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Biomedical subjects

N Hizuka

Publications and source records attributed to N Hizuka.

At least 19 recordsLinked to original sources
PubMed1997

Estrogen and parathyroid hormone regulate insulin-like growth factor binding protein-4 in SaOS-2 cells.

The effect of 17beta-estradiol and parathyroid hormone (PTH) on the expression of insulin-like growth factor-binding protein-4 (IGFBP-4) messenger RNA (mRNA) was studied in the cultured human osteoblast-like SaOS-2 cells. Treatment of SaOS-2 cells with PTH for 3 h caused 3.3-fold increase in IGFBP-4 mRNA levels which was determined by reverse transcription-polymerase chain reaction. 17beta-Estradiol had no effect on either the stimulation of mRNA level by PTH or the basal level. Together with our previous report that 17beta-estradiol inhibits the PTH-induced reduction of IGFBP-4 proteolysis in these cells, the results obtained may help to explain the mechanisms of determining IGFBP-4 availability by systemic hormones in osteoblast cells.

Blotting, Western↗
PubMed1996

Growth hormone (GH) secretory dynamics in a case of acromegalic gigantism associated with hyperprolactinemia: nonpulsatile secretion of GH may induce elevated insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 levels.

We describe a case of pituitary gigantism with low levels of growth hormone (GH), elevated insulin-like growth factor-I (IGF-I), and IGF-binding protein-3 (IGF-BP-3). The patient had characteristic clinical features of gigantism and acromegaly. The basal serum GH levels ranged from 1.2-1.9 micrograms/L, which were considered to be within normal limits. Serum GH response to either insulin-induced hypoglycemia or GH-releasing hormone was blunted. Frequent blood samplings during daytime and at night showed nonpulsatile GH secretion. Serum prolactin, IGF-I and IGF-binding protein-3 levels were elevated. After unsuccessful surgery, bromocryptine treatment normalized serum prolactin without affecting serum GH and IGF-I levels. Combined administration of octreotide and bromocryptine reduced serum GH and IGF-I levels. GH bioactivity as measured by Nb2 cell proliferation assay was within reference range. In the present case, nonpulsatile GH secretion and enhanced tissue sensitivity to GH may induce hypersecretion of IGF-I and IGF-BP-3 and cause clinical acromegalic gigantism.

Acromegaly↗
PubMed1995

Long-term effects of growth hormone treatment on height in Turner syndrome: results of a 6-year multicentre study in Japan. Committee for the Treatment of Turner Syndrome.

Patients with Turner syndrome have many somatic characteristics, including short stature. We report the results of a 6-year multicentre clinical trial of recombinant human growth hormone (GH) therapy in 63 patients with Turner syndrome. Twenty-six patients received GH at a dose of 0.5 IU/kg/week, while 37 received GH, 1.0 IU/kg/week, by daily subcutaneous injection. At the start of GH treatment, there was no significant difference between the two groups in chronological age, bone age, height or growth rate. Both treatment groups showed a significant growth increase during treatment. The current mean height of the 12 patients over the age of 16 treated with GH, 0.5 IU/kg/week, is 145.1 +/- 4.7 cm, and in the 16 patients treated with GH, 1.0 IU/kg/week, is 144.0 +/- 2.2 cm. In conclusion, treatment with GH does increase final height in patients with Turner syndrome. However, further studies are needed to determine the optimum age for the initiation of GH therapy, the best dose regimen and the optimal time and manner of sex and anabolic steroid use.

Body Height↗
PubMed1995

Big insulin-like growth factor II-producing hepatocellular carcinoma associated with hypoglycemia.

A 76-year-old female with a hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) was hospitalized because of fasting hypoglycemia. Her sera contained a low concentration of immunoreactive insulin and insulin-like growth factor (IGF)-I, while the IGF-II level was normal. However, most of the IGF-II consisted of the high molecular weight form (big IGF-II). The tumor tissue contained fetal type of IGF-II mRNA (6.0 kb). Furthermore, we found that one of the four patients examined with HCV-related HCC had big IGF-II in serum. This indicates that non-islet cell tumor hypoglycemia (NICTH) in HCV-related HCC might be accompanied by production of big IGF-II by the tumor.

Aged↗
PubMed1995

Acromegalic gigantism with low serum level of growth hormone and elevated serum insulin-like growth factor-I.

In a case of acromegalic gigantism with hyperprolactinemia is reported, the basal serum growth hormone (GH) levels ranged from 1.2 to 1.9 ng/ml. Serum GH response to either insulin-induced hypoglycemia or GH-releasing hormone was blunted. Frequent blood sampling showed non-pulsatile GH secretion. Serum prolactin and insulin-like growth factor-I (IGF-I) levels were elevated. After unsuccessful surgery, bromocriptine treatment normalized serum prolactin without affecting serum GH and IGF-I levels. Combined administration of octreotide with bromocriptine reduced serum GH and IGF-I levels. In this case, non-pulsatile GH secretion and enhanced tissue sensitivity to GH may induce hypersecretion of IGF-I and cause clinical acromegalic gigantism.

Acromegaly↗
PubMed1994

Expression of insulin-like growth factor II by a gastric carcinoma associated with hypoglycaemia.

A gastric cancer with liver metastases was associated with low morning levels of plasma glucose (24 mg/dl), insulin (< 2.5 microU/ml) and growth hormone (0.23 ng/ml). Primary and metastatic tumour tissue stained positively with anti-insulin-like growth factor II (IGF-II) monoclonal antibody. Western immunoblot analysis revealed a high molecular weight IGF-II in the serum: 15 kDa (normal: 7.5 kDa). Postmortem reverse transcription polymerase chain reaction on mRNA from both sites revealed 471 base pairs size cDNA encoding prepro-IGF-II. These results suggest that the gastric carcinoma encoded, expressed, and secreted IGF-II, probably causing the extrapancreatic tumour hypoglycaemia.

Aged↗
PubMed1994

Increased activity of insulin-like growth factor-binding protein in human thyroid papillary cancer tissue.

It has been shown that both insulin-like growth factor-I (IGF-I) and IGF-binding proteins (IGFBPs) are produced by thyroid cells in culture and that the cells respond to IGF-I with increased DNA synthesis, suggesting an autocrine/paracrine role of IGF-I in the regulation of thyroid cell growth. We investigated the tissue contents of immunoreactive IGF-I (irIGF-I) and IGFBPs in human papillary carcinoma and compared them with those of normal thyroid tissue. When irIGF-I was measured after separation of the IGFBPs by gel-filtration, its content in carcinoma tissue was not different from that in adjacent normal tissue (566 +/- 58 vs. 424 +/- 75 pg/mg protein, N = 10). Nor was there any difference in the abundance of IGF-I mRNA expression determined by slot blot analysis. On the other hand, IGFBP activity measured in terms of 125I-IGF-I binding was significantly higher in cancer extracts. Western ligand blot analysis of IGFBPs revealed several species (24-42 kDa) of IGFBPs. The IGF-I-binding activity of 38-41 kDa species (corresponding to IGFBP-3) was not different between extracts of cancer tissue and those of normal tissue, whereas that of 28-32 kDa species was significantly higher in cancer tissue extracts. Since IGFBPs have been reported to modulate cellular responses to IGF-I, the present data suggest that higher IGFBP activity in cancer tissue is involved in regulating growth of thyroid papillary carcinoma cells.

Adenoma↗
PubMed1994

IGF-I as an early indicator of malnutrition in patients with end-stage renal disease.

The present study was performed to clarify the possibility of IGF-I as an early indicator of malnutrition in patients with end-stage renal disease. Thirty-two patients (19 males, 13 females; mean age 49.6 +/- 10.0 years) undergoing dialysis were enrolled in the study. Body weight, skinfold thickness, and midarm muscle circumferences (MAMCs) were measured for anthropometric nutritional indices. Blood samples were collected to measure the following endocrinological, biochemical and hematological indices: IGF-I, growth hormone, (GH), total protein, prealbumin, albumin, transferrin, hematocrit, and lymphocyte count. Nutritional indices were measured again 1 month later to calculate the percent difference among them. Moreover, 2 patients who showed a decrease in IGF-I and suffered from malnutritional complications, such as hypoproteinemia and emaciation, which could not be successfully treated by conventional therapies were selected in order to confirm the nutritional role of IGF-I mediated by recombinant human GH (r-hGH). The serum IGF-I concentration distribution ranged from 22 to 225 ng/ml. In 15 patients (10 males, 5 females), it fell from 22 to 82 ng/ml below the normal range. Partial correlation coefficient analysis demonstrated that baseline IGF-I and the percent difference of each the body weight, MAMC, prealbumin and albumin were highly significantly correlated (r = 0.431, 0.641, 0.624 and 0.348, respectively; p = 0.014, 0.001, 0.001 and 0.028, respectively). The percent difference of IGF-I did not correlate significantly with that of any other nutritional index during the 1-month observation without administration of r-hGH.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Increase of serum growth hormone-binding protein in patients with ossification of the posterior longitudinal ligament of the spine.

Serum growth hormone-binding protein (GHBP) was measured in 26 patients with ossification of the posterior longitudinal ligament of the spine (OPLL) and 19 age-matched controls. Serum GHBP level was significantly higher in the OPLL group than in the controls, whereas there was no statistical difference between the two groups in serum level of growth hormone, insulin-like growth factor (IGF)-1, and IGF-2. These results, taken together with the hypothesis that serum GHBP reflects the number of GH receptors in tissue, suggest that GH receptors are increased in patients with OPLL.

Carrier Proteins↗
PubMed1993

Characterization of new monoclonal antibodies to human insulin-like growth factor-II and their application in western immunoblot analysis.

Four immunoglobulin G1 class monoclonal antibodies (mAbs; 1D5, 1D9, 2B11, and 2H11) were produced against recombinant human insulin-like growth factor-II (rhIGF-II). Enzyme-linked immunosorbent assay established that these four mAbs specifically recognized rhIGF-II and hIGF-II, but not rhIGF-I. mAbs 1D5, 1D9, and 2H11 did not cross-react with mouse rIGF-II, although there are only six amino acid differences between mouse IGF-II and human IGF-II. The epitope for each mAb was partially defined by enzyme-linked immunosorbent assay using mouse-human chimera IGF-II mutants and other IGF-II mutants that were prepared by site-directed mutagenic procedures. These results indicated that the epitopes of mAbs 1D5, 1D9, and 2H11 are in the C-domain of hIGF-II around Ala32 to Ser36, and that of 2B11 is in the carboxyl-terminal end of the B- and A-domains of hIGF-II. A specific and sensitive RIA was developed using mAb 2H11. In this RIA, IGF-II variant ([RLPG/S29]IGF-II) and rhIGF-II competed equally with [125I]IGF-II for binding to mAb 2H11. Similar results were produced when mAbs 1D5, 1D9, and 2B11 substituted for 2H11. The potential usefulness of mAb 2H11 in an immunoblot procedure to characterize the heterogeneity of IGF-II in the sera and tumor tissues of patients with nonislet cell tumor hypoglycemia was evaluated. A procedure that combined acid-ethanol extraction of serum or tumor tissues and immunoaffinity concentration of the extracted IGF-II with mAb 2H11-immobilized resin was found to be an effective way to prepare the samples. In Western immunoblots, a quantity of rhIGF-II as low as 3 ng could be identified, whereas 200 ng rhIGF-I or rat IGF-II were not recognized. The levels of IGF-II in the sera of 12 patients with nonislet cell tumor hypoglycemia varied from normal to about twice normal. The mol wt (M(r)) of this IGF-II was between 10-17K. There was little of the processed 7.5K M(r) IGF-II in the sera of these patients. Finally, the source of the high M(r) forms of IGF-II was the tumor, because the ratios of high M(r) forms of IGF-II to 7.5K IGF-II changed dramatically from 99:1 and 91:9 to 4:96 and 32:68 in two patients after successful excision of their tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Characterization of insulin-like growth factor II (IGF-II) and IGF binding proteins in patients with non-islet-cell tumor hypoglycemia.

Insulin-like growth factor II (IGF-II) in serum and tumor extracts from five patients with non-islet-cell tumor hypoglycemia (NICTH) has been characterized. These tumors contained large quantities of IGF-II (2.4-14.2 micrograms/g tissues). The serum IGF-II levels in four of five patients were a little high and the serum IGF-I levels in five patients were low. The serum IGF-II/IGF-I ratios in these patients ranged from 24.1 to 64.2, and the values were significantly greater than those in normal subjects (1.7-7.1). When the sera were gel-filtered on a Sephacryl S-200 column under neutral conditions, the proportion of the free form of IGF-II was not increased. However, in four of five patients, an abnormal IGF-II-IGF binding protein complex was found. When serum IGF binding proteins (IGFBPs) were analyzed by Western ligand blotting, serum IGFBP-2 increased in these patients. When the tumor extracts and sera were gel-filtered on a Biogel P-60 column under acidic conditions, the majority of IGF-II in these sera was a big form of IGF-II. As compared to authentic IGF-II, insulin receptor reactivities and IGF-II receptor reactivities of tumor extracted IGF-II increased in two of three patients. These data indicate that in patients with NICTH, heterogenous IGF-II is produced in respect of size and bioactivities, and that the characteristics of IGF binding protein are altered. Thus, to find IGF-II producing tumors among extrapancreatic tumors associated with hypoglycemia, the quality of IGF-II as well as the quantity should be studied.

Aged↗
PubMed1993

Responses of insulin-like growth factor binding protein-1 (IGFBP-1) and the IGFBP-3 complex to administration of insulin-like growth factor-I.

The importance of insulin-like growth factor binding proteins (IGFBPs) in modulating the bioactivity of administered IGFs is poorly understood. This study examines responses of IGFBP-1 and the IGFBP-3 complex to recombinant human IGF-I. Eight fasted subjects received a single dose of 0.1-0.125 mg/kg IGF-I sc. This caused a 10-fold rise in IGFBP-1 over 6 h, falling rapidly after food intake. Peak (6-h) IGFBP-1 values were highly correlated with peak post-prandial (8-h) glucose values (r = 0.941). IGFBP-3 showed little response, decreasing slightly over the 48-h period following IGF-I. Adaptive changes in IGFBPs were studied in fed adults injected daily for 7 days with IGF-I, 0.1 mg/kg sc. Following the first injection, IGFBP-1 had a markedly blunted response compared to that in fasted subjects. However, after the seventh IGF-I injection, a 3.5-fold greater IGFBP-1 response to the same IGF-I dose was seen. Concomitantly with the increased IGFBP-1 responsiveness, mean immunoreactive IGFBP-3 and acid-labile subunit levels decreased significantly (p < 0.005), whereas IGFBP-2 detected by immunoblotting increased. Thus IGF-I administration causes changes in IGFBPs which may be important in regulating IGF-I bioavailability.

Adult↗
PubMed1993

IGF-II producing hepatic fibrosarcoma associated with hypoglycemia.

A 67-year-old male was admitted with the complaint of weakness at hunger early in the morning, when blood glucose was less than 40 mg/dl. The abdominal ultrasonogram and computerized tomogram demonstrated a huge tumor in the right liver lobe. Hypoglycemia disappeared after transcatheter arterial embolization. Then hepatic lobectomy was performed. The tumor was histologically shown to be a fibrosarcoma. Insulin-like growth factor-II was intensely stained in the Golgi area of the tumor cells, suggesting its role in the mechanism of hypoglycemia.

Aged↗
PubMed1992

[Serum growth hormone binding protein (GHBP) and insulin-like growth factor binding protein (IGFBP)].

Insulin--like growth factors bind to specific binding proteins (IGFBPs) in serum and tissues. At present, six different IGFBPs have been characterized. Recent studies suggest that IGFBPs act as a reservoir for IGFs but also modulate the bioavailability of IGFs. Binding protein for growth hormone (GH) in serum has been recognized recently. Interestingly, the high affinity GH binding protein (GHBP) is identical with the extracellular domain of GH receptor and is absent in patients with Laron-type dwarfism, suggesting that serum GHBP might serve as a marker for the GH receptor in tissue. In this short review, updated information on serum GHBP and IGFBP is presented.

Amino Acid Sequence↗
PubMed1992

An insulin-like growth factor II-producing histiocytoma associated with hypoglycemia: analysis of the peptide, its gene expression, and glucose transporter isoforms.

An insulin-like growth factor II (IGF-II)-producing histiocytoma was detected in a patient presenting with the classical findings of tumor-related hypoglycemia (low serum insulin and IGF-I concentrations, glucose intolerance, and only modestly increased serum IGF-II levels). Acid-gel filtration of serum extracts showed a single peak of IGF-II immunoreactivity that emerged at the same site as the 125I-labeled human IGF-II standard. High-performance liquid chromatography (HPLC) analysis of the tumor IGF-II demonstrated that it had an identical retention time to that of recombinant human IGF-II. The tumor IGF-II content was extremely high, messenger RNA (mRNA) for IGF-II showed a 100-fold increase in expression compared with normal human liver tissue. Of special interest, a newly identified exon (hE1) was shown to be predominantly expressed in the tumor by Northern blot analysis using leader exon-specific rat IGF-II complementary DNA (cDNA) probes. Although the significance of this finding remains uncertain, this is the first evidence of a new transcription unit in the human IGF-II gene. In addition, immunoblotting showed that the levels of the glucose transporters, GLUT1 and GLUT4, in the tumor were low and undetectable, respectively. This finding makes it unlikely that increased glucose consumption by the tumor accounted for the hypoglycemia in this patient. This case report provides an interesting insight into the pathophysiology of tumor-induced hypoglycemia and new evidence of the abnormal regulation of IGF-II gene expression in human tumors.

Animals↗