| Co-Investigator(Kenkyū-buntansha) |
FUKUDA Izumi Tokyo Women's Medical College, Department of Medicine, Clinical Associate, 医学部, 助手 (80238477)
HIZUKA Naomi Tokyo Women's Medical College, Department of Medicine, Associate Professor, 医学部, 助教授 (80147397)
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| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1995: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1994: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
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
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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
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