特发性矮小生长激素受体外显子3基因多态性与生长激素轴的关系

摘要： 目的 探讨生长激素受体 （GHR） 外显子 3 基因型与特发性矮小 （ISS） 患者生长激素-胰岛素样生长因子- 胰岛素样生长因子结合蛋白 （GH-IGFs-IGFBPs） 轴的关系。方法 选取 108 例 ISS 儿童, 提取外周血 DNA 并采用多重 PCR 法进行 GHR 外显子 3 基因分型, 根据基因型结果分为 GHRfl 组和 GHRd3 组。测量 2 组身高、 体质量, 并计算体质指数 （BMI） 及 BMI 标准差计分 （SDS）; 测定空腹胰岛素样生长因子(IGF)-1、 胰岛素样生长因子结合蛋白（IGFBP） -3, 计算 IGF-1 SDS、 IGFBP3 SDS; 同时进行生长激素激发试验, 测定血清 GH 峰值。108 例中选取 55 例自愿接受重组人生长激素[rhGH, 0.15 IU/ （kg·d） ]治疗 3 个月, 分析基因型与 rhGH 治疗后 IGF-1 水平的关系。结果 108 例 ISS 中 GHRfl 63 例, GHRd3 45 例。2 组间 BMI、 IGF-1、 IGFBP3、 GH 峰值以及 IGF-1 SDS、 IGFBP3 SDS 差异均无统计学意义(均 P > 0.05); 多元逐步回归分析示年龄、 IGFBP3、 lg （BMI）、 lg （GH 峰值） 是 lgIGF-1 的影响因素 （均 P < 0.05）; 55例接受rhGH治疗ISS中GHRd3组 （34例） IGF-1和IGF-1 SDS治疗前后差值 （△IGF-1,△IGF-1 SDS） 高于 GHRfl组 （21例）。结论 ISS儿童GHR外显子3基因多态性可能与IGF-1及IGFBP3水平无关, 与GH敏感性有关。     

重组人生长激素在老年人肺部感染治疗中的应用

目的 探讨重组人生长激素(rhGH)在老年患者肺部感染治疗中的应用价值.方法 53例肺部感染老年患者随机分为观察组(25例)和对照组(28例),观察组应用小剂量rhGH(0.1 U·Kg-1·d-1)于入院后第二天起每晚皮下注射,疗程10 d;对照组给予等量的注射用水;两组其他治疗相同,包括抗感染、氧疗、营养支持等.观察两组疗效、治疗前后体重指数(BMI)、血清生长激素、胰岛素样生长因子-1、白蛋白、瘦素水平等变化情况.结果 观察组总有效率88.0%,对照组为60.7%,两组比较差异有统计学意义(P＜0.05);观察组治疗后体重指数、血清白蛋白、生长激素、胰岛素样生长因子-1、瘦素水平分别为:(26.I±4.1)kg/m2、(38.4±6.6)g/L、(7.0±0.9)μg/L、(27.3±6.1)μg/L、(6.9±1.1)μg/L,与对照组治疗后的(21.8±3.4)kg/m2、(29.5±5.1)g/L、(4.0±0.4)μg/L、(22.0±3.8)μg/L、(3.8±0.8)μg/L相比较,差异均有统计学意义(均P＜0.05).结论 重组人生长激素辅助治疗老年人肺部感染,能改善患者的营养状态,提高治疗效果.     

重组生长激素改善肾病综合征患者低蛋白血症的研究

目的观察基因重组生长激素(recombinanthumangrowthhormone,rhGH)对肾病综合征(nephro-ticsyndrom,NS)患者血清总蛋白、白蛋白、胰岛素样生长因子-1(insulin-likegrowthfactor-1,IGF-1)和胰岛素样生长因子结合蛋白-3(insulin-likegrowthfactorbindingprotein-3,IGFBP-3)的作用。方法原发性NS患者100例,随机分为2组,治疗组50例,在常规治疗的基础上加用rhGH治疗;对照组50例用常规治疗。以放射免疫法测血清IGF-1及IGFBP-3水平,S-丽春红测24h尿蛋白定量,全自动生化仪检测血清蛋白。结果①rhGH治疗2周后血清IGF-1、IGFBP-3和血清蛋白与对照组相比显著上升;②rhGH治疗组与NS对照组相比尿蛋白排出差异无统计学意义。结论短期小剂量使用外源性rhGH能在不增加尿蛋白排出的情况下提高NS患者血清蛋白水平,且安全可靠。     

手术前应用重组人生长激素对成年手术病人骨骼肌结构和功能的影响

目的:手术前应用重组人生长激素(rhGH)对成年手术病人氮平衡、骨骼肌组织结构和功能及IGF-1mRNA基因表达的影响进行临床研究.方法:采用随机、双盲、安慰剂对照的方法.对20例外科病人于手术前3d开始进行GH的合成治疗.结果:病理学检查发现,两组病人腹直肌组织中肌萎缩和肌营养不良的程度和比例无明显差别(P>0.05),Ⅰ型和Ⅱ型肌纤维的分布比例及总RNA的含量也无明显差别(P>0.05);但GH组病人腹直肌组织的胰岛素样生长因子-1信使核糖核酸(IGF-1 mRNA)水平较对照组增高1.6倍(P=0.03);GH组病人术后氮平衡、双手握力、行走速度以及体重等指标明显优于对照组(P<0.05).结论:手术前开始短期应用rhGH的合成治疗,可以调控组织特异性基因的表达,同时保持了外科手术后病人良好的代谢和生理机能状态,可能更有利于术后病人的康复.     

阿仑膦酸钠对原发性骨质疏松症患者血清IGF-1和IGFBP-3的影响

目的观察阿仑膦酸钠治疗原发性骨质疏松症患者的疗效,通过检测血Ⅰ型胶原N末端肽（NTX）、骨钙素（BGP）及血清胰岛素样生长因子-1（IGF-1）及其结合蛋白（IGFBP-3）的水平来探讨二磷酸盐的可能作用机制。方法选择80例原发性骨质疏松症患者,随机分为钙剂组40例（仅给予钙剂治疗）、阿仑膦酸钠组40例（在给予钙剂治疗的同时每周口服阿仑磷酸钠1片）。所有患者均连续治疗6个月。治疗前后都用DXA双能X线骨密度仪测定腰椎及左股骨近端骨密度（BMD）值,同时测定空腹血Ⅰ型胶原N末端肽（NTX）、BGP及IGF-1、IGFBP-3含量,并进行比较。结果阿仑膦酸钠组BMD较治疗前有明显升高,腰椎为3.08%,左股骨近端5.05%（P〈0.01）,其NTX水平下降（P〈0.05）,BGP水平升高,而IGF-1、IGFBP-3均有不同程度的升高;钙剂组BMD有下降（P〉0.05）,且NTX水平升高,BGP水平下降（P〈0.05）,而IGF-1、IGFBP-3均下降（P〉0.05）。结论阿仑膦酸钠治疗可明显升高BMD值,降低NTX,增加BGP的水平,并且可能通过提高IGF-1的活性达到促进成骨的作用。     

Effectiveness of GH isoform differential immunoassay for detecting rhGH doping on application of various growth factors

The analytical method for detecting growth hormone (GH) doping, the so-called GH isoform differential immunoassay, is currently approved by the World Anti-Doping Agency (WADA). Anti-doping laboratories often face challenges by athletes' lawyers and need to have various types of scientific evidence against the claim that the adverse analytical finding (AAF) result was caused by excess ectopic or abnormal excretion. In this work, a population study of Japanese athletes (255 male and 256 female) and administration studies of recombinant human GH (rhGH) in Japanese females were conducted to confirm the applicability of GH isoform differential immunoassay. The present paper describes the effectiveness of the GH isoform differential immunoassay under abnormal excretion of endogenous GH as determined by administration studies of GH releasing hormone (GHRH(1-44)) and insulin-like growth factor-1 (IGF-1). No false positive findings were found in Japanese athletes. The GH isoform differential immunoassays could detect application of rhGH for approximately 12-24?h. The administration of GHRH(1-44) and IGF-1 as well as ghrelin receptor agonists did not affect the isoform ratio (no false positives). We conclude that the GH isoform differential immunoassay is a highly specific method for detecting rhGH doping. Subject-based profiling (i.e. athlete biological passport) very likely will represent a highly sensitive approach for detecting rhGH doping. Copyright ? 2012 John Wiley & Sons, Ltd.     

重组人生长激素对小于胎龄儿血清胰岛素样生长因子1、胰岛素样生长因子结合蛋白3及身高均值标准差积分的影响

目的探讨血清胰岛素样生长因子1（IGF-1）、胰岛素样生长因子结合蛋白3（IGFBP-3）、两者比值及身高均值标准差积分（HtSDS）在重组人生长激素（rhGH）治疗小于胎龄儿（SGA）中的临床应用价值。方法对32例确诊为追赶生长失败的SGA患儿应用rhGH治疗（0．15～0．20u·b^-1·d^-1）,每晚睡前皮下注射,治疗3、6、9、12个月后进行随访,比较治疗前后的血清IGF-1、IGFBP-3,HtSDS、年生长速率（GV）的变化。结果GV治疗前为（4．1±0．5）cm／年,治疗后3、6、9、12个月分别升至（12．4±3．2）cm／年、（11．0±2．3）cm／年、（10．1±3．5）cm／年、（9．4±1．8）cm／年,显示治疗后追赶生长明显（F=51．35,P〈0．01）;HtSDS治疗前为（-2．81±0．64）,治疗后分别为（-2．55±0．73）、（-2．39±0．65）、（-2．21±0．58）和（-2．09±0．94）,显示治疗后身高与同年龄同性别正常儿童差距逐步缩小,与治疗前相比差异有统计学意义（F=4．99,P〈0．01）。IGF-1、IGFBP-3明显升高,各监测时间点和治疗前相比差异有统计学意义（F=34．52、14．04,均P〈0．01）,以IGF-1升高更明显,3个月之后维持在较高的水平,6个月达高峰;IGF-1／IGFBP-3比值和治疗前相比有所上升,但差异无统计学意义（F=1．82,P〉0．05）。rhGH治疗6个月内,血清IGF-1和身高标准差积分相对治疗前的变化（AHtSDS）存在显著正相关（r3=0．72,r6=0．91）,9个月后不存在相关性（r9=0．26,r12=0．33）。治疗期间未发生严重不良事件。结论rhGH治疗SGA后IGF-1、IGFBP-3升高,以IGF-1升高更明显,6个月内血清IGF-1和AHtSDS存在显著正相关,9个月后不存在相关。rhGH治疗小于胎龄儿是安全有效的。     

生长激素在肝纤维化患者中的应用

生长激素不但能在生长过程中起重要作用,而且在碳水化合物,脂类代谢过程中起重要作用。慢性肝病的一个重要特征是生长激素抵抗现象,其表现为血清中生长激素的浓度较高而胰岛素样生长因子-1的水平降低。使用生长激素治疗慢性肝病,可提高患者血清中胰岛素样生长因子-1和胰岛素样生长因子结合蛋白-3升高,改善患者的生长激素抵抗现象,改善肝功能,纠正低蛋白血症。该文就使用生长激素治疗慢性肝病和肝纤维化的研究现状做一简要综述。     

Serum IGF-1 and IGFBP-3 levels in subclinical hypothyroid women

Thyroid status is known to influence growth in mammals. The aim of this study is to investigate the possible relationship between autoimmune subclinical hypothyroidism and growth hormone (GH), insulin-like growth factor-1(IGF-1) and insulin-like growth factor binding protein-3(IGFBP-3) levels. Thirty-five women with autoimmune subclinical hypothyroidism, 33 years of age, were used as controls and enrolled in the study. Free triiodothyronin (FT3), free thyroxin(FT4), thyrotropin(TSH), anti-thyroid peroxidase(Anti-TPO), anti-thyroglobuline(Anti-Tg), GH, IGF-1 and IGFBP-3 levels were measured in blood samples and correlations among these parameters were evaluated. We found no significant differences in GH, IGF-1 or IGFBP-3 between patients and controls. In patients and controls, there were no correlations among thyroid hormones and IGF-1 or IGFBP-3 levels, but GH levels were correlated with FT3, FT4 and TSH only in patients’ group. In controls, only IGF-1 and IGFBP-3 levels were correlated. The present study suggests that subclinical hypothyroidism with high TSH and antibody status does not affect IGF-1 and IGFBP-3 levels in adult women. To our knowledge, this is the first study concerning the relationship between autoimmune subclinical hypothyroidism and IGF-1 and IGFBP-3 levels.     

Growth Hormone–Releaser Diet Attenuates β-Amyloid(1-42)–Induced Cognitive Impairment via Stimulation of the Insulin-Like Growth Factor (IGF)-1 Receptor in Mice

We previously demonstrated that the growth hormone (GH)-releaser diet ameliorated β-amyloid (Aβ) (1-42)–induced memory impairment, but the underlying mechanism remained to be characterized. We show here that the GH-releaser diet significantly attenuated Aβ(1-42)-induced impairment in context-dependent conditioned fear, with a reduction in GH levels and changes in hippocampal acetylcholine, acetylcholinesterase, choline acetyltransferase, insulin-like growth factor (IGF)-1, and IGF-1–receptor activity in mice. JB-1, an IGF-1–receptor antagonist, significantly blocked GH-releaser diet–mediated pharmacological actions. Our results suggest that the GH-releaser diet prevents Aβ(1-42)-induced cognitive deficits via stimulation of the hippocampal IGF-1 receptor.     

胰岛素样生长因子-1对氯化钴诱导的PC12细胞凋亡的抑制作用

目的 探讨胰岛素样生长因子-1（IGF-1）对氯化钴（CoCl2）诱导的肾上腺嗜铬细胞瘤 PC12细胞凋亡的作 用及机制。方法 取对数生长期的 PC12细胞,分别以 10、20、40、80 μmol/L的 CoCl2溶液和 100、200、400 μg/L的 IGF- 1溶液处理细胞,CCK-8法检测细胞活力,得出 CoCl2和 IGF-1最佳干预浓度。根据选定的实验条件,应用 CoCl2处理 PC12细胞建立 HIE细胞模型,实验分为对照组、CoCl2处理组、IGF-1+CoCl2处理组。分组处理 24 h后采用 CCK-8法 检测细胞存活率;TUNEL染色检测细胞凋亡情况;Western blot检测各组细胞 Bax、Bcl-2及 Caspase-3的蛋白的表达 水平。最后在上述实验的基础上,设 CoCl2处理组、CoCl2+IGF-1处理组、HIF-1α抑制剂 2-甲氧雌二醇（2-MeOE2）+ CoCl 2组和 CoCl2+2-MeOE2+IGF-1组,Western blot观察 IGF-1、2-MeOE2及两者共用对 PC12细胞 HIF-1α及 Bax的表 达水平的影响。结果 CCK-8检测结果显示,40 μmol/L CoCl2和 200 μg/L IGF-1为最佳干预浓度。利用以上浓度分 组干预细胞 24 h后,与 CoCl2组相比,IGF-1+CoCl2处理组细胞存活率明显提升,TUNEL阳性细胞数和细胞比例降低, 同时抗凋亡蛋白 Bcl-2表达上调,促凋亡蛋白 Bax、Caspase-3,HIF-1α表达下调,差异均有统计学意义（均P＜0.05）。 应用 2-MeOE2对细胞进行预处理后,CoCl2+2-MeOE2组与 2-MeOE2+IFG-1组 HIF-1α和 Bax蛋白表达差异无统计 学意义,但均较 CoCl2+IGF-1组明显下调（P＜0.01）。结论 IGF-1可抑制 CoCl2诱导的 PC12细胞凋亡,其保护作用 可能与 HIF-1α表达下调有关。     

重组人生长激素治疗儿童生长激素缺乏症的临床观察

目的：探讨重组人生长激素（rhGH）对生长激素缺乏症（GHD）患儿的治疗效果及对甲状腺功能、血清胰岛素生长因子-1（IGF-1）、25羟维生素D（25（OH）D）水平的影响。方法：选取我院2013年1月至2017年12月我院门诊治疗的70例GHD患儿作为试验组,另外选取70名同龄健康儿童作为对照组,试验组采用rhGH治疗,分析试验组在治疗6个月、治疗12个月后的身高、身高标准差积分、生长速率、骨龄/实际年龄,检测试验组治疗前及治疗12个月后的血清游离三碘甲状腺原氨酸（FT3）、游离甲状腺激素（FT4）、促甲状腺激素（TSH）、IGF-1、25（OH）D水平,并与对照组进行比较。结果：在治疗6个月、12个月后,试验组患儿的身高、身高标准差积分、生长速率、骨龄/实际年龄测定值较治疗前均显著的增加,差异有统计学意义（P<0.05）;在治疗12个月后,试验组患儿的血清FT3、IGF-1、25（OH）D水平升高,差异具有统计学意义（P<0.05）,对照组的血清FT3高于试验组治疗前水平（P<0.05）,对照组的血清IGF-1、25（OH）D高于试验组治疗前及治疗后的水平（P<0.05）。结论：rhGH对GHD患儿的治疗效果显著,能明显改变患儿FT3、血清IGF-1、25（OH）D水平。     

格列吡嗪控释片对2型糖尿病病人血清胰岛素样生长因子的影响

目的 :探讨格列吡嗪控释片对 2型糖尿病病人血糖、胰岛素及胰岛素样生长因子Ⅰ ,Ⅱ (IGF Ⅰ ,Ⅱ )的影响。方法 :糖尿病组初次诊断的 2型糖尿病病人 6 8例 ,对照组健康体检者 4 3例。糖尿病组予格列吡嗪控释片 5～ 10mg ,每日 1次 ,早餐前服用 ,疗程 4wk。观察治疗前后空腹血糖 (FBG)、糖化血红蛋白 (HbA1c)、空腹胰岛素 (FINS)、IGF Ⅰ和IGF Ⅱ的情况。结果 :与对照组比 ,糖尿病组治疗前FINS ,IGF Ⅰ ,IGF Ⅱ水平较低 ,FBG和HbA1c水平较高 (均P <0 .0 1)。治疗后 ,FBG和HbA1c下降 ,FINS ,IGF Ⅰ ,IGF Ⅱ升高 (P <0 .0 1)。结论 :每日服用 1次格列吡嗪控释片可以改善 2型糖尿病病人的糖代谢及血清IGF Ⅰ和IGF Ⅱ的水平。     

Clinical evaluation of recombinant human growth hormone injection in children with growth hormone deficiency

Recombinant human growth hormone (rhGH) has been widely used in the clinical treatment of growth hormone deficiency. To simplify the injection process and increase drug compliance, application of the GH injection has become a new treatment plan in recent years. The purpose of the current study was to evaluate the efficacy and safety of rhGH injection for the treatment of growth hormone deficiency (GHD) in children in China. In a nationwide, noncomparative, prospective, randomized, open trial, 31 children with confirmed complete GHD received subcutaneous injection of rhGH at 0.25 mg/kg·wk (0.107 IU/kg·d). The injection was given daily and the total weekly amount was separated into 6–7 injections. The patients were followed up at 3-month intervals and the treatment duration was 12 months. The height (HT), annual growth velocity (GV), mean height standard deviation score (HT SDS), blood serum insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGFBP-3), and bone maturity before and after treatment were compared, and the safety of the treatment was analyzed. The mean HT, GV, and HT SDS were increased from 109.0±14 cm, 2.7±0.9 cm/yr, and −4.62 ±1.46 at baseline to 121.8±13.4 cm, 12.9±3.3 cm/yr, and −2.47±1.86 after 12 months of treatment, respectively (P<0.001). At the same time, blood IGF-I and IGFBP- 3 were increased significantly [41.27±64.43 μg/L vs 159.21±167.92 μg/L and 1540.00±1325.11 mg/L vs 3533.93±1413.82 mg/L, respectively (P<0.001)]. The bone age assessments performed 6 and 12 months after the treatment showed that no advanced bone maturation was noted. No serious adverse events occurred during the treatment, and the drug-related adverse events were mainly decreased thyroid function. We conclude that rhGH injection is a safe and effective drug for treatment of growth hormone deficiency in children.     

Dose-dependent effect of alcohol on insulin-like growth factor systems in male rats

1. Chronic alcohol treatment has been reported to be associated with liver and kidney damage. The insulin-like growth factor (IGF) is the major growth factor related to alcohol consumption. However, the effect of alcohol on the IGF system in the liver and kidney has not been fully elucidated. Thus, the present study was conducted to investigate this issue. 2. Alcohol reduced the level of IGF-I in a dose-dependent manner in the serum, liver and kidney. Alcohol also decreased the level of IGF-II in the liver. In contrast, alcohol increased the level of IGF-II in the serum and kidney. These observations were correlated with IGF-I and IGF-II mRNA expression in the liver and kidney. 3. To examine the effect of alcohol on IGF receptors in the liver and kidney, IGF-I receptor mRNA was measured. Alcohol decreased IGF-I receptor mRNA in the liver and kidney. 4. In experiments performed to examine the regulation of IGF-binding proteins (IGFBP), alcohol increased serum levels of IGFBP-1. However, alcohol had no effect on serum levels of IGFBP-2, -3 and -4. These effects were also observed in the liver and kidney. 5. In conclusion, alcohol alters the IGF system in rat liver and kidney in a tissue-specific manner, which may contribute to the metabolic dysfunction following chronic alcohol consumption.     

心力衰竭患者血中生长激素水平的研究

目的研究心力衰竭患者血中生长激素(GH)和胰岛素样生长因子(IGF)-1水平。方法选择心力衰竭患者56例和正常对照者30名,使用Immulite全自动化学发光免疫分析仪,用化学发光免疫分析方法测定GH,使用Gamma-C12计数仪,用免疫放射分析方法测定IGF-1。结果心力衰竭患者血中GH和IGF-1水平均低于正常对照组(P<0.01和P<0.05)。心力衰竭患者血中GH和IGF-1水平呈正相关关系(r=0.676,P<0.05)。不同程度心力衰竭患者血中GH和IGF-1水平不同,心功能Ⅲ级组低于心功能Ⅱ级组(P<0.05和P<0.05),心功能Ⅳ级组低于心功能Ⅱ级组(P<0.01和P<0.05),而心功能Ⅲ级组与心功能Ⅳ级组之间差异无显著性(P均>0.05)。不同疾病引起的心力衰竭患者血中GH和IGF-1水平与相应的对照组比较,扩张型心肌病组明显低于对照组(P均<0.01),缺血性心肌病组低于对照组(P<0.01和P<0.05),高血压心脏病组GH低于对照组(P<0.05),IGF-1与对照组的差异无显著性(P>0.05),风湿性心脏病组均低于对照组(P均<0.05)。结论心力衰竭患者血中GH和IGF-1水平降低,并且两者呈正相关关系。不同程度心力衰竭患者血中GH和IGF-1水平不同,心力衰竭程度重者(心功能Ⅲ级和Ⅳ级组)较心力衰竭程度轻者(心功能Ⅱ级组)低。扩张型心肌病和缺血性心肌病引起的心力衰竭患者血中GH和IGF-1水平     

Formononetin induces the mitochondrial apoptosis pathway in prostate cancer cells via downregulation of the IGF-1/IGF-1R signaling pathway

Context: Formononetin, an isoflavone, can inhibit the proliferation of cancer cells, including those of the prostate. However, its antitumor mechanism remains unclear.

Aim: To investigate whether the insulin-like growth factor 1 (IGF-1)/insulin-like growth factor 1 receptor (IGF-1?R) signaling pathway mediates the formononetin antitumor effect on prostate cancer cells.

Materials and methods: The viability of PC-3 cells was measured by MTT assay 48?h after formononetin treatment (25, 50 and 100?μM). Formononetin-induced cell apoptosis was measured by Hoechst 33258 staining and flow cytometry. Expression of Bax mRNA was detected by real-time PCR, and the expression levels of Bax and IGF-1?R proteins were detected by western blots.

Results: At concentrations >12.5?μM, formononetin significantly inhibited the proliferation of human prostate cancer cells. Formononetin increased Bax mRNA and protein expression levels and decreased the expression levels of pIGF-1?R protein in a dose-dependent manner.

Conclusion: High concentrations of formononetin-induced apoptosis in androgen-independent prostate cancer cells through inhibition of the IGF-1/IGF-1?R pathway.