Study for biological effect of IGF-II and the Pathological significance.

IGF-II的生物学效应及病理意义研究。

• 批准号: 06671059
• 负责人: TAKANO Kazue
• 金额: $ 1.34万
• 依托单位: Tokyo Women's Medical College
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06671059/
• 关键词: insulin-like growth factor (IGF); IGF-II; IGF-I; IGF binding protein (IGFBP); インスリン様成長因子

In this study, we have investigated biological effect of IGF-II and the pathological significance as follows. 1) In normal serum, major form of insulin-like growth factor II (IGF-II) was 7.5Da and small amount of 11kDa IGF-II was found. By contrast, in patients with non-islet cell tumor hypoglycemia (NICTH), most of IGF-II was detected at 11-18kDa. We investigated whether the big IGF-II from patients with NICTH was O-glycosylated, and if so, whether the size of sugar moiety is different among the cases. In normal subjects, and patients with acromegaly, size of 11kDa IGF-II was reduced to 9.5kDa after O-Glycanase. In 11 patients with NICTH,size of 11-18kDa IGF-II was reduced to 9.5kDa as same as normal subjects. These data indicated that big IGF-II from patients with NICTH was O-glycosylated, and the size of sugar moiety was different among cases. Insulin-like efect of the big IGF-II from NICTH did not differ from that of authentic IGF-II in adipocytes. Human IGF-II gene (IGF2) is mater … More nally imprinted, and only the paternal allele of IGF2 is usually expressed. Recently, loss of imprinting (LOI) of IGF2 has been reported in some embryonal tumors, such as Wilms' tumor and rhabdomyosarcoma, suggesting that biallelic expression of the gene leads to overexpression of IGF-II peptide and increased mitogenic activity. We examined allelic gene expression of IGF2 in NICTH using the Apa I restriction nzyme fragment length polymorphism (RELP) in exon 9 of IGF2. IGF2 was expressed bialleically (LOI) in five of six informative tumors, suggesting that LOI might lead overexpression of IGF-II.2) In the insulin resistant mice, insulin did not decrease the blood glucose levels, but, the blood glucose levels decreased after IGF-1 and IGF-II injection. The IGF-II mutant without affinity for IGF-II receptor but with affinities for both IGF-I and insulin receptors as same as IGF II,caused hypoglycemia as same as IGF-II.However, the IGF-II mutant with markedly decreased affinities for both insulin and IGF-I receptors did not decrease blood glucose levels, and the IGF-II mutant with slightly decreased affinities for both insulin and IGF II receptors slightly decreased blood glucose levels. These data indicate that the hypoglycemic effect of IGF-II is acted through mainly insulin and/or IGF-I receptor but not IGF-II receptor. Furthermore, the data suggest that IGF-II might be also useful for treatment of insulin resistant status. 3) IGFBPs interfere with the measurement of IGF-II in RIA.We developed dot blot method to detect directly IGF-II without interference by IGFBPs and measured IGF-II in cerebrospinal fluid (CSF) by this method. We found that this dot blot system is useful to evaluate IGF-II values in CSF. Less

本研究探讨了IGF-II的生物学效应及其病理学意义。1)正常人血清中IGF-Ⅱ主要分布在7.5Da，少量分布在11 kDa，而非胰岛细胞瘤性低血糖（NICTH）患者血清中IGF-Ⅱ主要分布在11- 18 kDa。我们研究了NICTH患者的大IGF-II是否是O-糖基化的，如果是，糖部分的大小是否在病例中不同。在正常人和肢端肥大症患者中，11 kDa的IGF-II的大小在O-聚糖酶后减少到9.5kDa。11例NICTH患者11- 18 kDa IGF-Ⅱ的分子量减少至9.5kDa。提示NICTH患者的大IGF-Ⅱ是O-糖基化的，且糖基的大小在不同病例间存在差异。胰岛素样作用的大IGF-II从NICTH没有不同的真正的IGF-II在脂肪细胞。人IGF-II基因（IGF 2）是一种重要的 ...更多信息 通常只有IGF 2的父系等位基因被表达。最近，IGF 2的印迹丢失（LOI）已在一些胚胎性肿瘤，如肾母细胞瘤和横纹肌肉瘤中报道，表明该基因的双等位基因表达导致IGF-II肽的过表达和促有丝分裂活性增加。我们使用IGF 2第9外显子的阿帕I限制性酶切片段长度多态性（RFLP）检测了NICTH中IGF 2的等位基因表达。2）在胰岛素抵抗小鼠中，胰岛素不降低血糖水平，但注射IGF-1和IGF-II后，血糖水平降低。对IGF-II受体没有亲和力但对IGF-I和胰岛素受体的亲和力与IGF-II相同的IGF-II突变体引起的低血糖与IGF-II相同。然而，对胰岛素和IGF-I受体的亲和力显著降低的IGF-II突变体不降低血糖水平，对胰岛素和IGF-II受体的亲和力略微降低的IGF-II突变体略微降低血糖水平。这些数据表明，IGF-II的降血糖作用主要是通过胰岛素和/或IGF-I受体而不是IGF-II受体起作用。此外，数据表明IGF-II也可能用于治疗胰岛素抵抗状态。3)IGFBPs对IGF-II的测定有干扰作用，我们建立了不受IGFBPs干扰的直接测定IGF-II的斑点杂交法，并应用该方法测定了脑脊液中的IGF-II。我们发现，这种斑点杂交系统是有用的，以评估IGF-Ⅱ值在CSF中。少

项目成果

Takano K et al.: "Long-Term effects of growth hormone treatment on height in Turner Syndrome:Results of a 6 year multicentre study in Japan" Horm. Res.43. 141-143 (1995)

Takano K 等人：“生长激素治疗对特纳综合征患者身高的长期影响：日本一项为期 6 年的多中心研究的结果”Horm。

Takano K et al.: "Long-Term effects of growth hormone treatment on height in Turner syndrome: Pesults of a 6year raultientre stady in Japan" Horm. Res.43. 141-143 (1995)

Takano K 等人：“生长激素治疗对特纳综合征患者身高的长期影响：在日本进行 6 年 Raultientre 治疗的结果”Horm。

Takano K.et al.: "Psychosocial consequences of growth hormone deficiency(GHD) in adults" Clin Pediatr Endocrinol. 3(supple 4). 79-85 (1994)

Takano K. 等人：“成人生长激素缺乏 (GHD) 的心理社会后果”Clin Pediatr Endocrinol。

Hizuka N. et al.: "Hypoglycemic effect of IGF-II is acted through mainly insulin and/or IGF-I receptor but not IGF-II receptor" Clinical Pediatric Endocrinology. (in press). (1996)

Hizuka N. 等人：“IGF-II 的降血糖作用主要通过胰岛素和/或 IGF-I 受体而非 IGF-II 受体发挥作用”《临床儿科内分泌学》。

Fukuda I,Hizuka N,Takano K,Asakawa-Yasumoto K,Okubo Y,Shimojoh, Shizume K,Demura H: "Circulating forms of insulin-like growth factor II (IGF-II) in patients with non-islet cell tumor hypoglycemia." Endocrinol Metab. 1. 89-95 (1994)

Fukuda I、Hizuka N、Takano K、Asakawa-Yasumoto K、Okubo Y、Shimojoh、Shizume K、Demura H：“非胰岛细胞肿瘤低血糖患者中胰岛素样生长因子 II (IGF-II) 的循环形式。