Biomedical subjects

N Hizuka

Publications and source records attributed to N Hizuka.

At least 19 recordsLinked to original sources

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↗

PubMed1992

Thyroid hormone modulation of the hypothalamic growth hormone (GH)-releasing factor-pituitary GH axis in the rat.

Both thyroid hormone and hypothalamic growth hormone (GH)-releasing factor (GRF) facilitate pituitary somatotroph function. However, the pathophysiological role of thyroid hormone in GRF secretion is less well understood. Thyrotoxicosis, induced by administration of thyroxine (T4) in rats, inhibited both pituitary GH levels and immunoreactive GRF secretion from incubated hypothalamus. At the highest dose of T4 given for 12 d, GRF secretion and pituitary GH decreased by 50 and 39%, respectively. Hypothyroidism induced by thyroidectomy (Tx) enhanced GRF secretion approximately twofold while depleting pituitary GH by greater than 99%. Both of these hypothalamic and pituitary effects were reversed by replacement of T4 but not human GH for 7 or 14 d. Human GH was as potent as T4 in restoring decreased body weight gains or serum insulin-like growth factor-1 levels in Tx rats. These results indicate that at both physiological and pathological concentrations in serum, thyroid hormone acts as an inhibitory modulator of GRF secretion, probably not involving a feedback mechanism through GH. A biphasic effect of thyroid hormone on pituitary GH levels appears to derive from the difference in primary target tissues of hyper- and hypothyroidism, the hypothalamus and the pituitary, respectively.

Animals↗

PubMed1992

Effects of insulin-like growth factor I or human growth hormone in fasted rats.

To study the effect of insulin-like growth factor I (IGF-I) treatment on growth and metabolism in fasted rats and compare it with the effect of human growth hormone (hGH), we infused 120 micrograms/ml IGF-I continuously or injected 200 micrograms hGH twice a day in fasted rats. After a 3 1/2-day administration of IGF-I in fasted rats, the body weights, kidney, spleen and adrenal gland weights were greater than those for untreated fasted rats (control). The body weights and the organ weights in hGH treated rats did not differ from those in control rats. Serum IGF-I levels in control, hGH treated and IGF-I treated rats were 64.0 +/- 6.1, 107.5 +/- 6.9 and 129.8 +/- 6.3 ng/ml, respectively, which were significantly different from each other. Blood urea nitrogen (BUN) levels were 13.9 +/- 1.1 ng/ml in IGF-I treated rats, which were significantly lower than those of control rats. Human GH treatment did not change BUN but affected nonesterified fatty acid (NEFA) and triglyceride. In IGF-I treated rats three-day urinary excretion of nitrogen and creatine were 163.5 +/- 14.6 mg and 9.53 +/- 1.53 mg, which were significantly less than those in control rats. These data indicate that IGF-I infusion inhibits body weight loss and catabolism in fasted rats and might be a useful therapy in catabolic conditions.

Adrenal Glands↗

PubMed1991

Identification of a novel transcription unit in the human insulin-like growth factor-II gene.

The human insulin-like growth factor-II (hIGF-II) gene has until now been thought to be composed of eight exons, including three independent leader exons. In the present study two additional exons, one leader exon and one alternatively used ordinate exon, have been newly identified. They were abundantly expressed in human histiocytoma tissue, generating mRNA species of about 5.0 kb in length. The new leader exon shows significant sequence similarity with the rE1 exon, previously reported to be transcribed only in the rat, and is mapped at nearly the same genomic location as in the rat. On the other hand, sequence similarity with another exon in the corresponding region of the rat genome was also found. It was, however, obvious that the rat sequence would not work as an active exon, since both splice acceptor and donor sites were deviated considerably from the consensus sequences. It has thus become apparent that the complex transcription unit of a single-copy hIGF-II gene comprises at least 10 exons, including four leader exons, one alternative exon and three common protein-coding exons.

Amino Acid Sequence↗

PubMed1991

Single sc administration of insulin-like growth factor I (IGF-I) in normal men.

Total and free form of IGF-I in plasma increased in a dose dependent manner after sc IGF-I administration. Peak values of total IGF-I were obtained at 3-4 h after the administration, and then the values decreased gradually. However, peak values of free form of IGF-I were obtained at 2 h, and then rapidly decreased thereafter. The blood glucose, serum insulin and C-peptide levels decreased until 4 h after IGF-I administration in a dose dependent manner. Plasma IGF-II values significantly decreased at 4-12 h after IGF-I administration. Urinary urea nitrogen and sodium excretion decreased after IGF-I administration. Urinary GH excretion also decreased after 0.06 mg/kg IGF-I administration. These data demonstrate that IGF-I may play a role in glucose, protein and electrolyte metabolism, and plasma IGF-II levels and GH secretion might be regulated by IGF-I in man.

Adult↗

PubMed1991

Somatic growth in corticosteroid-treated rats with passive Heymann nephritis--effects of recombinant human growth hormone on growth impairment.

We evaluated the efficacy of recombinant human growth hormone (r-hGH) on corticosteroid (CS)-induced growth-impaired rats with proteinuria (passive Heymann nephritis. R-hGH (2 IU twice daily) improved growth in rats treated with 20 mg/kg per day of prednisolone succinate in our 4-week study. Although plasma hGH was significantly increased in rats treated with r-HGH, plasma insulin-like growth factor-1 levels were not different between treated and untreated rats. The food utilization rate was significantly improved by r-hGH. R-hGH did not affect proteinuria, renal function, or calcium and phosphate metabolism. Our results suggest that r-hGH may be effective in improving growth impairment due to CS administration.

Animals↗

PubMed1991

Potential effects of recombinant human growth hormone (r-hGH) on somatic growth in uremic rats.

In this study, we investigated both the efficacy of growth hormone (GH) in the improvement of growth disturbances in uremia and the effects on the remaining kidney, using uremic rats. Twenty 5/6 nephrectomized uremic rats were divided into two groups. One half of them were injected intraperitoneally with 2IU of human recombinant growth hormone (r-hGH) twice daily. The others were injected only with the vehicle. Sham operated control rats were also injected with the vehicle. These rats were pairfed and observed for as long as 4 weeks, during which, the growth in stature in uremic rats without r-hGH was markedly retarded, with a gain of only 15.8 +/- 3.7 mm of body length. It was significantly less than the 48.0 +/- 5.1 mm (p less than 0.01) gained by control sham-operated rats. By contrast uremic rats treated with r-hGH gained 37.8 +/- 2.9 mm, which was significantly greater than uremic rats without r-hGH (p less than 0.01) but less than controls (p less than 0.01). Increments of body stature paralleled those of skeletal bones. The food utilization rate was significantly improved in uremic rats treated by r-hGH. Throughout the experiment, serum creatinine and urea nitrogen levels remained constant and there were no intergroup differences in the uremic rats including insulin like growth factor I (IGF-1) and other chemical parameters except for plasma GH levels. These results suggest that r-hGH stimulates somatic growth in rats with chronic renal failure through improving food utilization and a probable direct effect on growing cartilage.

Animals↗

PubMed1991

Measurement of free form of insulin-like growth factor I in human plasma.

A method to measure free form of insulin-like growth factor I (IGF-I) in human plasma using octadecylsilyl silica (Sep-Pak C18) cartridge has been developed. IGF-I was adsorbed by Sep-Pak C18 cartridge and eluted with 75% ethanol--0.01 M HCl. Labeled and non-labeled IGF-I were recovered in yields 92.5 +/- 2.1% (Mean +/- SEM) and 94.4 +/- 6.3% after adsorption to and elution from the Sep-Pak, respectively. When EDTA plasma was applied to the Sep-Pak, less than 5% of total IGF-I was recovered in the eluate. However, when acid-ethanol extracted plasma was applied to the Sep-Pak, IGF-I was recovered in yields greater than 75% of total IGF-I. When the Sep-Pak eluate was gel filtered, 88.4 +/- 4.0% of immunoreactive IGF-I eluted in the same fraction as synthetic IGF-I did, but the fraction passed through the Sep-Pak was observed as a high molecular weight form (bound form) of IGF-I. These data indicate that this Sep-Pak method does not extract all of the IGF-I in plasma, but extracts mainly the free form IGF-I. Using this method, IGF-I values of free form (fIGF-I) in EDTA plasma were measured. The fIGF-I values in normal adults, patients with acromegaly, and patients with growth hormone (GH)-deficiency were 2.4 +/- 0.1, 13.8 +/- 1.6, and 1.1 +/- 0.1 ng/ml, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Acromegaly↗

PubMed1991

Repeated sc administration of recombinant human insulin-like growth factor I (IGF-I) to human subjects for 7 days.

Recombinant human insulin-like growth factor I (rhIGF-I) was administered subcutaneously to 6 normal subjects and 2 patients with GH deficiency at a dose of 0.1 mg/kg for 7 consecutive days after breakfast. In normal subjects, plasma IGF-I levels increased from 217 +/- 22 ng/ml (Mean +/- SEM) to maximal levels of 581 +/- 6 ng/ml 4 h after the first administration of IGF-I. The blood glucose levels were statistically depressed 4 h after injection at 69 +/- 2 mg/dl. Similar plasma IGF-I and blood glucose profiles were observed after the seventh administration of IGF-I. The free form of IGF-I in plasma was 2.3 +/- 0.3 ng/ml in normal subjects and increased to maximal levels of 43.5 +/- 5.1 ng/ml 2 h after the first IGF-I administration. A similar pattern for the free form of IGF-I was observed after the seventh administration; however, the values obtained at 0, 1 and 2 h were greater after the seventh administration. In patients with G-deficiency, the plasma IGF-I and blood glucose profiles were similar to those observed in normal subjects, although the total IGF-I levels were low in these patients at all sampling points during the study. Slight decreases in serum insulin, uric acid, and creatinine were observed after the seventh administration of IGF-I. There were no changes in the excretion of urea nitrogen, creatine, creatinine, sodium, potassium, chlorine, calcium or C-peptide in the urine during the 7 days of IGF-I administration.

Adult↗

PubMed1990

Effects of short-term growth hormone therapy in short children without growth hormone deficiency.

Evaluation of 24-hour endogenous growth hormone (GH) secretion was carried out in 62 children, aged 7-16 years, who did not have classic GH deficiency (GHD). The mean 24-hour GH concentration, determined at 20-minute intervals over 24 hours, was variable, ranging from 1.28 to 11.39 micrograms/l with a mean of 4.95 +/- 2.55 micrograms/l (+/- SD). There was a positive correlation between mean 24-hour GH concentration and plasma insulin-like growth factor I (IGF-I) values (r = 0.54; p less than 0.01). Recombinant human GH, 0.1 IU/kg/day was administered to 30 of the 62 children for 6 months followed by 6 months' observation without treatment. Thereafter, GH was administered at the same dose for a further 6 months to 16 children. The mean height velocities before, during, and after the first treatment period were 4.3 +/- 0.9, 7.3 +/- 1.9 and 4.9 +/- 2.0 cm/year (mean +/- SD), respectively. The height velocity during treatment was greater than pre- and post-treatment values (p less than 0.001). The height velocity increased again during the second treatment period to a mean of 8.5 +/- 2.0 cm/year (p less than 0.001). Nine other children were treated continuously in a similar manner for 1 year and their height velocity increased significantly from 4.1 +/- 1.4 to 6.0 +/- 1.9 cm/year (p less than 0.001). According to our criteria, 29 of the 39 children (74.4%) who were treated for 6-12 months showed a GH-dependent height increase during therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1990

Effects of sc administration of recombinant human insulin-like growth factor I (IGF-I) on normal human subjects.

Recombinant human insulin-like growth factor I (IGF-I) was administered subcutaneously to each of 5 normal human subjects at doses of 0 mg/kg (control), 0.06 mg/kg, or 0.12 mg/kg successively at one week intervals. After 0.06 mg/kg or 0.12 mg/kg IGF-I injections, plasma IGF-I levels increased from 185 +/- 17 ng/ml (mean +/- SEM) to maximal levels of 396 +/- 21 ng/ml at 3 hours and from 169 +/- 14 ng/ml to 480 +/- 27 ng/ml at 4 hours, respectively. These two peak values were statistically different (p less than 0.05). After 0.06 mg/kg and 0.12 mg/kg IGF-I administration, blood glucose levels decreased from 85 +/- 2 mg/dl to minimal levels of 73 +/- 3 mg/dl at 3 hours and from 83 +/- 1 mg/dl to 50 +/- 4 mg/dl at 2 hours, respectively. These two minimal values were statistically different (p less than 0.001). Serum insulin and C-peptide levels were decreased in a dose dependent manner after IGF-I administration. There were no changes between blood urea nitrogen levels before and 4 hours after IGF-I administration. The urinary GH concentration decreased after 0.06 mg/kg IGF-I administration, but increased and maintained normal values after 0.12 mg/kg IGF-I administration.

Adult↗

PubMed1990

Radioimmunoassay for insulin-like growth factor II (IGF-II).

Insulin-like growth factor II (IGF-II) levels in human plasma were measured in physiological and pathological conditions by radioimmunoassay (RIA) with biosynthetic IGF-II. This RIA was specific for IGF-II and cross-reactivity with IGF-I was 1%. The sensitivity was 15 pg/tube with 50% displacement at 50 pg/tube. The intra- and inter-assay coefficients of variation for IGF-II were 6.3 and 9.3%, respectively. The plasma IGF-II levels in normal adults, patients with hypopituitarism and patients with active acromegaly were 589.6 +/- 15.8, 800.9 +/- 45.6 and 330.3 +/- 24.3 ng/ml, respectively. After human growth hormone (hGH) treatment in hypopituitarism, IGF-II slightly increased, but not significantly. After adenomectomy in patients with acromegaly, IGF-II significantly decreased. These data indicate that IGF-II concentrations in plasma were partially GH dependent. This GH dependency was less than that of IGF-I. IGF-II was low in patients with anorexia nervosa and with liver cirrhosis and high in patients with renal failure. In two cases with extrapancreatic tumor-associated hypoglycemia, plasma IGF-II was increased to 1123.8 and 843.5 ng/ml, and returned to normal after tumor resection. These data showed that IGF-II was partly dependent on GH and nutritional conditions and that IGF-II was the most likely cause of some cases of hypoglycemia with extrapancreatic tumor. This specific and sensitive RIA of IGF-II would be useful in evaluating its physiological and pathological role in plasma and tissue.

Acromegaly↗

PubMed1990

Effects of insulin-like growth factor-I on insulin and glucagon release from isolated perfused rat pancreas.

The infusion of recombinant insulin-like growth factor I (IGF-I) causes a decrease in plasma glucose and insulin. In this study we examined whether or not IGF-I directly affects islet hormone release by means of a rat pancreas perfusion system. A superphysiologic concentration of IGF-I (2 nM) elicited a slight but significant decrease in insulin release under the perfusate glucose concentration of 120 mg/dl. A pharmacological concentration of IGF-I (200 nM) significantly suppressed the increase in insulin release in response to an increase in the perfusate glucose concentration (from 4.5 mM to 12.8 mM), but did not affect the decrease in insulin release in response to a decrease in the perfusate glucose concentration (from 6.9 mM to 2.8 mM). Glucagon release was not influenced by IGF-I in these experiments. These results suggest that IGF-I potentially inhibits the insulin release from islet B-cells directly, but its pathophysiological significance may be slight considering its partial inhibition at superphysiologic concentrations and its stable plasma level.

Animals↗

PubMed1989

Growth hormone and insulin-like growth factor I stimulate Leydig cell steroidogenesis.

Leydig cells from 40 days old rats were incubated with or without human growth hormone (hGH) or insulin-like growth factor I (IGF-I) in the presence or absence of human chorionic gonadotropin (hCG), and testosterone and cyclic AMP (cAMP) levels in the medium were measured. Neither hGH nor IGF-I increased testosterone production in the absence of hCG in concentrations up to 1000 and 100 ng/ml, respectively. However, both peptides increased hCG-induced testosterone production in a dose-dependent manner. The maximal stimulatory concentrations of hGH and IGF-I were 100 and 50 ng/ml, respectively. Human GH did not further enhance the IGF-I-stimulated steroidogenesis. The hGH-augmented steroidogenesis was inhibited by anti-hGH IgG and anti-IGF-I IgG. hGH also enhanced hCG-stimulated cAMP production time dependently, suggesting that the stimulatory effect of hGH on steroidogenesis was due to an increased cAMP production. These data suggest that the effect of hGH might be mediated by locally produced IGF-I, which may act as a modulator on gonadal development in the presence of gonadotropin.

Animals↗

PubMed1989

Human growth hormone stimulates liver regeneration in rats.

To study the effect of human growth hormone (hGH) on liver regeneration in rats, 200 micrograms hGH was administered to partial hepatectomized rats twice a day for three days. The bw of hGH-treated rats was higher than that in untreated rats. After three day administration, the liver weight was 3.18 +/- 0.13 g, significant higher than that of untreated rats (2.68 +/- 0.17 g). Human GH also stimulated the mitosis in the liver. Serum insulin-like growth factor I (IGF-I) and albumin levels were significantly increased and urea nitrogen levels were significantly decreased in hGH-treated rats compared with those in untreated rats. When 120 micrograms/day IGF-I was continuously administered to partial hepatectomized rats for three days, the bw and the liver weight were not higher than those of controls. These data indicate that hGH directly stimulates liver regeneration and recover liver dysfunction in rats.

Animals↗

PubMed1989

Effects of ingestion of glucose on GH and TSH secretion: evidence for stimulation of somatostatin release from the hypothalamus by acute hyperglycemia in normal man and its impairment in acromegalic patients.

Ingestion of glucose is known to induce suppression of GH secretion in normal subjects and this phenomenon is often absent in acromegalic patients. To clarify the mechanism of GH suppression in acute hyperglycemia in normal subjects and disturbed GH response in acromegalic patients, the effects of acute hyperglycemia on plasma GH and TSH levels were examined in normal subjects and acromegalic patients. Plasma GH levels were significantly lowered 45-60 min after ingestion of 75 g glucose and elevated at 210 and 240 min in nine normal subjects. Plasma TSH levels were also significantly lowered between 45 and 120 min after ingestion; levels then gradually rose. Subcutaneous administration of 50 micrograms SMS 201-995, a long acting somatostatin analog, lowered plasma TSH levels in both normal subjects and acromegalic patients, and there was no significant difference in the degree of decrease in plasma TSH levels between the normal subjects and patients. These results, taken together with several reports that somatostatin suppresses TSH secretion as well as GH secretion, suggest that acute hyperglycemia stimulates somatostatin release from the hypothalamus, thus causing inhibition of GH and TSH secretion. However, in ten acromegalic patients, only two showed suppression of plasma GH levels to below 50% of basal level and the degree of suppression of TSH secretion was significantly less than in normal subjects in the glucose tolerance test. It is, therefore, suggested that somatostatin release in response to acute hyperglycemia is impaired in most acromegalic patients and that this abnormality may be one of causes for the absence of the normal GH response to acute hyperglycemia in this disorder.

Acromegaly↗

PubMed1989

Measurement of nocturnal urinary growth hormone values.

Nocturnal urinary growth hormone values were measured by a sensitive enzyme immunoassay in normal adults, patients with GH deficiency, patients with Turner's syndrome, normal but short children who had normal plasma GH responses to provocative tests, and patients with acromegaly. The mean nocturnal urinary GH values in patients with acromegaly were significantly greater than those in normal adults (1582.3 +/- 579.8 vs 53.5 +/- 8.6 pmol/mmol creatinine (+/- SEM); p less than 0.05). In the normal but short children and patients with Turner's syndrome, the mean nocturnal urinary GH values were 83.1 +/- 5.2 and 79.8 +/- 29.5 pmol/mmol creatinine, respectively. In patients with GH deficiency, the nocturnal urinary GH values were undetectable (less than 5.3 pmol/mmol creatinine) except in one patient where the value was 6.3 pmol/mmol creatinine. The nocturnal urinary GH values of the patients with GH deficiency were significantly lower than those of the other groups (p less than 0.05). In normal but short children, the nocturnal urinary GH values correlated significantly with mean plasma nocturnal GH concentrations (r = 0.76, p less than 0.001), and 24-hour urinary GH values (r = 0.84, p less than 0.001), respectively. In 4 patients with GH deficiency who had circulating anti-hGH antibody, the urinary GH values were also undetectable. These data indicate that nocturnal urinary GH value reflects endogenous GH secretion during collection time, and that measurement of the nocturnal urinary GH values is a useful method for screening of patients with GH deficiency and acromegaly.

Acromegaly↗