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Study for pathophysiological significance of insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs)

胰岛素样生长因子（IGF）和IGF结合蛋白（IGFBP）的病理生理学意义研究

基本信息

批准号：
16590913
负责人：
HIZUKA Naomi
金额：
$ 1.92万
依托单位：
Tokyo Women's Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

In this study, we have investigated pathophysiological significance of insulin-like growth factor s (IGFs) and IGF binding proteins (IGFBPs) as follows.1) Clinical features of insulin-like growth factor-II producing non-islet-cell tumor hypoglycemiaIn some patients with non-islet-cell tumor hypoglycemia (NICTH), a high molecular weight form of IGF-II (big IGF-II) derived from tumors is present in the circulation and might be associated with recurrent hypoglycemia. In this study, in order to survey the clinical characteristics of patients with IGF-II producing NICTH, we analyzed the medical records of 78 patients with NICTH (M/F 44/34, age 62±1.8, range; 9-86 years.) whose serum contained a large amount of big IGF-II. Hepatocellular carcinoma and gastric carcinoma were the most common causes of NICTH. The diameters of the tumors were more than 10 cm in 70% of the patients. Basal immunoreactive insulin (IRI) levels were less than 3 lU/dl in 79% of the patients. Hypoglycemic attack was th … More e onset of disease in 31 of 65 cases (48%), but the tumor was revealed prior to the occurrence of hypoglycemia in 34 cases (52%). Twenty-five of 47 (53%) patients had decreased serum potassium levels. These data suggested that hypoinsulinemic hypoglycemia associated with the presence of a large tumor supports the diagnosis of IGF-II producing NICTH. Hypokalemia was associated with hypoglycemia in some patients. The BMI (21.4±0.6 kg/m^2) and serum total protein levels (6.6±0.1 g/dl) were preserved at the occurrence of first hypoglycemic attack suggesting that malnutrition might not be the main cause of hypoglycemia in most patients.2) Type I Insulin-like growth factor receptor (IGF1R) expression and function in thyroid tissuesIn the thyroid tissue, IGF-I stimulates DNA synthesis, but the roles of the IGF-I system in thyroid diseases are not clear. Some patients with acromegaly have thyroid tumors, indicating that increased circulating IGF-I might have some effects on cellular growth in the thyroid tissue. The aim of this study is to determine whether we can detect an abnormal IGF1R system in primary-cultured thyroid cells established from from five subjects with papillary cancer (PC) and an acromegalic subject. The mono-layered cells were stimulated with IGF-I. The cell lysates were immuno-precipitated with anti-IGF1R antibody and the immuno-precipitates were fractionated and immuno-blotted with anti-phospho-tyrosine or IGF1R antibody. IGF1R gene expressions were also analyzed by a quantitative RT-PCR. In a patient with acromegaly, papillary cancer had increased IGF1R protein level and IGF1R gene expression compared with the non-cancerous tissue, but there was no difference in IGF1R phosphorylation rates in both tissues. Cells from five patients with PC showed similar changes. The cells from adenomatous nodules in an acromegalic subject had a higher phosphorylation rate of IGF1R per IGF1R protein. These results indicate increased IGF1R and functional changes might contribute to thyroid tumor growth in acromegaly. Less

本研究从以下几个方面探讨了胰岛素样生长因子（IGF）及其结合蛋白（IGFBPs）在非胰岛细胞肿瘤性低血糖中的病理生理意义：1）产生IGF-Ⅱ的非胰岛细胞肿瘤性低血糖的临床特点在部分非胰岛细胞肿瘤性低血糖（NICTH）患者中，源自肿瘤的高分子量形式的IGF-II（大IGF-II）存在于循环中，并且可能与复发性低血糖有关。在这项研究中，为了调查IGF-II产生NICTH患者的临床特征，我们分析了78例NICTH患者的病历（男性/女性44/34，年龄62±1.8，范围; 9-86岁）。其血清中含有大量的IGF-II。肝癌和胃癌是最常见的NICTH的原因。肿瘤直径> 10 cm者占70%。79%的患者基础免疫反应性胰岛素（IRI）水平低于3 IU/dl。低血糖发作是 ...更多信息 65例中31例（48%）在低血糖发生前即发现肿瘤，34例（52%）在低血糖发生前即发现肿瘤。47例患者中有25例（53%）血清钾水平降低。这些数据表明，与大肿瘤相关的低胰岛素血症性低血糖支持产生IGF-II的NICTH的诊断。低钾血症与一些患者的低血糖有关。的BMI（21.4±0.6 kg/m^2）和血清总蛋白水平（6.6±0.1 g/dl）在第一次低血糖发作时保持不变，表明营养不良可能不是大多数患者低血糖的主要原因。2）甲状腺组织中I型胰岛素样生长因子受体（IGF 1 R）的表达和功能在甲状腺组织中，IGF-I刺激DNA合成，但IGF-I系统在甲状腺疾病中的作用尚不清楚。一些肢端肥大症患者有甲状腺肿瘤，这表明循环IGF-I的增加可能对甲状腺组织中的细胞生长有一些影响。本研究的目的是确定我们是否可以检测到异常的IGF 1 R系统建立从乳头状癌（PC）和肢端肥大症受试者的5个主题的原代培养的甲状腺细胞。单层细胞用IGF-I刺激。细胞裂解物用抗IGF 1 R抗体免疫沉淀，免疫沉淀物分级分离并用抗磷酸酪氨酸或IGF 1 R抗体免疫印迹。还通过定量RT-PCR分析了IGF 1 R基因表达。在肢端肥大症患者中，乳头状癌与非癌组织相比IGF 1 R蛋白水平和IGF 1 R基因表达增加，但两种组织中IGF 1 R磷酸化率无差异。来自5名PC患者的细胞显示出类似的变化。肢端肥大症患者的腺瘤性结节中的细胞具有较高的IGF 1 R/IGF 1 R蛋白磷酸化率。这些结果表明，增加IGF 1 R和功能的变化可能有助于甲状腺肿瘤的生长在肢端肥大症。少