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Biomedical subjects

W H Daughaday

Publications and source records attributed to W H Daughaday.

At least 37 records · Page 2Linked to original sources
PubMed1990

Whole body nitrogen kinetics and their relationship to growth in short children treated with recombinant human growth hormone.

We studied the effects of growth hormone on retention of 15N-labeled amino acids in 34 short, prepubertal, growth hormone-sufficient children and three growth hormone-deficient subjects. All 34 non-growth hormone-deficient children had apparently normal circulating growth hormone molecules and no mutations were detected in the growth hormone or IGF-I genes of any subjects. Fibroblasts from 34 children responded normally when challenged with recombinant human IGF-I. During the last 72 h of a 4-d challenge with recombinant human growth hormone (16 micrograms/kg body wt), retention of a mixed 15N-amino acid dose varied between 5.7 and 50.5%. Whole body protein synthesis, breakdown, and net anabolism calculated from the 15N kinetics were all increased by the acute growth hormone challenge. However, no routine clinical feature or laboratory determination correlated with the nitrogen retention response. After subsequent treatment (75 micrograms/kg three times a week) with recombinant human growth hormone for 1 y, there was a significant increase in height velocity, but this increase was not related significantly to pretreatment variables other than inversely to pretreatment height velocity. There was a significant (p = 0.03) correlation between the change in height velocity Z score and the degree of nitrogen retention to acute challenge with growth hormone, but this correlation was too weak (r = 0.37) to be of practical value in predicting the treatment growth response in an individual child.

Adolescent↗
PubMed1990

Hypersomatotropism in pregnant women, as measured by a human liver radioreceptor assay.

Radioreceptor assays (RRAs) provide useful information about the bioactivity of peptide hormones. We have developed a RRA for human GH using membranes prepared from human liver. The assay has 1% cross-reactivity with human PRL, 0.11% cross-reactivity with human chorionic somatomammotropin, and negligible cross-reactivity with bovine and rat GH. The assay has distinct advantages over the IM-9 lymphocyte RRA in having reduced nonspecific interference from serum proteins and providing a uniform source of receptors which can be stored for long periods at -70 C. The coefficient of variation of the assay is 13%. In studies of 55 sera from short children with normal or elevated serum GH concentrations the mean ratio of RRA GH to immunoradiometric assayed GH was 1.28. This assay provided important information about the total GH activity in pregnancy. There was a progressive rise in RRA GH during pregnancy, reaching 64.7 +/- 2.5 (+/- SE) micrograms/L at term. This level is 2-3 times higher than suggested by earlier estimates made with monoclonal antibody RIAs for pituitary GH. At term the contributions to total GH activity of serum are less than 3% from the pituitary, 12% from human chorionic somatomammotropin reacting with the GH receptor, and 85% from placental GH. Despite this great increase in receptor-reactive GH, somatomedin activity by bioassay is reduced, and IGF-I, determined by RIA after acid-gel filtration, is minimally elevated.

Adult↗
PubMed1990

Abnormal processing of pro-IGF-II in patients with hepatoma and in some hepatitis B virus antibody-positive asymptomatic individuals.

Hepatomas are a common malignancy in countries with a high prevalence of hepatitis B virus infections. These tumors may present with severe persistent hypoglycemia. We have studied the possible relationship of production of insulin-like growth factor II (IGF-II) by these tumors and the development of hypoglycemia. Mean IGF-II concentration was not significantly higher in 23 patients with hypoglycemia than in nine patients with euglycemia (542 +/- 61 [SE] micrograms/L vs 382 +/- 52 micrograms/L). Serum IGF-I was more suppressed in patients with hypoglycemia (16 +/- 3 micrograms/L) than in patients with euglycemia (57 +/- 18 micrograms/L). Because an increased percentage of IGF-II in serum of patients with hypoglycemia who have other tumors is present as partially processed pro-IGF-II ("big" IGF-II), we passed sera of patients with hypoglycemia and patients with euglycemia with hepatomas through acidic Bio-Gel P-60 columns. We found that 57% +/- 4.6% of the IGF-II in sera from patients with hypoglycemia was present as big IGF-II compared with 22% +/- 3% in patients with euglycemia with hepatomas (not significantly different from that in normal controls). Four of 11 apparently healthy control subjects who were hepatitis B virus positive also had increased percentages of big IGF-II, suggesting that abnormal processing of pro-IGF-II may result from subtle changes in liver function with this infection. It remains to be determined whether these subjects with increased big IGF-II are at increased risk for the development of hepatomas. In conclusion, we have confirmed marked suppression of IGF-I in the sera of patients with hepatoma and hypoglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Insulin-like growth factor II acts as an autocrine growth and motility factor in human rhabdomyosarcoma tumors.

Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood and appears to arise from developing striated muscle-forming cells. Since insulin-like growth factor II (IGF-II) is involved in normal muscle growth and maturation and elevated IGF-II mRNA levels have previously been reported in rhabdomyosarcomas, we have been studying the possible role of IGF-II in the unregulated growth and invasive potential of these embryonal tumors. In this study, we demonstrate that 13 of 14 rhabdomyosarcoma tumors express high levels of IGF-II mRNA relative to normal adult muscle and also express mRNA for the type I IGF receptors on their cell surface, the receptor thought to mediate the effects of IGF-II on muscle cells. We have established several rhabdomyosarcoma cell lines in mitogen-free media and demonstrate that these cells express type I IGF receptors on their cell surface and secrete IGF-II into the media. Exogenous IGF-II is able to stimulate cellular motility in these cell lines as assayed in a modified Boyden chamber. Finally, alpha IR-3, a type I receptor antagonist, inhibits the growth of these cell lines in serum-free media but does not inhibit IGF-II-induced motility of these cells. These data suggest that endogenously produced IGF-II functions as an autocrine growth and motility factor in many rhabdomyosarcoma tumors. The mitogenic actions of IGF-II are mediated through a domain of the type I IGF receptor that is blocked by alpha IR-3. IGF-II-induced motility may be mediated through an alternative signaling pathway.

Cell Division↗
PubMed1989

Significance of abnormal serum binding of insulin-like growth factor II in the development of hypoglycemia in patients with non-islet-cell tumors.

We reported that serum and tumor from a hypoglycemic patient with a fibrosarcoma contained insulin-like growth factor II (IGF-II), mostly in a large molecular form designated "big IGF-II." We now describe two additional patients with non-islet-cell tumor with hypoglycemia (NICTH) whose sera contained big IGF-II. Removal of the tumor eliminated most of the big IGF-II from the sera of two patients. Because specific IGF-binding proteins modify the bioactivity of IGFs, the sizes of the endogenous IGF-binding protein complexes were determined after neutral gel filtration through Saphadex G-200. Normally about 75% of IGFs are carried as a ternary complex of 150 kDa consisting of IGF, a growth hormone (GH)-dependent IGF-binding protein, and an acid-labile complexing component. The three patients with NICTH completely lacked the 150-kDa complex. IGF-II was present as a 60-kDa complex with variable contributions of smaller complexes. In the immediate postoperative period, a 110-kDa complex appeared rather than the expected 150-kDa complex. Abnormal IGF-II binding may be important in NICTH because the 150-kDa complexes cross the capillary membrane poorly. The smaller complexes present in our patients' sera would be expected to enter interstitial fluid readily, and a 4- to 5-fold increase in the fraction of IGFs reaching the target cells would result.

Adult↗
PubMed1989

Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations.

There is currently widespread interest in the IGFs (IGF-I and IGF-II) and their roles in the regulation of growth and differentiation of an ever increasing number of tissues are being reported. This selective review focused on the current state of our knowledge about the structure of mammalian IGFs and the multiple forms of mRNAs which arise from alternative splicing and promoter sites which arise from gene transcription. Current progress in the immunological measurement of the IGF is reviewed including different strategies for avoiding binding protein interference. The results of measurements of serum IGF-I and IGF-II in fetus and mother and at various stages of postnatal life are described. Existing knowledge of the concentration of these peptides in body fluids and tissues are considered. Last, an attempt is made to indicate circumstances in which the IGFs are exerting their actions in an autocrine/paracrine mode and when endocrine actions predominate. In the latter context it was concluded that an important role for GH action on skeletal tissues via hepatic production of IGF-I and endocrine action of IGF-I on growth cartilage is likely.

Amino Acid Sequence↗
PubMed1989

Sensitization of human fibroblasts to insulin-like growth factor I by serum deprivation and dexamethasone pretreatment.

Pretreatment of confluent human fibroblast cultures for two days in dexamethasone, serum free medium increased 10-20 fold the sensitivity of the cells to insulin-like growth factor I (IGF I) stimulation of amino acid uptake using the amino acid analog alpha-aminoisobutyric acid (AIB). This increased sensitivity resulted both from the use of serum free medium and the addition of dexamethasone to the serum free media. Pretreatment of the cells for 1, 2, or 3 days before assay showed that the maximum increase in sensitivity was obtained after a two day pretreatment. Pretreatment of the cells also increased their sensitivity to insulin and bovine insulin-like growth factor II stimulation of AIB uptake similar to that seen for IGF I. No consistent effect of the pretreatment was observed on either the basal level of AIB uptake or the maximal hormonal stimulation of AIB uptake. Nor was any change noted in the shape of the dose response curves. Addition of IGF I to the pretreatment medium greatly reduced the sensitivity of pretreated cells. [125I]IGF I binding studies done on suspended fibroblasts indicated that there was up to a two fold increase in the number of receptors with no increase in their affinity for IGF I. Thus, pretreatment of fibroblasts with dexamethasone and serum free medium greatly enhances their sensitivity to IGF I stimulation of AIB uptake and makes this an excellent in vitro bioassay system for IGF I.

Aminoisobutyric Acids↗
PubMed1989

Hypoglycemia in patients with non-islet cell tumors.

Persistent hypoglycemia occasionally is associated with tumors of many types. Usually these tumors are of large size and often are of mesenchymal origin. There is evidence of increased glucose uptake from the blood, some of which may occur in the tumor itself. In addition, hepatic glucose production may also be impaired. While increased levels of insulin have never been unequivocally established in the plasma of these patients, a number of insulin-like peptides have been reported. One such peptide may be related to insulin-like growth factor II, but reports from different laboratories are conflicting. Recently, the possible role of oncogenes in stimulating tumor glucose metabolism and tissue necrosis factor and other cytokines in stimulating general glucose uptake have received attention. Treatment of the condition includes surgery, radiation, or chemotherapy directed at the primary tumor and supportive measures with increased glucose administration and corticosteroids.

Adenoma, Islet Cell↗
PubMed1988

Synthesis and secretion of insulin-like growth factor II by a leiomyosarcoma with associated hypoglycemia.

We describe a case of recurrent hypoglycemia apparently caused by secretion of insulin-like growth factor II (IGF-II) by a leiomyosarcoma. A 67-year-old woman presented with recurrent severe hypoglycemia and a large mass in the thorax. During hypoglycemia, plasma cortisol was elevated, but insulin and growth hormone levels were low. After resection of a large leiomyosarcoma, the hypoglycemia resolved. After an eight-year remission, both the tumor and symptomatic hypoglycemia recurred. During a second operation a second large tumor was removed, with relief of the patient's hypoglycemia. The tumor contained high concentrations of IGF-II mRNA and 2100 ng of IGF-II immunoreactive peptide per gram. Filtration through a BioGel P-60 gel column established that 77 percent of the IGF-II was present as a larger molecule, demonstrating incomplete processing of the pro-IGF-II peptides. A similar fraction of high-molecular-weight IGF-II was present in the serum, indicating that the tumor was the chief source of IGF-II. The high-molecular-weight IGF-II found in both the tumor and serum was fully reactive with the IGF-II receptor. Radioimmunoassay showed that the concentrations of insulin-like growth factor I (IGF-I) in tumor and serum were low, suggesting feedback inhibition of growth hormone secretion by IGF-II. Eight months after reoperation, plasma concentrations of IGF-I and IGF-II were normal, and high-molecular-weight IGF-II was virtually undetectable. We conclude that the most likely cause of this patient's recurrent hypoglycemia was IGF-II produced by the leiomyosarcoma.

Aged↗
PubMed1988

Reduced 125I-hGH binding by serum of dwarf pigs but not by serum of dwarfed poodles.

1. Normal and growth-deficient poodle and swine strains were characterized for serum growth hormone-binding protein (GH-BP) content as well as other growth-related hormones, and the relationship between these factors and body size was examined. 2. GH-BPs were found in all strains of pigs and poodles. Concentrations of GH-BPs (as expressed by specific bindings) did not vary among the poodle breeds, but did correlate with body size in pigs. 3. Insulin-like growth factors (IGFs) I and II were decreased 71 and 44% respectively in miniature compared to standard size poodles. 4. Only the Yucatan micro pig strain had reduced serum IGF-I concentrations compared to normal controls. 5. Growth hormone concentrations however were normal to elevated in all micro and miniature pig strains. 6. Serum triiodothyronine concentrations were reduced in Yucatan mini and micro pigs in spite of normal circulating levels of thyroxine. 7. Body size reductions in the swine and dog strains are probably attributable to different primary defects of various growth related hormones or hormone receptors. 8. Each species breed therefore could serve as a model for a different human growth-deficient condition.

Animals↗
PubMed1988

Release of growth hormone binding protein from IM-9 lymphocytes by endopeptidase is dependent on sulfhydryl group inactivation.

The hydrophilic GH-binding protein of serum is a derivative of the GH receptor. Little is known how this GH binding protein is released from the receptor which is firmly anchored in the plasma membrane. The IM-9 lymphocytes provide a useful laboratory model for studying this process because they are richly endowed with GH receptors and, under special conditions, are able to shed these receptors during incubation. Incubation of IM-9 cells for 90 min at 30 C did not result in the appearance of significant [125I]hGH binding in conditioned medium as determined with an ultrogel AcA 44 minicolumn. When iodoacetamide, 20 mM, or N-ethylmaleimide, 5 mM, was added during incubation, the conditioned medium bound 20-35% of [125I]human(h)GH. p-Chloromercuriphenyl sulfonic acid was less effective in promoting shedding of GH-binding protein. In contrast, aprotinin, phenylmethylsulfonylfluoride (PMSF), bacitracin, leupeptin, pepstatin, phosphoramidon, or chloroquine did not promote release of GH binding protein and did not affect iodoacetamide-induced release. Release was not inhibited by the addition of serum lacking GH binding protein. GH binding protein release was markedly temperature sensitive and practically ceased at 4 C. GH binding protein incubated with [125I] hGH was cross-linked with disuccinimidyl suberate. After sodium dodecyl sulfate-polyacrylamide gel electrophoresis in the presence of dithiothreitol the complex migrated with an estimated molecular weight of 100,000 whereas [125I]hGH cross-linked to the membrane-bound GH receptor of the IM-9 cells migrated with an estimated molecular weight of 135,000. The smaller size of the binding protein is consistent with its derivation from the extracellular domain of the GH receptor. Because the release of this GH binding is greatly augmented by iodoacetamide and N-ethylmaleimide, two known sulfhydryl reactive reagents, we suggest that a free sulfhydryl group, either on the GH receptor or on a neighboring protein normally maintains the integrity of the receptor. The loss of this sulfhydryl group destabilizes the receptor and permits a membrane endopeptidase to release the GH binding protein. Cleavage is not dependent on lysosomal action and is not inhibited by protease inhibitors.

4-Chloromercuribenzenesulfonate↗
PubMed1988

Radioimmunoassay of serum IGF-I and IGF-II in patients with chronic liver diseases and hepatocellular carcinoma with or without hypoglycemia.

Insulin-like growth factor (IGF) I and IGF-II were measured by radioimmunoassay in the sera of seven patients with acromegaly, 36 normal control subjects, 15 patients with chronic hepatitis, 15 patients with cirrhosis, 25 patients with hepatocellular carcinomas (HCCs) who did not have hypoglycemia, 20 patients with HCCs who did have hypoglycemia, and 10 patients with metastatic liver tumors. Both IGF-I and IGF-II levels decreased as liver disease progressed from the normal control stage to chronic hepatitis and cirrhosis, and both levels reflected the severity of liver disease. Patients with HCCs who had hypoglycemia had relatively higher IGF-II levels in their sera in comparison with those who did not have hypoglycemia (272 +/- 167.5 ng/ml vs 110.4 +/- 85.9 ng/ml [mean +/- SD], p less than 0.0005), despite the fact that those with hypoglycemia had more advanced liver cancer and had lower IGF-I levels in sera (16.7 +/- 14.1 ng/ml vs 46.8 +/- 47.9 ng/ml, p less than 0.002). It is possible that a labile IGF-II material is produced by the cancer cells of patients with hypoglycemia. This factor is reactive to the IGF-II receptor and partially cross-reacts with an antibody to IGF-II; it accounted for the mildly elevated levels of serum IGF-II. Hypoglycemia may be an integral effect of relatively elevated IGF-II like material and an advanced liver cancer. Also, higher serum alpha-fetoprotein (AFP) levels were more frequently found in patients with hypoglycemia who had relatively elevated IGF-II levels and short survivals.

Adolescent↗