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

在本研究中，我们研究了胰岛素样生长因子s （IGFs）和IGF结合蛋白（igfbp）的病理生理意义如下。1)胰岛素样生长因子- ii产生非胰岛细胞肿瘤低血糖的临床特征在一些非胰岛细胞肿瘤低血糖（NICTH）患者中，一种来源于肿瘤的高分子量形式的IGF-II（大IGF-II）存在于血液循环中，可能与反复低血糖有关。本研究为了探讨IGF-II产生型NICTH患者的临床特点，我们分析了78例血清中含有大量大IGF-II的NICTH患者（M/F 44/34，年龄62±1.8，范围9-86岁）的病历。肝细胞癌和胃癌是NICTH最常见的病因。70%的患者肿瘤直径大于10cm。基础免疫反应性胰岛素（IRI）水平在79%的患者中低于3 lU/dl。65例患者中有31例（48%）以低血糖发作为主，34例（52%）在低血糖发生前已发现肿瘤。47例患者中有25例（53%）血清钾水平下降。这些数据表明，与大肿瘤存在相关的低胰岛素性低血糖支持IGF-II产生NICTH的诊断。在一些患者中，低钾血症与低血糖有关。首次低血糖发作时的BMI（21.4±0.6 kg/m^2）和血清总蛋白水平（6.6±0.1 g/dl）保持不变，提示营养不良可能不是大多数患者低血糖的主要原因。2) I型胰岛素样生长因子受体（IGF1R）在甲状腺组织中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，表明循环中增加的igf - 1可能对甲状腺组织的细胞生长有一定影响。本研究的目的是确定我们是否可以在5例乳头状癌（PC）患者和1例肢端肥大症患者的原代培养甲状腺细胞中检测到异常的IGF1R系统。用igf - 1刺激单层细胞。用抗IGF1R抗体对细胞裂解液进行免疫沉淀，用抗磷酸酪氨酸或IGF1R抗体对免疫沉淀物进行分离和免疫印迹。定量RT-PCR分析IGF1R基因表达。在一例肢端肥大症患者中，与非癌组织相比，乳头状癌的IGF1R蛋白水平和IGF1R基因表达增加，但两种组织中IGF1R磷酸化率没有差异。5例PC患者的细胞表现出类似的变化。肢端肥大症患者的腺瘤结节细胞中IGF1R蛋白磷酸化率较高。这些结果表明，IGF1R的增加和功能改变可能有助于肢端肥大症甲状腺肿瘤的生长。少

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