血糖AUC=(C1+C2)×(t1+t2)/2,C1和C2代表不同时间点的血糖浓度,t1和t2代表不同的检测时间点[16]

1.4 大鼠FBG和INS水平检测

末次灌胃给药后,大鼠被禁食12 h,采用乌拉坦(1g·kg-1)进行麻醉,经腹主动脉取血,3500 r·mim-1离心10 min,分离血清于-80℃保存待用。采用葡萄糖氧化酶法检测大鼠FBG水平,放射性免疫分析法检测血清INS水平,具体操作方法参照试剂盒说明书,并计算胰岛素敏感指数(insulin sensitivity index,ISI),ISI= Ln(FBG×INS)-1[15]

1.5 大鼠血清中炎症因子水平检测

采用ELISA法检测大鼠血清中IL-6、CRP、IL-1β、TNF-α和NF-κB水平,具体操作方法参照试剂盒说明书。

1.6 HE染色观察大鼠胰腺组织病理形态表现

快速取出上述各组大鼠胰腺组织,并置于10%中性甲醛溶液中固定24 h以上,酒精脱水,二甲苯透明,石蜡包埋,切成厚度为5 μm的切片,行常规HE染色。在普通光学显微镜下观察大鼠胰腺组织病理形态表现。

1.7 统计学分析

采用SPSS 22.0统计软件进行统计学分析。各组大鼠血清中FBG、INS和炎症因子水平及ISI经正态性检验呈正态分布,均以x±s表示,多组间样本均数比较采用单因素方差分析,组间两两比较采用SNK-q法。以P < 0.05为差异有统计学意义。

2 结果 2.1 各组大鼠血清中FBG和INS水平及ISI

与正常对照组比较,模型组大鼠FBG水平明显升高(P < 0.01),INS水平和ISI明显降低(P < 0.05或P < 0.01),提示T2DM大鼠建模成功。与模型组比较,各剂量SCP组大鼠血清中FBG水平均明显降低(P < 0.05或P < 0.01),但仍高于正常对照组(P < 0.05或P < 0.01);各剂量SCP组大鼠血清中INS水平和ISI均明显升高(P < 0.05或P < 0.01),但仍低于正常对照组(P < 0.05)。与低剂量SCP组比较,中和高剂量组大鼠FBG水平明显降低(P < 0.05),高剂量SCP组大鼠血清中INS水平明显升高(P < 0.05)。见表 1

表 1 各组大鼠血清中FBG和INS水平及ISI Tab. 1 Levelsof FBG and INS in serum and ISI of rats in various groups
(n=10, x±s)
Group FBG [cB /(mmol·L-1)] INS [λB / (mU·L-1)] ISI
Normal control 4.92±0.64 32.10±5.00 -5.13±0.61
Model 17.30±2.30** 14.07±1.39** -5.58±0.66*
SCP
  Low dose 12.41±2.74**△ 17.71±3.85**△ -5.46±0.13*
  Middle dose 9.76±2.10*△# 23.55±4.01**△ -5.35±0.12*△
  High dose 7.34±1.66*△△# 26.90±4.46*△# -5.28±0.32
* P < 0.05, * * P < 0.01 vs normal control group; P < 0.05, △△ P < 0.01 vs model group; # P < 0.05 vs low dose of SCP group.
2.2 各组大鼠糖耐量水平和血糖AUC

正常对照组、模型组和各剂量SCP组大鼠在葡萄糖注射后30min血糖水平达峰值。在接下来的90min内,正常对照组大鼠血糖水平逐渐下降,在注射120min后基本恢复到正常血糖水平;模型组大鼠血糖水平缓慢下降,其血糖水平与正常对照组、各剂量SCP组比较一直维持在较高水平。此外,模型组大鼠血糖AUC明显高于正常对照组;各剂量SCP组大鼠血糖AUC远低于模型组。见图 1

1:Normal control group; 2:Model group; 3:Low dose of SCP group; 4:Middle dose of SCP group; 5:High dose of SCP group. 图 1 各组大鼠糖耐量水平(A)和血糖AUC(B) Fig. 1 Glucose tolerance levels(A) and AUC of blood glucose(B) of rats in various groups
2.3 各组大鼠血清中炎症因子水平

与正常对照组比较,模型组大鼠血清中IL-1β、IL-6、CRP、TNF-α和NF-κB水平均明显升高(P < 0.01),各剂量SCP组大鼠血清中IL-1β和IL-6水平明显升高(P < 0.05或P < 0.01),低、中剂量SCP组大鼠血清中CRP、TNF-α和NF-κB水平明显升高(P < 0.05或P < 0.01),而高剂量SCP组大鼠血清中CRP、TNF-α和NF-κB水平差异无统计学意义(P > 0.05);与模型组比较,各剂量SCP组大鼠血清中IL-1β、IL-6、CRP、TNF-α和NF-κB水平均明显降低(P < 0.05或P < 0.01)。见表 2

表 2 各组大鼠血清中炎症因子水平 Tab. 2 Levels of inflammatory factors in serum of rats in various groups
[n=10, x±s, cB/(μmol·L-1)]
Group IL-1β IL-6 CRP TNF-α NF-κB
Normal control 42.18±5.88 58.41±9.79 33.52±4.77 150.78±34.65 3.52±1.77
Model 171.12±18.72** 111.28±18.98** 50.16±8.00** 224.27±29.57** 15.16±2.00**
SCP
  Low dose 162.97±17.91**△ 94.33±16.99**△ 47.36±9.58*△ 199.78±32.76*△ 11.36±1.58**△△
  Middle dose 121.28±16.77**△ 77.55±20.82**△△ 39.26±9.84*△△ 170.69±26.97*△△ 5.63±1.04*△△
  High dose 100.33±9.88**△△ 74.66±16.99*△△ 38.63±8.04△△ 165.08±21.64 4.26±1.84△△
* P < 0.05, * * P < 0.01 vs normal control group; P < 0.05, △△ P < 0.01 vs model group.
2.4 各组大鼠胰腺组织病理形态表现

正常对照组大鼠胰岛形状规则,呈圆形或椭圆形团索状,边界清晰,胰岛内β细胞分布均匀,排列紧密,胞浆丰富。模型组大鼠胰岛萎缩,结构不清、边缘不整;各剂量SCP组大鼠胰岛内细胞数明显减少,排列稀疏,随着SCP给药剂量的增加,各剂量SCP组胰岛边界逐渐清晰,细胞数目明显增加,细胞形态趋于完好。见图 2(插页三)。

A:Normal control group; B: Model group; C: Low dose of SCP group; D: Middle dose of SCP group; E: High dose of SCP group. 图 2 各组大鼠胰腺组织病理形态表现(HE, ×200) Fig. 2 Pathomorphology of pancreas tissue of rats in various groups (HE, ×200)(seen on page 54 in paragraph)
3 讨论

五味子始载于《神农本草经》,具有解除因体液不足和糖尿病引起的口渴的功能。1993年张志军[17]首次明确了五味子对临床糖尿病患者具有改善血糖和糖化血红蛋白(HbA1C)的作用。研究[18]显示:SCP能明显降低糖尿病模型小鼠体质量,减轻烦渴、多尿和高血糖表现,促进肝糖原生成,改善小鼠糖尿病的脂质代谢紊乱。本研究结果也显示:SCP可明显降低高脂饮食联合STZ诱导的T2DM大鼠FBG,升高血清INS水平,提高ISI,显示出对T2DM良好的治疗效果。

T2DM发病的主要环节是IR和胰岛β细胞功能缺陷导致不同程度的INS缺乏。本研究采用高脂高胆固醇饮食喂养大鼠,诱导大鼠出现IR,并联合应用小剂量STZ破坏胰岛β细胞,进而发展为类似于人类T2DM的动物模型。本研究中胰岛病理及OGTT检测结果显示:模型组大鼠胰岛受损、萎缩,葡萄糖耐量明显降低,而SCP治疗可明显改善T2DM大鼠的胰岛病理学变化和葡萄糖耐量,改善了IR。

炎症反应参与T2DM的发生发展过程[19-20]。研究[21-23]显示:在肥胖者脂肪组织中M1型巨噬细胞的浸润,促进IL-6和TNF-α等炎症细胞因子的产生,进而干扰INS信号的转导。巨噬细胞从M2型到M1型的转变对T2DM胰岛功能紊乱起着至关重要的作用[24-25]。此外,M1型巨噬细胞释放的细胞因子刺激胰岛β细胞分泌IL-1β等,从而加速胰岛炎症[26]。因此,直接靶向炎症对血糖控制、β细胞功能和IR均具有有益的影响。研究[27-28]证实:IL-1受体拮抗剂或抗IL-1β的单克隆抗体可降低啮齿类动物和人类的高血糖及炎症细胞因子水平,并减轻巨噬细胞浸润。水杨酸前体药物双水杨酸酯通过抑制NF-κB信号通路,进而降低T2DM患者的血糖、HbA1C和CRP水平[29]。高脂饮食联合STZ诱导的T2DM动物模型通常伴有炎症反应。本研究结果也显示:应用高脂饮食联合小剂量STZ一次性腹腔注射建立的T2DM模型大鼠血清中炎症相关因子IL-6、IL-1β、CRP、TNF-α和NF-κB水平明显升高,而使用SCP治疗后,大鼠血清中IL-6、CRP、IL-1β、TNF-α和NF-κB水平均明显降低,提示SCP治疗能够抑制T2DM大鼠机体的炎症反应,发挥改善IR和修复受损的胰岛β细胞的作用,进而发挥降血糖的作用。

综上所述,SCP可降低T2DM大鼠FBG水平,提高INS水平,改善IR,减轻胰岛损伤。SCP对T2DM有治疗作用,其作用机制可能与抑制机体的炎症反应有关。本研究结果为五味子的进一步开发和利用奠定了理论基础。

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