Study for pathophysiological significance 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

• 批准号: 08671184
• 负责人: HIZUKA Naomi
• 金额: $ 1.47万
• 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 Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08671184/
• 关键词: insuline-like growth factor (IGF); insuline-like growth factor binding protein (IGFBP); non-islet cell tumor hypoglycemia (NICTH); loss of imprinting; Acid labile subunit; インスリン様成長因子(IGF); インスリン様成長因子結合蛋白(IGFBP)

Insulin-like growth factors (IGFs) bind to specific binding proteins (IGFBPs), and it has been speculated that the IGFBPs might modulate IGF action. In this study, we have investigated pathophysiological significance of IGFs and IGFBPs as follows. 1)IGFs and IGFBPs in anorexia nervosa : Malnutrition results in decreased serum IGF-I levels associated with altered profiles of IGFBPs. In the present study, to clarify further the effect of the nutritional status on the serum IGFs and IGFBPs levels, we investigated 48 patients with aunorexia nervosa. lGF-I,-II and lGFBP-3 levels by lRMA and IGFBP-2 levels by RIA were measured in 66 serum samples from the patients. The serum IGF-I and IGFBP-3 levels were lower than those in normal subjects, and the values positively correlated with the BMI as a nutritional parameter (r=0.54 ; p<0.001, and r=0.42 ; p<0.001, respectively). The serum IGFBP-2 levels were remarkably elevated in these patients and the levels inversely correlated with the BMI (r=0. … More 60 ; p<0.001). Funthemore, we found that the elevated serum IGFBP-2 levels decreased in accordance with the improvement of the BMI in these patients. The serum IGF-II levels did not correlate with the BMI (r=0.23 ; p=0.06). To investigate the correlation with the BMI further, the partial correlation coefficients were calculated, and the value for serum IGFBP-2 was higher than those for IGF-I,IGFBP-3, and IGF-II.These data indicate that serum IGFBP-2, IGF-I and IGFBP-3 levels are nutritional predictors in the patients with anorexia nervosa, and serum IGFBP-2 is better predictor than the IGF-I and IGFBP-3.2)IGFs and IGFBPs in IGF-II producing non-islet cell tumor hypoglycemia (NICTH) : In the patients with IGF-II producing NICTH, serum lGF-II levels ranged from 294 to l492 ng/ml with a mean of 718(]SY.+-。[)53 ng/ml, and the elevated IGF-II levels were found in only 13 patients (Normal range : 378-804 ng/ml). Serum IGF-I levels were low in all patients, with a mean of 22.7(]SY.+-。[)2.2 ng/ml (Normal range : 88-240 ng/ml). The serum IGFBP-3 levels by IRMA were significantly lower than those in normal subjects (1.51 (]SY.+-。[) 0.11 vs.3.13(]SY.+-。[)0.05 mug/ml ; p<0.001). The serum IGFBP-2 levels by RIA were significantly greater than those in normal subjects (1982(]SY.+-。[)208 vs.383(]SY.+-。[)20 ng/ml : p<0.00l). After successful tumor resection, serum IGFBP-2 levels decreased and the IGFBP-3 levels were normalized. The altered levels of serum IGFBPs could be related to bioavailable IGF-II in the IGF-II producing NICTH.3)Loss of imprinting (LOI) of IGF-II gene in NICTH : IGF-II gene (IGF2) is maternally imprinted. Rrcently, LOI of IGF2 has been reported in some embryonal tumors, suggesting that biallelic expression of the gene leads to overexpression of IGF-II peptide and increased mitogenic activity. In this study, we examined LOI of IGF2 in tumor from NICTH.IGF2 was expressed biallelically (LOI) in 8 of 11 informative tumors, suggesting that LOI of IGF2 could be relat Less

胰岛素样生长因子（IGFs）与特异性结合蛋白（igfbp）结合，并推测igfbp可能调节IGF的作用。在本研究中，我们从以下方面探讨了igf和igfbp的病理生理意义。1)神经性厌食症的igf和igfbp：营养不良导致血清IGF-I水平下降，与igfbp的改变有关。在本研究中，为了进一步阐明营养状况对血清IGFs和igfbp水平的影响，我们调查了48例神经性失食患者。采用lRMA法测定66例患者血清中lGF-I、-II、lGFBP-3水平，RIA法测定IGFBP-2水平。血清igf - 1、IGFBP-3水平均低于正常人，且与营养指标BMI呈正相关（r=0.54, p<0.001, r=0.42, p<0.001）。这些患者血清IGFBP-2水平显著升高，且与BMI呈负相关（r=0）。…更多60；p < 0.001)。此外，我们发现这些患者升高的血清IGFBP-2水平随着BMI的改善而降低。血清IGF-II水平与BMI无相关性（r=0.23; p=0.06）。为进一步研究其与BMI的相关性，计算偏相关系数，血清IGFBP-2高于IGF-I、IGFBP-3和IGF-II。这些数据表明，血清IGFBP-2、IGF-I和IGFBP-3水平是神经性厌食症患者的营养预测指标，血清IGFBP-2比IGF-I和IGFBP-3.2更好地预测产生IGF-II的非胰岛细胞肿瘤性低血糖（NICTH）：在产生IGF-II的NICTH患者中，血清lGF-II水平范围为294 ~ l492 ng/ml，平均为718（]SY.+-）。[)53 ng/ml，仅有13例患者IGF-II水平升高（正常范围：378-804 ng/ml）。所有患者血清igf - 1水平均较低，平均为22.7([SY.+-] .)2.2 ng/ml（正常范围：88-240 ng/ml）。经IRMA检测的血清IGFBP-3水平明显低于正常对照组（1.51(0.05)）。[) 0.11 vs.3.13(]SY.+- .[)0.05杯/毫升；p < 0.001)。血清IGFBP-2水平显著高于正常受试者（1982 [SY.+-]）。[3][参考译文][)20 ng/ml: p<0.00l)。肿瘤切除成功后，血清IGFBP-2水平下降，IGFBP-3水平恢复正常。血清igfbp水平的改变可能与产生IGF-II的NICTH中生物可利用的IGF-II有关。3)NICTH中IGF-II基因印记缺失（LOI）： IGF-II基因（IGF2）是母体印迹的。最近，IGF2的LOI在一些胚胎肿瘤中有报道，表明该基因的双等位基因表达导致IGF-II肽的过表达和有丝分裂活性的增加。在本研究中，我们检测了NICTH肿瘤中IGF2的LOI。IGF2在11个信息性肿瘤中有8个呈双等位表达（LOI），提示IGF2的LOI可能相对较少

项目成果

Kudo Y.et al.: "Estrogen and parathyroid hormone reglulate IGFBP-4 in SaOs-2 cells." Life Sci. 61. 165-170 (1997)

Kudo Y.et al.：“雌激素和甲状旁腺激素调节 SaOs-2 细胞中的 IGFBP-4。”

Ohyama T,Sato M,Niimi M,Hizuka N,Takahara J: "Effects of short-and long-term dexamethasone treatment on growth and growth hormone (GH)-releasing hormone (GRH)-GH-insulin-like growth factor-I axis in conscious rats." Endorine J. 44. 827-835 (1997)

Ohyama T，Sato M，Niimi M，Hizuka N，Takahara J：“短期和长期地塞米松治疗对生长和生长激素（GH）释放激素（GRH）-GH-胰岛素样生长因子-I的影响

Hizuka N.et al.: "Hypoglycemic effect of IGF-II is mediated mainly through insulin and/or IGF-I receptor but not IGF-II receptor" Clin Pediatr Endocrinal. 5(Suppl 8). 75-81 (1996)

Hizuka N.等人：“IGF-II 的降血糖作用主要通过胰岛素和/或 IGF-I 受体介导，但不是 IGF-II 受体”Clin Pediatr Endocrinal。

Hizuka N, et al.: "Divergent effects of octneotide on glucose tolerance in patients with acromegaly" Intern Med. 36. 319-320 (1997)

Hizuka N 等人：“奥克肽对肢端肥大症患者葡萄糖耐量的不同影响”实习医学。

Ohyama T.et al.: "Effects of short-and long-term dexamethasone treatment on growth and GRH-GH-IGF-I axis in conscious rats." Endocrine J. 44. 827-835 (1997)

Ohyama T. 等人：“短期和长期地塞米松治疗对清醒大鼠生长和 GRH-GH-IGF-I 轴的影响。”