津力达颗粒对STZ诱导糖尿病大鼠下丘脑—垂体—甲状腺轴的作用及机制探讨

发布时间：2018-05-13 23:09

本文选题：津力达颗粒 + 下丘脑-垂体-甲状腺轴　；参考：《第二军医大学》2016年硕士论文

【摘要】：研究目的:糖尿病和甲状腺疾病是两种最常见的内分泌疾病,他们两者都是涉及多器官多系统的临床综合征。糖尿病的甲状腺功能异常发生率增高,而甲状腺功能异常又可加重糖尿病病情和并发症。津力达颗粒作为中药治疗糖尿病的代表药物之一,通过促进胰岛素分泌,改善胰岛素抵抗,保护胰岛β细胞等多条途径治疗糖尿病。尽管国内外临床和动物实验已经有糖尿病甲状腺激素变化的报道,但对下丘脑-垂体-甲状腺(HPT)轴的激素及相应受体的改变尚缺乏系统的研究,特别是对糖尿病中甲状腺激素在靶器官肝脏中甲状腺激素受体、脱碘酶和炎症通路的关系尚不了解。本研究通过链脲佐菌素诱导糖尿病大鼠模型,拟观察糖尿病大鼠对下丘脑-垂体-甲状腺轴(HPT轴)的改变及津力达颗粒、二甲双胍等降糖药物等干预后的作用,并初步探讨糖尿病甲状腺功能异常及津力达颗粒改善HPT轴的机制。研究方法:将48只SD雄性大鼠,随机分为糖尿病组(n=42)和正常对照组(NC组,n=6)。糖尿病组采用链脲佐菌素(STZ,65mg/kg)一次性腹腔注射制备糖尿病模型,建模成功后随机分组为模型组(即无药物干预组,DM)、低剂量津力达组(JL)、中剂量津力达组(JM)、高剂量津力达组(JH)、二甲双胍组(Met)、沙格列汀组(Sax)和中剂量津力达加通心络组(JM+T),每组6只,分别于每日晨8:00予相应药物或安慰剂灌胃8周,处死大鼠,并留取血样、甲状腺、垂体和肝脏等器官或组织。采用电化学发光法和放射免疫法等方法检测血清空腹葡萄糖(FBG),T3、T4和TSH的浓度;RT-PCR检测肝脏TH-R、肝脏脱碘酶Dio1、甲状腺钠碘转运体NIS、甲状腺TSH-R和下丘脑proTRH的mRNA表达水平,Western Blot检测甲状腺NIS,肝脏脱碘酶D1、pIκB、pNF-κB、TNFα和IL-6水平的变化,以及对甲状腺组织进行HE染色。实验结果:1、DM大鼠明显低于正常组大鼠体重(P0.05),DM与各用药组体重无明显差异。实验终点时测量各组大鼠血糖浓度,结果显示:与NC组比较,DM组空腹血糖升高(p0.05);与dm组相比,jh组、jm+t组和met组空腹血糖降低(p0.05),其余无统计学差异。2、与nc组大鼠比较,dm大鼠体内t3和t4浓度明显下降(p0.01);而tsh浓度和下丘脑protrhmrna的表达水平二组均无统计学差异。与dm组比较,给药组中的jh组、jm+t组、met组和sax组t3和t4浓度均升高(p0.05,其中met组t4浓度升高更明显,p0.01);3、与nc组比较,dm大鼠体肝脏th-rmrna的表达水平明显下降(p0.01),甲状腺tsh-rmrna的表达水平明显升高(p0.01)。与dm组相比,jh组和jm+t组肝脏th-rmrna的表达明显升高(p0.01),met组和sax组的表达水平也升高(p0.05);与dm组相比,jm组、jh组、jm+t组和met组甲状腺tsh-rmrna水平表达明显升高(p0.01),jl组和sax组的表达水平也升高(p0.05)。4、dm组大鼠甲状腺中钠碘转运体nismrna水平与nc组比较表达明显降低(p0.01);与dm组比较,jm+t组和met组nismrna的表达明显升高(p0.01),jh组和sax组钠碘转运体nismrna的表达也升高(p0.05);而jl、jm组和dm比较无统计学差异。5、与nc组比较,dm大鼠肝脏中脱碘酶d1mrna的表达明显降低(p0.01);与dm组比较,jh组、jm+t组和sax组脱碘酶d1mrna的表达明显降低(p0.01),met组dio1mrna的表达也降低(p0.05);而jl、jm组和dm比较亦无统计学差异。6、与nc组比较,dm大鼠肝脏组织piκb、pnf-κb、tnfα和il-6的水平均升高,差异有统计学意义,其中piκb和tnfα(p0.05),pnf-κb和il-6(p0.01);与dm组比较,met组和jm+t组pi-κb的水平均下降(p0.05),其余各组与dm组比较piκb的水平无统计学差异;将各组pnf-κb的水平与dm组相比,jh组、jm+t组和met组都降低(p0.05),余各组无统计学差异;与dm组肝脏tnfα和il-6水平比较,jm组、jh组、jm+t组和met组水平均下降(p0.05),其余各组与dm组比较亦无统计学差异。7、dm组甲状腺平均滤泡上皮降低,胶体面积增加,滤泡面积减小,表明糖尿病状态下甲状腺激素合成、重吸收、分泌功能受损。而jh、jm+t、met组改善较为明显。结论:STZ诱导的糖尿病大鼠表现为NTIS的表现,即T3、T4下降而TSH无明显改变,津力达颗粒可改善HPT轴的功能紊乱,其具体机制可能与抗炎等作用,降低NF-κB通路对脱碘酶D1和TRβ的抑制作用有关。
[Abstract]:Objective: diabetes and thyroid diseases are two of the most common endocrine diseases. Both are clinical syndromes involving multiple organ and multiple systems. The incidence of abnormal thyroid function in diabetes is higher, while abnormal thyroid function can aggravate diabetes and complication. One of the drugs for the treatment of diabetes by promoting insulin secretion, improving insulin resistance and protecting islet beta cells. Although there have been reports of changes in the thyroid hormone in the clinical and animal experiments at home and abroad, the changes in the hormones and corresponding receptors of the hypothalamus pituitary thyroid (HPT) axis are still lacking systematic study. In particular, the relationship between thyroid hormone receptor, deiodenin and inflammatory pathways in the liver of the target organs is not yet understood. This study was designed to observe the changes in the hypothalamus pituitary thyroid axis (HPT axis) and zinjida granules, metformin and other drops in diabetic rats by streptozotocin induced diabetic rats. The effect of sugar drugs and other dry prognosis, and preliminary study on the mechanism of diabetes thyroid dysfunction and zinida granule to improve the HPT axis. Methods: 48 SD male rats were randomly divided into diabetes group (n=42) and normal control group (NC group, n=6). Diabetic group was injected with streptozotocin (65mg/kg) in one time to prepare diabetes model by intraperitoneal injection. Model group (DM), low dose Zink group (JL), middle dose Zenda group (JM), high dose Zink group (JH), metformin group (Met), shaglitin group (Sax) and middle dose zigan Tongxinluo group (JM+T), each group of 6 in each group were given the corresponding drugs or placebo gavage 8 at 8:00 a. m. each day. At week, the rats were killed and the blood samples, thyroid, pituitary, and liver tissues were retained. The concentrations of serum fasting glucose (FBG), T3, T4 and TSH were detected by electrochemiluminescence and radioimmunoassay, and RT-PCR of liver TH-R, liver deiodidenzyme Dio1, thyroid gland sodium iodide transporter NIS, thyroid TSH-R and mRNA expression of proTRH in the hypothalamus were detected by RT-PCR. Level, Western Blot detection of thyroid NIS, liver deiodinated enzyme D1, pI kappa B, pNF- kappa B, TNF alpha and IL-6 levels, and HE staining of thyroid tissue. Experimental results: 1, DM rats were significantly lower than the normal group of rats weight. Compared with the NC group, the fasting blood glucose in the DM group increased (P0.05). Compared with the DM group, the fasting blood glucose decreased (P0.05) in the JH group, the jm+t group and the met group, and the rest had no statistical difference, and the T3 concentration and the concentration in the DM rats were significantly lower than those in the NC group. The concentration of T3 and T4 increased in group JH, jm+t, met and sax (P0.05, and T4 concentration in met group was more obvious, P0.01). 3, compared with NC group, the expression level of rat liver was obviously decreased and the expression level of thyroid gland was obviously increased. The expression level of Xian Shenggao (P0.01), group met and sax also increased (P0.05). Compared with group DM, the expression of thyroid tsh-rmrna level in JM group, JH group, jm+t group and met group increased significantly (P0.01), and the expression level of JL group and group also increased. The expression of nismrna in group jm+t and group met increased significantly (P0.01), and the expression of nismrna in group JH and sax group increased (P0.05), while JL, JM group and DM group had no statistical difference. Compared with the group, the expression of deiodinated enzyme in the liver of the rats was significantly lower than that in the group of JL and JM. The expression of dio1mrna decreased significantly (P0.01), and the expression of dio1mrna in group met also decreased (P0.05), while JL, JM group and DM had no statistical difference.6. The level of pi- kappa B decreased (P0.05), and the level of PI kappa B in the other groups was not statistically different from that in the DM group, and the level of pnf- kappa B in each group was lower than that of the DM group, and the JH, jm+t and met groups had no statistical difference. There was no significant difference between the groups and the DM group.7. The average follicular epithelium of the thyroid gland decreased, the colloid area increased, the area of the follicle decreased, indicating that the thyroid hormone synthesis, reabsorption and secretory function were impaired in the diabetic state. The improvement of the JH, jm+t and met groups was more obvious. Conclusion: STZ induced diabetic rats showed NTIS performance, that is T3, T4. There was no obvious change in the TSH, and the Jin Lida granules could improve the dysfunction of the HPT axis. The specific mechanism may be related to the anti-inflammatory effect and the reduction of the inhibition of the deiodinated enzyme D1 and TR beta by the NF- kappa B pathway.

【学位授予单位】：第二军医大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R587.1

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