Study for pathological significance of insulin-like growth factor binding proteins.

胰岛素样生长因子结合蛋白的病理意义研究。

• 批准号: 06671058
• 负责人: HIZUKA Naomi
• 金额: $ 1.15万
• 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 General Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06671058/
• 关键词: insulin-like growth factor (IGF); insulin-like growth factor binding protein (IGFBP); インスリン様成長因子; インスリン様成長因子結合蛋白; (IGF); (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 pathological significance of IGFBPs as follows. 1) Pathophysiological roles of IGFBP-6 have not been elucidated. Recently we measured serum IGFBP-6 by Western immunoblot (WIB), and have found that serum IGFBP-6 levels are not GH dependent and increase in patients with chronic renal failure (CRF). In the present study, to investigate further clinical significance and regulation of serum IGFBP-6, we measured serum IGFBP-6 levels in patients with CRF after renal transplantation. Furthermore, we also measured IGFBP-2 levels. Serum IGFBP-2 and -6 levels remarkably increased in all patients with CRF.The levels did not change after hemodialysis. Serum IGFBP-6 levels dramatically decreased 1 day after renal transplantation and decreased further with the improvement of renal function. In contrast to IGFBP-6, seru … More m IGFBP-2 levels did not decrease during 14 days after renal transplantation. In addition, we demonstrated IGFBP-6 in urine. These data indicate that IGFBP-6 might be excreted by the kidneys and serum IGFBP-6 levels might be related with renal function, and that regulation of serum IGFBP-6 levels are different from that of IGFBP-2.2) Serum levels of IGFBP-2 and IGFBP-3 in cord sera were higher and lower than those in adult sera. Serum levels of IGFBP-2 in cord sera inversely correlated with birth weight and the levels of free from of IGFs. The birth weight positively correlated with serum IGF-I,and free form of IGFs. These findings suggest that changes in IGFBP-2 in fetal sera might modulate the relative concentrations of free IGFs, supposed to be active from of IGFs, and then modulate fetal growth. 3) It has been hypothesized that IGFBP-1 play a role in counter regulation of blood glucose. We found that serum IGFBP-1 did not increase in 3h after insulin-induced hypoglycemia. Therefore, we could not support the hypothesis. 4) It has been reported that IGFBPs were regulated by various agents in osteoblast-like cells, but these data were different among species. In the present study, we took advantage of cultured human osteoblasts obtained from trabecular bone, and undertook a study of effect of various agents. The cultured human osteoblasts secreted IGFBPs, mainly IGFBP-3, -4, and -2.1,25-(OH)_2D_3 inhibited the proliferation of osteoblasts, and increased osteocalcin in the media. 1,25-(OH)_2D_3 increased IGFBP-3 and slightly IGFBP-4. E_2 did not affect on the cell proliferation and osteocalcin in the media, but, increased IGFBP-3, -4 and -2. These data demonstrate that IGFBPs of human osteoblasts are regulated by effectors of bone metabolism. However, it remains to be elucidated how IGFBPs modulate IGF action in bone metabolism. Less

胰岛素样生长因子(IGF)与特异性结合蛋白(IGFBPs)结合，推测IGFBPs可能调节IGF的作用。在本研究中，我们研究了IGFBPs的病理意义如下。1)IGFBP-6的病理生理作用尚未阐明。最近，我们用免疫印迹法(WIB)检测了血清IGFBP-6水平，发现慢性肾功能衰竭(CRF)患者血清IGFBP-6水平不依赖于GH且升高。在本研究中，我们检测了肾移植后CRF患者血清IGFBP-6水平，以进一步探讨血清IGFBP-6的临床意义和调节。此外，我们还测量了IGFBP-2水平。所有CRF患者血清IGFBP-2和IGFBP-6水平均明显升高，血液透析后无明显变化。肾移植术后第1天血清IGFBP-6水平明显下降，随着肾功能的改善而进一步下降。与IGFBP6相比，SERU…更多的IGFBP-2水平在肾移植后14天内没有下降。此外，我们还检测了尿液中的IGFBP-6。提示IGFBP-6可能由肾脏分泌，血清IGFBP-6水平可能与肾功能有关，血清IGFBP-6水平的调节与IGFBP-2不同。2)脐血IGFBP-2、IGFBP-3水平高于和低于成人血清。脐血IGFBP-2水平与出生体重、IGFS游离水平呈负相关。出生体重与血清IGF-I、游离IGFS呈正相关。这些发现提示，胎儿血清中IGFBP-2的变化可能通过调节游离IGFS的相对浓度，进而调节胎儿的生长发育。3)推测IGFBP-1具有反向调节血糖的作用。我们发现，在胰岛素诱导的低血糖后3h，血清IGFBP-1没有升高。因此，我们不能支持这一假设。4)已有报道IGFBPs在成骨细胞样细胞中受多种因素的调节，但这些数据在不同物种中是不同的。在本研究中，我们利用培养的人骨小梁成骨细胞，并对各种因素的作用进行了研究。培养的人成骨细胞分泌IGFBPs，主要是IGFBP-3、-4和-2.1，25-(OH)_2D_3抑制成骨细胞的增殖，增加培养上清液中的骨钙素。1，25-(OH)_2D_3使IGFBP-3升高，IGFBP-4略有升高。E_2对细胞增殖和培养液中骨钙素无影响，但使IGFBP-3、-4和-2升高。这些数据表明，人成骨细胞的IGFBPs受骨代谢效应物的调节。然而，IGFBPs如何调节IGF在骨代谢中的作用仍有待阐明。较少

项目成果

Fukuda I et al.: "Circulating forms of insulin-like growth factor II(IGF-II) in patients with non-islet cell tumor hypogly cemia" Endocrinol Metab. 1. 89-95 (1994)

Fukuda I 等人：“非胰岛细胞瘤低血糖患者中胰岛素样生长因子 II (IGF-II) 的循环形式”Endocrinol Metab。

Hizuka N.et al.: "Effect of IGF-I administrations on serum IGFBPs in patients with growth thormore deficiency." Advances in Experimental Medicine and Biology. 343. 301-309 (1994)

Hizuka N.et al.：“IGF-I 给药对生长激素缺乏症患者血清 IGFBP 的影响。”

Sanaka T.et al.: "IGF-I as an early indicator of malnutrition in patients with end-stage venel dise." Nephron. 67. 73-81 (1994)

Sanaka T. 等人：“IGF-I 是终末期静脉疾病患者营养不良的早期指标。”

福田いずみ,肥塚直美: "膵外腫瘍に伴う低血糖" 内分泌糖尿病科. 1. 210-215 (1995)

Izumi Fukuda、Naomi Hizuka：“与胰外肿瘤相关的低血糖”内分泌和糖尿病系 1. 210-215 (1995)。

Sanaka T,Shinobe M,Ando M,Hizuka N,Kawaguchi H,Nihei H: "IGF-I as an early indicator of malnutrition in patients with end-stage renal disease." Nephron. 67. 73-81 (1994)

Sanaka T、Shinobe M、Ando M、Hizuka N、Kawaguchi H、Nihei H：“IGF-I 作为终末期肾病患者营养不良的早期指标。”