外源性牛初乳短链IGF-1治疗改善糖尿病大鼠GH/IGF-1轴的紊乱

目的　观察外源性牛初乳短链胰岛素样生长因子 - 1(BC- t IGF- 1)对糖尿病生长激素 GH/ IGF- 1轴的影响。方法　链脲佐菌素 (STZ) 5 5 mg/ kg空腹腹腔注射 (IP)制备糖尿病大鼠模型 ,随机分为糖尿病对照组 (DM- C,生理盐水0 .1ml/ d IP)和糖尿病治疗组 (DM- BC,BC- t IGF- 12 5 0 ng/ kg· d- 1 IP)。并设正常对照组 (NC) ,每组 n=5。治疗前测定尾尖血血糖 (BG0 ) ,治疗 6周后测定尾尖血血糖 (BG)、血清果糖胺 (FMN)、甘油三酯 (TG)、胆固醇 (CHO)、GH、IGF- 1和肝脏 IGF- 1含量。结果　与 NC相比 ,DM- C血清 FMN、TG明显升高同时血清 GH升高而血清和肝脏 IGF- 1降低 ;与DM- C相比 ,DM- BC血清 FMN、TG明显降低同时血清 GH降低而肝脏 IGF- 1显著升高。结论　外源性 BC- t IGF- 1治疗改善糖尿病大鼠代谢同时改善了糖尿病时的 GH/ IGF- 1轴的紊乱     

糖尿病烫伤大鼠胰岛素强化治疗对生长激素轴的影响

本实验将30只糖尿病烫伤大鼠随机分为胰岛素强化治疗组和常规治疗组，测定各组血清生长激素（GH）和胰岛素样生长因子Ⅰ（IGF-Ⅰ）浓度，并观察死亡率。结果表明，胰岛素强化治疗使血糖控制在3．9～5．6mmol／L，能明显改善糖尿病烫伤大鼠GH—IGF-I轴紊乱，并显著降低死亡率。     

胰岛素样生长因子-1与糖尿病微血管并发症

本文介绍了胰岛素样生长因子-1(IGF-1)、IGF受体及IGF结合蛋白的结构和作用,其在维持血糖内环境稳定方面的作用,及其与糖尿病微血管病变(糖尿病肾病、糖尿病视网膜病和糖尿病神经病变)的关系.     

Insulin like growth factor-1 (IGF-1) decreases ischemia-reperfusion induced apoptosis and necrosis in diabetic rats

Previous evidence supports the view that insulin, as well as insulin like growth factor-1 (IGF-1) provides neurotropic support for neurons in the central nervous system (CNS) and peripheral nervous system (PNS). In the present study we evaluated the effects of the intravenous infusion of IGF-1 on both necrosis and apoptosis in the CNS of streptozotocin induced diabetic animals before and/or following middle cerebral artery occlusion (MCAO) with reperfusion. The lesion volume was used as an index of necrosis and the sensorimotor cortex (layers 5 and 6) as well as the CA1 and CA3 regions of the hippocampus were analyzed for apoptosis using TUNEL staining and Caspase-3 immunoreactivity. A large lesion volume was produced in diabetic animals after 2-h MCAO and 24-h reperfusion. Diabetic animals also had an elevated basal level of apoptotic cells that are bilaterally distributed. Apoptosis was further increased over basal after 2-h MCAO and 24-h reperfusion. The acute administration of IGF-1 30-min before or 2 h after MCAO followed by 24-h reperfusion decreased the lesion volume as well as the number of apoptotic cells in the cortical penumbra. Apoptosis as assessed by TUNEL and caspase-3 immunoreactivity was decreased in select sensorimotor cortex and hippocampal areas. We conclude that treatment with IGF-1 before or after ischemic insult significantly decreases both lesion volume and apoptosis in selected areas of the cortex and hippocampus.     

生长激素/胰岛素样生长因子-1与免疫系统的关系

生长激素(GH)及胰岛素样生长因子(IGF)-1与免疫系统具有相互调节作用。GH可恢复胸腺形态、结构,促进胸腺细胞的分化、成熟,并可激发免疫系统原始细胞的迁移、分化、成熟,提高中性粒细胞、淋巴细胞、巨噬细胞的作用。免疫系统主要通过炎症因子白细胞介素-6及肿瘤坏死因子-α的作用影响GH/IGF-1,减少其水平,降低其活性,削弱GH治疗的效应,导致GH抵抗。     

Serum IGF-1 concentration in diabetic retinopathy

Growth factors such as growth hormone and insulin-like growth factor 1 (IGF-1) may be important in the pathogenesis of diabetic retinopathy. We measured serum IGF-1 in 371 diabetic patients attending a diabetic retinopathy clinic and in 73 non-diabetic control subjects. No significant difference was observed in IGF-1 level between the diabetic and control groups (168 +/- 3.9 vs 177 +/- 7.4 micrograms/l [mean +/- SE]). Within the diabetic group, there was no difference between patients with no retinopathy and those with proliferative change (198.7 +/- 8.8 vs 190.5 +/- 11 micrograms/l). After adjusting for differences in age, duration of diabetes, and presence of proteinuria, only the inactive previously proliferative group showed any significant difference from the other patient subgroups (151.8 +/- 11.5 micrograms/l; p less than 0.05). Serum IGF-1 correlated with age in the control group (r = 0.49; p less than 0.001) and to a lesser extent in the diabetic group (r = -0.23; p less than 0.05). IGF-1 levels were higher in patients with proteinuria than in those without proteinuria (196.8 +/- 10.3 vs 138.8 +/- 4.4 micrograms/l; p less than 0.001).     

老年颈动脉粥样斑块与胰岛素样生长因子-1及血脂的相关性研究

目的探讨胰岛素样生长因子1(IGF1)对老年颈动脉斑块(CAP)的影响及其在脂代谢中的作用。方法检测48例经颅多普勒超声确诊的老年CAP患者的血清IGF1水平和血脂指标,并与40例无CAP的老年人对照,并将两组的数据进行相关性分析。结果老年CAP组血清IGF1水平明显低于对照组(P<0.05);而TC、TG、LDL水平均较对照组高(P<0.01);HDL水平无显著差异。斑块组TC、TG、LDL均与IGF1呈负相关;HDL与IGF1无相关性。结论脂代谢紊乱是动脉粥样斑块形成的主要危险因素,IGF1作为一种重要的循环内分泌多肽,参与CAP的形成及脂代谢的调节。     

Insulin-like growth factor binding protein-1 levels in diabetic adolescents and their relationship to metabolic control.

Circulating levels of the low molecular weight insulin-like growth factor binding protein-1 (IGFBP-1) are insulin dependent and vary markedly throughout the day. IGFBP-1 levels are abnormally high in diabetes but the relationship between this and the metabolic status of the patient has not been defined. We have therefore measured fasting IGFBP-1 levels at 0800 h in 32 diabetic adolescents. IGFBP-1 was measured in 19 of these patients after a normal night and in 27 after a night of euglycaemia, maintained with a glucose clamp. In 13 patients both studies were performed and could be compared. Puberty-matched control data were obtained from 69 normal children. In normal prepubertal children IGFBP-1 levels were high; lower levels were found with advancing pubertal development. This fall in IGFBP-1 correlated with pubertal stage (r= 0.68, p less than 0.001) and with fasting insulin levels (r = 0.60, p less than 0.001) which rose with pubertal advancement. In the diabetic children IGFBP-1 levels also correlated inversely with the 0800 h free insulin level but there was no clear relationship with pubertal development. However, when measured after overnight euglycaemia IGFBP-1 levels correlated inversely with pubertal development (r = 0.67, p less than 0.001) as in the normal children. In the patients studied on two comparable occasions the IGFBP-1 level measured after a normal night relative to that measured under standardized euglycaemic conditions was found to correlate closely with the glycosylated haemoglobin level (r = 0.71, p less than 0.005).     

血清IGF—1、IGFBP—1，GH水平与糖尿病慢性并发症关系的研究

目的：揭示胰岛素样生长因子－1,胰岛素样生长因子结合蛋白－1,生长激素对糖尿病慢性并发症的发生,发展的影响。方法：测定20例健康对照者和62例2例糖尿病,10例1例糖尿病患者的胰岛素样生长因子－1（IGF－1）,胰岛素样生长因子结合蛋白－1（IGFBP－1）,生长激素（GH）及血浆胰岛素（INS）,C肽（C－P）,糖化血红蛋白（HbAlc)指标,结果：（1）IGF－1水平,1型糖尿病患者显著低于对照组（P＜0．05）,2型糖尿病患者显著低于对照组（P＜0．05）,（2）IGFBP－1水平,1型糖尿病患者显著高于对照组（P＜0．05）,2型糖尿病肥胖型伴高胰岛素血症者显著低于对照组（P＜0．05）;（3）GH水平,1型糖尿病患者显著高于对照组（P＜0．05）,2型糖尿病与对照组无显著差异（P＞0．05）,（4）合并糖尿病肾病及视网膜病变患者IGF－1水平均较对照组增高（P＜0．05）,（5）IGF－1水平与HbAlc间呈负相关（P＜0．01 2型r=-0.62 1型r=-0.73)。结 论：IGF－1,IGFBP－1,GH水平的检测对糖尿病慢性并发症,特别是微血管病变的发生,发展有重要的临床意义。     

Common polymorphisms in the GH/IGF-1 axis contribute to growth in extremely tall subjects

Context/objective

The growth hormone (GH)/insulin-like growth factor-1(IGF-1) axis is the key regulator of somatic growth in humans and its genes are plausible candidates to study the genetics of height variation. Here, we studied polymorphic variation in the GH/IGF-1 axis in the extremely tall Dutch.

Methods

Case–control study of 166 tall cases with height > 2 SDS and 206 controls with normally distributed height < 2 SDS. Excluded were subjects with endocrine disorders or growth syndromes. We analyzed genomic DNA at 7 common polymorphisms in the GH-1, GH receptor (GHR), IGF-1 and IGFBP-3 genes.

Results

The association of the GH-1 1663 SNP with tall stature approached statistical significance, with the T-allele more present in the tall (allele frequency (AF): 0.44 vs. 0.36; p = 0.084). Moreover, haplotype frequencies at this locus were significantly different between cases and controls, with the GGT haplotype most commonly seen in cases (p = 0.01). Allele frequencies of GHR polymorphisms were not different. For the IGF-1 CA-repeat we observed a higher frequency of homozygous 192-bp carriers among tall males compared to control males (AF: 0.62 vs. 0.55; p = 0.02). The IGFBP-3 -202 C-allele occurred more frequently in cases than in controls (AF: 0.58 vs. 0.50; p = 0.002). Within cases, those carrying one or two copies of the -202 C-allele were significantly taller than AA genotype carriers (AC, p = 0.028 and CC, p = 0.009). Serum IGFBP-3 levels were highest in AA genotype carriers, the -202 SNP explained 5.8% of the variation.

Conclusion

Polymorphic variation in the GH-1, IGF-1 and IGFBP-3 genes is associated with extremely tall stature. In particular, the IGFBP-3 -202 SNP is associated not only with being very tall but also with height variation within the tall.     

Expression of FGF-2 and IGF-1 in diabetic rats with fracture

Objective:To observe the change of fibroblast growth factor-2(FGF-2),insulin-like growth factor-1(IGF—1)in serum and bone callus after fracture in diabetic rats,and to explore molecular biological mechanism of healing of diabetic fracture.Methods:Thirty male SD rats were designed into normal(n=13)and control(n=!5)groups randomly.Venous blood was extracted on the 1st,2nd,4th,6th,8th week after surgery.It was certificated and the serum was obtained.Left lower extremity was observed by X-ray.Bone callus at broken ends was observed under light microscope.Expressions of FGF-2 and 1GF-1 in tissue were detected by immunohistochemistry method,and ELISA was used to detect expression of FGF-2 and IGF-I in serum.Results:The results showed a significant increase in the density and area of newly formed bone in the distraction gaps of normal rats compared to control rats.Increased cell proliferation was also found in the distraction gaps of normal rats versus control rats.There was significant difference in serum levels of FGF-2 and IGF-1 between two groups.Conclusions:The decrease of FGF-2 and IGF-1 both in the serum and in the fracture region is one of the reasons for bad bone healing or delayed union in rats'fracture with diabetes.There are some synergistic effects possibly between FGF-2 and ICF-I.     

糖尿病大鼠骨量及骨形态学变化的研究

采用四氧啼晚制成ＳＤ雄性大鼠糖尿病模型，探讨糖尿病及胰岛素治疗后对骨量及骨形态学影响过程。设正常对照组、糖尿病未治组（按病程分ＤＭ４ｗ、ＤＭｅ”、ＤＭ“ｗ）、糖尿病胰岛素治疗组（按治疗时间分Ｔ４Ｗ、Ｔ８Ｗ、Ｔ１２Ｗ）。应用ＳＰＡ、ＳＥＱＣＴ两种方法对其股骨进行骨量测定，表明糖尿病早期即有股骨干皮质骨密度下降，且随病程进展，干骺端松质骨量也显著减少。光镜观察，糖尿病早期即显示股骨颈处皮质变薄、骨小梁细疏。随胰岛素治疗时间延长，骨量有所恢复，骨组织形态也相应得到改善。     

粉防己碱对糖尿病大鼠心肌保护作用及机制的研究

目的研究粉防己碱对糖尿病(DM)大鼠心肌的保护作用及相关机制。方法36只W istar大鼠用链脲佐菌素(STZ)诱发糖尿病模型后,随机分为粉防己碱治疗组、苯那普利治疗组及糖尿病未治疗组,以10只正常大鼠作为对照。12 w末检测血糖、血脂、心肌组织血管紧张素Ⅱ,应用RT-PCR检测心肌结缔组织生长因子(connective tissue growth factor,CTGR)mRNA的表达水平。结果DM未治疗组心肌组织血管紧张素Ⅱ含量、CTGR mRNA的表达分别为(26.5±3.38)和(1.0±0.10),明显高于对照组和治疗组(P<0.01)。结论粉防己碱能在一定程度上降低心肌血管紧张素Ⅱ含量,抑制CTGF mRNA表达,从而可能减轻糖尿病性心肌病的病理变化。     

胰岛素样生长因子-1对心脏的作用及在骨髓间充质细胞移植治疗心血管疾病中的角色

骨髓间充质细胞(BMSCs)移植治疗心血管疾病已经在大量基础研究中证实了其有效性,近年来也在不少临床试验中得到证实,但其改善心功能机制仍然有较多争议,移植细胞的旁分泌作用可能对移植后心功能的改善起着重要作用。业已证明胰岛素样生长因子-1(IGF-1)对心脏的发育、心肌细胞肥大、再生、抑制心肌细胞凋亡等具有重要作用,不少资料表明BMSCs移植后伴随着IGF-1等细胞因子的表达增加,推测IGF-1在BMSCs移植后的分子机制中具有重要的作用。本文将在简单讨论IGF-1在心脏病理生理状态下的作用后,进一步重点就IGF-1在BMSCs移植治疗心血管疾病中的研究进展及分子机制作一阐述。     

维生素D抗炎机制对糖尿病大鼠骨代谢的影响

目的 探讨活性维生素D3对糖尿病大鼠炎症因子及骨代谢指标的影响.方法 6～8周龄雄性SD大鼠30只,链脲佐菌素诱导建立糖尿病大鼠模型.将糖尿病大鼠分为2组：糖尿病组、维生素D组.选取健康同龄大鼠10只作为正常对照组.维生素D组给予1,25（OH）2D3（0.1μg·kg＾-1·d＾-1）溶于0.05 ml花生油灌胃,正常对照组及糖尿病组给予花生油0.05 ml/d灌胃.12周后处死各组大鼠,测定血清白介素17（IL-17）、钙、磷、骨钙素、24 h尿钙、24 h尿白蛋白（UAlb）水平;免疫组化法检测肾皮质内IL-17的表达;荧光定量RT-PCR检测骨组织骨钙素mRNA表达水平.结果 （1）糖尿病组24 h尿钙、24 hUAlb显著高于正常对照组[分别为（0.31±0.18）比（0.01±0.01） mmol/24 h、（1.15±0.13）比（0.43±0.09） mg/24 h,t值分别为5.125、13.948,均P＜0.05];维生素D组24 hUAlb显著低于糖尿病组[（0.82±0.13）比（1.15±0.13） mg/24 h,t=-5.798,P＜0.05].（2）与正常对照组、维生素D组相比,糖尿病组血清IL-17、肾皮质IL-17表达显著升高[分别为（494±28）比（137±18）、（250±20）pg/ml,（165.0±7.0）比（81.9±5.6）、（119.1±6.6）,t值分别为34.229、-23.263、29.238、-15.475,均P＜0.05].（3）与正常对照组、维生素D组相比,糖尿病组血清骨钙素、骨组织骨钙素mRNA表达显著降低[分别为（485±123）比（752±239）、（621±161）pg/ml,（19.8±2.9）比（24.1±2.9）、（22.9±3.1）,t值分别为-3.147、2.158、-3.220、2.265,均P＜0.05].（4）血清IL-17与血清骨钙素呈负相关（r=-0.544,P＜0.05）.结论 维生素D可抑制糖尿病大鼠IL-17等炎症因子的表达,改善骨代谢.     

Expression of ovine insulin-like growth factor-1 (IGF-1) stimulates alveolar bud development in mammary glands of transgenic mice

To determine whether murine mammary growth is modulated by local insulin-like growth factor-1 (IGF-1) production, expression of recombinant IGF-1 was directed to the mammary glands of transgenic mice using an ovine prepro IGF-1 cDNA under control of the mouse mammary tumor virus-long terminal repeat (MMTV-LTR) promoter. Bioactivity of recombinant IGF-1 in transgenic mouse milk extracts was demonstrated by a concentration-dependent increase in [³H]thymidine incorporation in clonal bovine mammary epithelial cells (MAC-T) compared with control mouse milk extracts; moreover, addition of excess recombinant human insulin-like growth factor binding protein-3 (rhIGFBP-3) abolished the increase in [³H]thymidine incorporation attributed to recombinant IGF-1 in transgenic mouse milk. Recombinant IGF-1 was produced in mammary tissue of virgin and pregnant transgenic mice, and secreted into milk of lactating mice. However, recombinant IGF-1 was not detected in serum from transgenic mice; and ligand blot analysis of serum insulin-like growth factor binding proteins (IGFBPs) indicated no differences owing to transgene presence. In peripubertal virgin mice at 49 d of age, the frequency of appearance of mammary alveolar buds was significantly higher in MMTV-IGF-1 than in CD-1 mice, and was unaffected by ovariectomy or estradiol treatment. In conclusion, mammary synthesis of recombinant IGF-1 enhances the rate of development of alveolar buds in mammary glands of virgin transgenic mice.     

IGF-1对去卵巢大鼠骨密度及骨力学强度的影响

目的 研究外源性胰岛素样生长因子-1(IGF-1)对去卵巢(OVX)骨质疏松大鼠骨密度、骨转换率、骨力学强度等方面的影响.方法 对大鼠施行双侧卵巢摘除术,术后3个月以骨密度测定证实骨质疏松的存在后,随机分为5组,分别以生理盐水、甲状旁腺激素1-34及3种不同剂量IGF-1进行干预.同时设立生理盐水干预的假手术大鼠作为对照.8周后检测血清钙、磷、骨钙素水平及碱性磷酸酶活性;测定腰椎骨密度、股骨力学强度;组织学染色测定股骨远端骨皮质厚度.结果 IGF-1虽未提高OVX大鼠腰椎骨密度却可以显著提高其股骨力学强度.血清学检测结果表明,IGF-1可降低血清钙、磷、骨钙素水平及碱性磷酸酶活性;组织学染色显示IGF-1可显著提高OVX大鼠股骨骨皮质厚度.结论 IGF-1可增加OVX大鼠股骨的力学强度,此作用可能是通过改善骨结构而非提高骨密度所实现的.     

Caloric restriction promotes the reproductive capacity of female rats via modulating the level of insulin-like growth factor-1 (IGF-1)

The insulin-like growth factor-1 (IGF-1) plays an important role in the regulation of reproductive function. In the present study, we examined the effects of caloric restriction (CR) on the reproductive lifespan in rats and investigated the potential role of IGF-1. After 10 weeks of treatment, we determined the distribution of the ovarian follicles at various stages and measured the plasma level of IGF-1, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estrogen (ESG). Our results show that IGF-1 level was decreased after CR and correlated with the decrease in the levels of LH, FSH and ESG. Moreover, a higher percentage of primordial follicles and surviving follicles was observed in CR rats than in control rats (P < 0.05). Immunohistochemical analysis showed that IGF-1 was extensively expressed in the cytoplasm of granulosa cells in the surviving follicles at different stages but not in the atretic follicles. Taken together, these results suggest that caloric restriction promotes the reproductive capacity of female rats via modulating the level of IGF-1, which then regulate pituitary gonadotrope cells to reduce the release of LH, FSH and ESG, and modulate follicular development.     

体重及其构成成分对2型糖尿病患者骨量的影响

目的探讨体重及其构成成分对2型糖尿病（T2DM）患者骨量的影响。方法DEXA测定131例T2DM患者及89名对照者的瘦体重、总体脂量、全身脂肪含量、全身骨密度（BMD）及骨矿含量（BMC）,计算BMI、校正骨矿含量（CBMC）,对比两组上述指标,分析体重及其构成成分与骨量关系。结果T2DM组体重、瘦体重及BMC大于对照组,两组间BMD、CBMC无差异。在T2DM组成员中,体重、瘦体重、总体脂量与骨量呈正相关,全身脂肪含量与骨量呈负相关。结论T2DM患者骨密度与正常人比较无下降,较高的体重、瘦体重及总体脂量是其骨量保护因素,瘦体重的保护作用更显著。     

老年2型糖尿病GH-IGF轴的变化及与脂质代谢关系

目的观察老年2型糖尿病患者生长激素胰岛素样生长因子(GHIGF)轴的变化,并探讨老年2型糖尿病患者胰岛素样生长因子Ⅰ(IGFⅠ),胰岛素样生长因子结合蛋白1(IGFBP1),胰岛素样生长因子结合蛋白3(IGFBP3)与大血管病危险因素糖、脂质代谢紊乱的关系。方法检测35例老年2型糖尿病患者(其中19例伴大血管病变,16例不伴大血管病变)的血清生长激素(GH),IGFⅠ,IGFBP1,IGFBP3,并与18名健康的老年人作对照。同时还进行了IGFⅠ、IGFBP1、IGFBP3与总胆固醇(TC),甘油三酯(TG),高密度脂蛋白胆固醇(HDLC),低密度脂蛋白胆固醇(LDLC),糖化血红蛋白(HbA1c)之间的相关关系的分析。结果(1)老年2型糖尿病伴大血管病变患者的IGFⅠ的水平显著低于对照组和不伴大血管病变患者(P<0.05),而血清GH、IGFBP1的水平显著的高于对照组和不伴大血管病变的患者(P>0.05),TGFBP3的水平3组之间无差异(P>0.05);(2)相关关系分析结果表明,老年2型糖尿病患者IGFⅠ的水平与HDLC呈正相关关系(P<0.05),与HbA1c呈负相关关系,而IGFBP1与TG、HbA1c呈正相关关系,与HDLC呈负相关关系(P<0.05)。结论老年2型糖尿病患者存在CHIGF轴的紊乱,且此紊乱与脂质代谢的紊乱相关。