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

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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