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Biomedical subjects

R C Baxter

Publications and source records attributed to R C Baxter.

At least 91 records · Page 5Linked to original sources
PubMed1997

Long-term effects of insulin-like growth factor (IGF)-I on serum IGF-I, IGF-binding protein-3 and acid labile subunit in Laron syndrome patients with normal growth hormone binding protein.

A minority of patients with Laron syndrome have normal serum GH binding protein (GHBP), indicating that the defect is elsewhere than in the extracellular domain of the GH receptor. We have evaluated the effect of long-term IGF-I treatment on serum IGF-binding protein (IGFBP)-3 and the acid-labile subunit (ALS) in three sibling with Laron syndrome caused by a GH post-receptor defect and with normal GHBP. The children (a boy aged 3 years, a girl aged 4 years and a boy aged 10 years) were treated by daily s.c. injection of IGF-I in a dose of 150 micrograms/kg. IGFBP-3 was measured by RIA and Western ligand blotting, ALS by RIA. Based values of IGFBP-3 and ALS were low. During IGF-I treatment, the IGFBP-3 concentrations in the girl gradually increased, whereas in the boys there was a 60% decrease during the first week, followed by gradual increase towards baseline. The ALS concentrations followed a similar pattern. We conclude that IGF-I treatment induces and initial suppression and then an increase in the IGFBP-3 and ALS concentrations, confirming data from animal experiments that IGFBP-3 synthesis is not solely under GH control. The differences in responsiveness between the female and male siblings may reflect genetic differences, or lower circulating concentrations of IGF-I in the boys compared with the girl.

Carrier Proteins↗
PubMed1997

Cloning and characterization of the rat gene for the acid-labile subunit of the insulin-like growth factor binding protein complex.

The acid-labile subunit (ALS) of the ternary insulin-like growth factor-binding protein complex has a central role in controlling the bioavailability of circulating insulin-like growth factors. We have shown that gene expression of ALS is regulated by a number of factors, particularly growth hormone. Our aim was to characterize the ALS gene in order to define the mechanism of its regulation. Southern analysis suggests a single copy of the ALS gene in the rat genome. The protein-coding and 3'-untranslated regions span approximately 3.5 kilobases of rat genome and are divided into two exons. The 5' flanking region of the gene lacks a consensus TATA-box or Inr sequence, and primer extension and reverse transcriptase PCR experiments locate multiple transcriptional initiation sites between -505 and -385 nucleotides relative to the translational initiation codon. This putative promoter region, when inserted upstream of the luciferase reporter gene, directs luciferase expression when transfected into H4-II-E cells. Our data demonstrate the uncomplicated structure of the rat ALS gene, and the promoter function and presence of potential regulatory elements in the region upstream of the protein-coding sequence.

Amino Acid Sequence↗
PubMed1997

Insulin-like growth factor-binding protein-2 in patients with prostate carcinoma and benign prostatic hyperplasia.

OBJECTIVE: Insulin-like growth factor-binding protein (IGFBP)-2 is a major prostatic IGFBP and may be involved in regulating prostate growth. Patients with prostate carcinoma (PC) have elevated serum IGFBP-2 levels which correlate with the specific PC marker, prostate-specific antigen (PSA). The aims of this study were to investigate whether elevated serum IGFBP-2 is unique to PC or also occurs in benign prostatic hyperplasia (BPH), to examine the relations among age, PSA and IGFBP-2 levels, and to examine longitudinal changes in serum IGFBP-2 with PSA in prostate carcinoma. DESIGN AND PATIENTS: Sixteen patients (61-83 years) with inoperable PC attending the oncology unit at a tertiary referral hospital were studied. Some serum samples were obtained retrospectively while the majority were collected prospectively over 13 months of treatment. The patients with PC were compared to 8 patients (66-73 years) with histologically proven BPH and 7 male control subjects (61-82 years) with no known prostate abnormality. MEASUREMENTS: A new IGFBP-2 RIA was developed. Serum PSA (by EIA), and IGFBP-2, IGFBP-3, IGF-I and IGF-II (by RIA) were measured in all subjects, and serially in patients with PC. RESULTS: Serum IGFBP-2 was significantly higher in PC with high PSA (560 +/- 66 micrograms/l, n = 12) than PC with normal PSA (292 +/- 65 micrograms/l, n = 4, P = 0.02), BPH (364 +/- 61 micrograms/l, P = 0.03) and controls (367 +/- 44 micrograms/l, P = 0.04). Mean IGFBP-2 in BPH was not different from controls. IGFBP-2 and PSA were significantly correlated with age (r = 0.543 and r = 0.433 respectively) and with each other even when the age effect was removed. Serum IGFBP-2 and PSA levels changed concordantly in all 7 PC patients who had serial sampling. Serum IGF-II but not IGF-I or IGFBP-3 was higher in PC and BPH than in controls (PC 332 +/- 23 micrograms/l), BPH 359 +/- 26 micrograms/l vs controls 241 +/- 37 micrograms/l; P = 0.03 and 0.02 respectively). CONCLUSIONS: Serum IGFBP-2 levels are uniquely elevated in active prostate carcinoma but not in benign prostatic hypertrophy. In PC, serum IGFBP-2 levels closely parallel those of PSA and probably reflect tumour burden. The relation between PSA and IGFBP-2 is partially independent of their individual relations with age. Although serum IGFBP-2 is less sensitive than PSA in PC, it may have adjunctive value in the management of prostate carcinoma.

Age Factors↗
PubMed1997

Insulin-like growth factor-binding protein-2 in patients with prostate carcinoma and benign prostatic hyperplasia.

OBJECTIVE: Insulin-like growth factor-binding protein (IGFBP)-2 is a major prostatic IGFBP and may be involved in regulating prostate growth. Patients with prostate carcinoma (PC) have elevated serum IGFBP-2 levels which correlate with the specific PC marker, prostate-specific antigen (PSA). The aims of this study were (i) to investigate whether elevated serum IGFBP-2 is unique to PC or also occurs in benign prostatic hyperplasia (BPH), (ii) to examine the relationships among age, PSA and IGFBP-2 levels, and (iii) to examine longitudinal changes in serum IGFBP-2 with PSA in PC. DESIGN AND PATIENTS: Sixteen patients (61-83 years) with inoperable PC attending the Oncology Unit at a tertiary referral hospital were studied. Some serum samples were obtained retrospectively while the majority were collected prospectively over 13 months of treatment. The patients with PC were compared to eight patients (66-73 years) with histologically-proven BPH and seven male control subjects (61-82 years) with no known prostate abnormality. MEASUREMENTS: A new IGFBP-2 RIA was developed. Serum PSA (by EIA), and IGFBP-2, IGFBP-3, IGF-I and IGF-II (by RIA) were measured in all subjects, and serially in patients with PC. RESULTS: Serum IGFBP-2 was significantly higher in PC with high PSA (560 +/- 66 micrograms/l, n = 12) than PC with normal PSA (292 +/- 65 micrograms/l, n = 4, P = 0.02), BPH (364 +/- 61 micrograms/l, P = 0.03) and controls (367 +/- 44 micrograms/l, P = 0.04). Mean IGFBP-2 in BPH was not different from controls. IGFBP-2 and PSA were significantly correlated with age (r = 0.543 and r = 0.433 respectively) and with each other even when the age effect was removed. Serum IGFBP-2 and PSA levels changed concordantly in all seven PC patients who had serial sampling. Serum IGF-II but not IGF-I or IGFB-3 was higher in PC and BPH than controls (PC 332 +/- 23 micrograms/l, BPH 359 +/- 26 micrograms/l vs. controls 241 +/- 37 micrograms/l; P = 0.03 and 0.02 respectively). CONCLUSIONS: Serum IGFBP-2 levels are uniquely elevated in active prostate carcinoma but not. In benign prostatic hyperplasia. In prostate carcinoma, serum IGFBP-2 levels closely parallel those of prostate-specific antigen and probably reflect tumour burden. The relationship between prostatic-specific antigen and IGFBP-2 is partially independent of their individual relationships with age. Although serum IGFBP-2 is less sensitive than prostate-specific antigen in prostate carcinoma it may have adjunctive value in its management.

Aged↗
PubMed1996

The cloning and expression of the baboon acid-labile subunit of the insulin-like growth factor binding protein complex.

The circulating insulin-like growth factors (IGF-I and -II) occur largely as components of a 140 kDa protein complex with IGF binding protein-3 and the acid-labile subunit (ALS). This ternary complex regulates the metabolic effects of the serum IGFs by limiting their access to tissue fluids. Since the tissue distribution of ALS gene expression has not been reported in humans or other primates, and the baboon has been developed as a model for human growth and metabolism, it was chosen for this study. A cDNA for baboon ALS was isolated by reverse transcriptase polymerase chain reaction and used to screen Northern blots of total RNA from the lung, liver, kidney, adrenal, muscle, intestine, and spleen of adult baboons. The expression of the single approximately 2.2 kb baboon ALS mRNA transcript was restricted to the liver, suggesting that serum ALS levels are controlled by regulation of hepatic expression of this peptide in primates.

Amino Acid Sequence↗
PubMed1996

Interaction of insulin, glucocorticoids, and protein kinase C in the regulation of insulin-like growth factor-binding protein-1 production by H4IIE rat hepatoma cells.

A sensitive RIA was used to examine regulation of IGFBP-1 in H4IIE rat hepatoma cells. IGFBP-1 was stimulated up to tenfold by dexamethasone and corticosterone, and this stimulation was abolished by RU486. The effect of dexamethasone increased with time in culture. Phorbol 12-myristate 13-acetate (PMA) stimulated IGFBP-1 up to fourfold with a maximal effect in short-term culture. Dexamethasone and PMA were additive in stimulating IGFBP-1. Under basal conditions IGFBP-1 production was linearly related to cell density: however, stimulation by dexamethasone was greatest in confluent cells, and PMA had a greater effect in sparse cultures. Insulin inhibited IGFBP-1 up to 80%, and this effect diminished with time in culture but was unaffected by cell density. Dexamethasone was stimulatory in the presence of a maximal inhibitory concentration of insulin, and insulin was inhibitory in the presence of maximal dexamethasone from 3-48 h in culture, regardless of cell density. PMA abolished the inhibitory action of insulin on IGFBP-1 secretion and mRNA expression during incubation periods of less than 4 h and not during longer incubations. PMA did not influence the stability of IGFBP-1 mRNA. We conclude that, in rat H4IIE cells, dexamethasone and PMA stimulate IGFBP-1 by independent mechanisms and speculate that when protein kinase C is activated the inhibitory action of insulin is blocked.

Animals↗
PubMed1996

Insulin-like growth factor bioactivity and its modification in growth hormone resistant states.

Acquired growth hormone (GH) resistance is an increasingly recognized feature of catabolic states. Low circulating levels of the insulin-like growth factors (IGF-I and II) have been shown to be associated with changes in the IGF binding proteins (IGFBP-1 to -6) that may significantly impact on IGF bioactivity. IGFBP-3 binds IGF and a third glycoprotein, the acid labile subunit (ALS), to form a stable 150 kDa ternary complex that serves as an intravascular store for IGFs and prolongs IGF half-life. IGFBP-1 is present at much lower concentration in serum but levels fluctuate acutely, suggesting regulation of IGF bioactivity in response to short-term metabolic changes. The function of IGFBP-2 remains unclear, but studies suggest that this protein may act as an alternative carrier for IGF when IGFBP-3 levels are low. Multiple regulatory influences on circulating IGFBP levels have been identified but three appear prominent. Nutritional influences, in particular substrate availability, appear to be a central regulatory influence on IGFBP levels in catabolic states. Low substrate availability increases IGFBP-1 levels acutely and decreases IGFBP-3 and IGFBP-2 levels in the intermediate term, with each of these changes likely to further limit IGF bioactivity. End organ failure, particularly of liver and kidney significantly affects production and clearance rates of the circulating IGFBPs and may contribute to the catabolism frequently seen in these states. Severe protein catabolism often accompanies malignancy and chronic sepsis and it is likely that additional ill-defined factors influence IGF bioactivity in this setting. Recent studies have identified post-translational modifications to the IGFBPs such as proteolysis and phosphorylation, which appear to further impact on IGF bioactivity. The relative contributions of these changes to the overall impairment of IGF bioactivity in GH-resistant states remains to be fully elucidated.

Human Growth Hormone↗
PubMed1996

Changes in HIV risk behavior among injecting drug users: the impact of 21 versus 90 days of methadone detoxification.

OBJECTIVE: To evaluate the hypothesis that long-term methadone detoxification would produce greater HIV risk reduction among injecting drug users (IDU) than short-term detoxification. DESIGN: Random assignment to 21 or 90 days of free detoxification. SETTING: Storefront offices in two cities, with referrals to outpatient methadone detoxification. PARTICIPANTS: Out-of-treatment IDU (n = 1803), recruited through street outreach and word of mouth, between April 1990 and March 1991. Of these, 62.6% were successfully located for 6-month follow-up. MAIN OUTCOME MEASURES: Self-reported drug injection and sexual practices at baseline and follow-up. RESULTS: Substantial reductions in risk behavior were observed at follow-up. Substantial percentages of subjects reported less frequent drug injection (54%), use of shooting galleries (85%), needle-sharing (67%), and number of sex partners (73%), and more frequent use of bleach to disinfect needles (67%) and condom use (31%). There were no significant differences in behavioral change between 21 and 90-day treatment, and subjects who entered treatment did not report significantly greater risk reduction than untreated subjects. Discriminant analyses showed a marginal effect for duration of treatment on risk reduction, although results were inconsistent. CONCLUSIONS: Large scale behavioral risk reduction appears to be occurring in this population regardless of treatment condition. In minimal service methadone detoxification, subjects treated under a longer-term detoxification protocol demonstrated no greater risk reduction than those receiving short-term detoxification.

Analgesics, Opioid↗
PubMed1996

Developmental differences in the IGF-I system response to severe and chronic calorie malnutrition.

Recent studies in children suggest that there are age-related differences in the insulin-like growth factor I (IGF-I) response to malnutrition. To extend this observation, immature 4-wk-old male rats were fasted for 3 days, fed ad libitum (control), or fed 60 or 40% of control calories (restricted) and compared with 8-wk-old young adults. Over the 3-wk study period, serum total IGF-I levels of the older rats were stable despite reduced insulin levels, whereas IGF-I increased 2.2-fold in the younger controls. With the 40% diet, younger and older rats changed body weight +1 and -1 body wt/day, respectively (P < 0.0001). The restricted younger animals reduced serum IGF-I IGF binding protein-3, acid-labile subunit, and growth hormone binding protein levels significantly more than the restricted older animals. Fasting decreased most of these parameters by 40%, serum insulin by approximately 80%, and body weight by 9%, regardless of age. We conclude that the suppression of the IGF-I system in response to chronic undernutrition, but not acute fasting, is greater in maturing than young adult rats.

Aging↗
PubMed1996

The role of insulin-like growth factors and their binding proteins in tumor hypoglycemia.

Tumors of nonislet cell origin may overexpress insulin-like growth factor (IGF)-II, leading to hypoglycemia with suppressed serum insulin levels (NICTH). Most of the serum IGF-II in NICTH patients is in precursor forms of 10-15 kD, and may be abnormally glycosylated. In NICTH, IGFs and IGF-binding protein-3 (IGFBP-3) are mainly found in binary complexes of 50-60 kD, instead of the normal ternary complex of about 140 kD with the acid-labile subunit (ALS). Factors contributing to the defect are: (1) low ALS levels, secondary to suppressed growth hormone (GH); (2) defective IGFBP-3 binding to ALS; (3) reduced ability of pro-IGF-II forms to complex normally, and (4) very high levels of other IGFBPs, including IGFBP-2 and IGFBP-6, which might limit the formation of complexes with IGFBP-3. While both GH and glucocorticoids can restore normoglycemia and increase high-molecular-weight IGFBP-3 complexes, corticosteroid treatment suppresses tumor IGF-II, whereas GH can restore normoglycemia despite continuing high IGF-II levels. Both treatments increase serum ALS, IGFBP-3, and IGF-I levels, and decrease IGFBP-2, whereas IGFBP-6 is unaffected. The reversal of hypoglycemia, by surgery, GH, or glucocorticoid treatment, is always accompanied by improved ternary complex formation, emphasizing the importance of the components of this complex, in particular ALS, in normal blood sugar regulation.

Humans↗
PubMed1996

Soluble insulin-like growth factor-II/mannose 6-P receptor inhibits deoxyribonucleic acid synthesis in cultured rat hepatocytes.

Insulin-like growth factor-II/mannose 6-P (IGF- II/M6P) receptor is released from cultured cells and tissues in a soluble form that retains its affinity for IGF-II. To test the possibility that soluble receptor can therefore modulate the activity of IGF-II, we determined the effect of purified soluble receptor on DNA synthesis in cultured rat hepatocytes stimulated with epidermal growth factor (EGF) (5 ng/ml) and IGF-II (200 ng/ml). Thymidine incorporation in hepatocytes in the presence of EGF and IGF-II was inhibited by soluble receptor (50% inhibition at 212 +/- 45 ng/ml). However, thymidine incorporation in the presence of EGF alone was also inhibited with similar potency. This inhibitory effect was removed by immunodepletion of receptor from the purified preparation, demonstrating the absence of nonspecific cytotoxic effects of the preparation. Although soluble receptor blocked IGF-II binding to hepatocytes, inhibition of EGF-stimulated DNA synthesis was not due to inhibition of EGF binding or uptake by the cell. These results suggest that soluble IGF-II/M6P receptor not only plays a role in modulating the action of IGF-II but may also have IGF-independent actions on cells, possibly by modulating M6P protein action.

Animals↗
PubMed1996

Differential long-term effects of insulin-like growth factor-I (IGF-I) growth hormone (GH), and IGF-I plus GH on body growth and IGF binding proteins in hypophysectomized rats.

The long-term effects of recombinant human insulin-like growth factor-I (rhIGF-I) and GH (rhGH) on body growth and the IGF-I/IGF binding protein (IGFBP)/acid-labile subunit (ALS) axis were investigated in hypophysectomized (hypox) rats given excipient, rhIGF-I (2 mg/kg.day s.c., minipumps), rhGH (2 mg/kg.day, s.c., daily injections), or rhIGF-I plus rhGH for 28 days. The relative growth-promoting activity of the treatments was rhGH plus rhIGF-I more than rhGH more than rhIGF-I. Weight gain induced by rhIGF-I progressively declined after 4 days, compared with a more maintained effect of rhGH. At day 28, growth responses did not correlate with serum IGF-I levels [rhGH plus rhIGF-I (492 +/- 140) > rhIGF-I (322 +/- 75) > rhGH (85 +/- 26) > control (39 +/- 7 ng/ml)]. Serum ALS concentrations in hypox rats were remarkably low (0.42 +/- 0.04 micrograms/ml) but were restored toward normal by rhGH (12.55 +/- 4.78) or rhGH plus rhIGF-I (12.85 +/- 6.64) but not by rhIGF-I alone (0.85 +/- 0.25). Antibodies against rhGH were present at day 28, with titer being negatively related to weight gain, IGF-I, and ALS levels. All treatments increased serum IGFBP-3. The molecular size distribution of IGFBP-3 in rhGH-treated rats was similar to that of normal rats (IGFBP-3 in the 150K mol wt range), due to rhGH increasing serum ALS, but was altered by rhIGF-I (IGFBP-3 in the 200-300K and 44K mol wt range). In a GH-deficient animal, restoring the IGF/IGFBP-3/ALS axis towards normal is associated with greater growth promotion.

Animals↗
PubMed1996

Regulation of soluble insulin-like growth factor-II/mannose 6-phosphate receptor in hepatocytes from intact and regenerating rat liver.

A soluble, circulating form of the insulin-like growth factor-II/mannose 6-phosphate receptor has been proposed to result from proteolytic cleavage of intact cellular receptors. This study examines receptor release in hepatocytes from normal and regenerating rat liver, where receptor levels are elevated. After partial hepatectomy, serum receptor increased from 0.64 +/- 0.02 to 1.36 +/- 0.15 microgram/ml at 72 h after surgery, reflected by an increase in receptor secretion from 18.5 +/- 3.6 ng/mg protein per 24 h in cells from sham-operated animals (n = 14) to 100.9 +/- 10.8 ng/mg protein per 24 h in cells from regenerating liver (n = 8). A wide range of protease inhibitors had little or no effect on soluble receptor secretion, indicating that extracellular proteolysis of cell surface receptor is not the major route of production in hepatocytes. Neither insulin-like growth factor-II nor mannose 6-phosphate altered receptor secretion, suggesting that neither ligand has a role in elevating receptor levels in liver regeneration. Inhibitors of endocytosis were examined to determine whether soluble receptor formation occurred during receptor recycling. Chloroquine, NH4Cl and monensin did not inhibit soluble receptor release, whereas the microtubule disrupting agents, colchicine and nocodazole, caused a dose-related increase that was reversible by the microtubule stabilizing agent, taxol. This suggests that alteration of early endosome pH does not alter soluble receptor production, but that subsequent disruption of late endosomes may result in increased formation and release of soluble receptor into the culture medium.

Animals↗
PubMed1996

Monitoring of growth hormone replacement therapy in adults, based on measurement of serum markers.

The optimal dose for GH replacement therapy in GH-deficient (GHD) adults is not known, nor is there a consensus as to which method is the most appropriate for the monitoring of treatment. To establish a general guideline for GH replacement therapy in adults, we evaluated the relationship between the administered GH dose and the achieved serum levels of three GH-dependent serum markers. Serum levels of insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) were measured in 46 GHD men participating in a 1-yr, double blind, and placebo-controlled dose-response study. The doses of recombinant human GH ranged from 0.33-3.0 IU/m(2)-day. During GH treatment, dose reduction was necessary because of side-effects in 18 of 46 patients, i.e. in 18% of the patients receiving a maintenance dose of 1 IU/M(2)-day, in 35% of the patients receiving a dose of 2 IU/m(2)-day, and in 67% of the patients receiving a dose of 3 IU/M(2)-day. In the untreated state, serum levels of all three markers were below the normal range in 90% of the patients. The rise in serum marker concentrations during the first month of treatment was dose dependent. Significant increases in IGF-I, IGFBP-3, and ALS levels were observed with a dose as low as 0.33 IU/M(2)-day. The minimal GH dose required for normalization of the serum IGF-I concentration was 0.66 IU/M(2)-day, and it was 1.0 IU/M(2)-day for ALS and IGFBP-3. In patients receiving 2.0 IU/M(2)-day, the mean serum IGF-I concentration rose to an abnormally high level, whereas at this dose, the mean IGFBP-3 and ALS levels were not different from normal. The lower sensitivity of IGFBP-3 and ALS to GH doses in the high range was also apparent during long term treatment. The number of patients who developed IGFBP-3 or ALS levels that exceeded the upper normal limit was substantially smaller than the number of patients with elevated IGF-I concentrations (2, 8, and 19 of 46 patients, respectively). In conclusion, serum IGF-I appears to be the preferred biochemical marker for the detection of GH excess in adults receiving GH replacement therapy, because it is more sensitive than IGFBP-3 and ALS to GH doses in the high range. If normalization of the serum IGF-I concentration is taken as the criterion for optimal GH replacement therapy, the predicted optimal GH dose for GHD men 20 - 40 yr old is 1.4 IU/M(2)-day, and the 95% confidence interval is 1.2-1.6 IU/M(2)-day.

Adult↗
PubMed1996

Insulin-like growth factor binding protein-3: factors affecting binary and ternary complex formation.

IGF binding protein-3 (IGFBP-3), the major serum carrier of IGF-I and IGF-II in adults, circulates predominantly in a ternary complex with IGF and the acid-labile subunit (ALS). The affinities of IGF and ALS binding have not previously been determined under conditions of temperature, ionic strength and pH which approximate those in the circulation. IGF-I and -II binding was optimal at pH 4.0-5.5, and relatively poor at pH 7.4. The addition of 0.1 mol/l NaCl to 50 mmol/l phosphate buffer increased the affinity of IGF-II for IGFBP-3 by 2-fold, and of IGF-I by 4-fold. ALS binding peaked at pH 5.5-6.0, and was markedly reduced at pH 7.4, where only approximately 0.4 mol ALS was bound per mol IGFBP-3, with greatly reduced affinity. ALS affinity was further reduced at 37 degrees C compared to 22 degrees C, and in the presence of 0.1 mol/l NaCl compared to its absence. Under 'physiological' conditions, the affinities of ALS binding to IGF-I-IGFBP-3 and IGF-II-IGFBP-3 complexes (2.5 x 10(8) l/mol and 5.8 x 10(7) l/mol, respectively) are 300-fold and 2000-fold lower than the constants for the formation of the corresponding binary complexes. Thus, ALS binding to IGFBP-3 complexes is much weaker than previously recognised, emphasising the importance of ALS dissociation as a controlling factor in the regulation of IGF bioavailability.

Adult↗
PubMed1995

Evidence that human bone cells in culture secrete insulin-like growth factor (IGF)-II and IGF binding protein-3 but not acid-labile subunit both under basal and regulated conditions.

Insulin-like growth factors (IGFs) are found in human circulation predominantly as part of a growth hormone (GH)-dependent complex of 125-150 kD, which is composed of three subunits: IGF-I or IGF-II, an acid stable IGF binding protein (IGFBP)-3, and an acid labile subunit (ALS). Although recent studies demonstrate that a number of cell types in culture secrete IGFs and IGFBP-3, very little is known with regard to the origin of circulating ALS. To test the hypothesis that human bone cells (HBCs), which produce abundant amounts of IGF-II and IGFBP-3, also produce ALS, we measured the IGF-I, IGF-II, IGFBP-3, and ALS levels using specific radioimmunoassays (RIAs) in the conditioned medium (CM) of untransformed normal HBCs and SaOS-2 osteosarcoma cells treated with various effectors (IGF-II, osteogenic protein-1 [OP-1, bone morphogenetic protein-7] and human GH) for 48 h. No detectable levels (< 3 ng/ml) of ALS were found in the CM of various HBC types under basal conditions. In contrast, CM collected from liver explants in culture contained significant amount of ALS prepared and assayed under identical conditions. The IGF-I level was also undetectable in the CM of various HBC types. In the IGF-II (3, 30 ng/ml)-treated HBC CM, the IGFBP-3 level was increased in a dose-dependent manner but neither IGF-I nor ALS could be detected. In the SaOS-2 cell culture, OP-1 (1, 100 ng/ml) increased both IGF-II and IGFBP-3 secretion but neither ALS nor IGF-I secretion. Treatment of HBCs with GH (1, 10, 100 ng/ml) had no significant effect on the secretion of either IGF-I, IGF-II, IGFBP-3, or ALS.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Insulin-like growth factor binding proteins as glucoregulators.

Circulating insulin-like growth factors (IGFs) represent an important pool of potential hypoglycemic activity, which is largely inhibited by their sequestration in a heterotrimeric complex comprising growth factor, IGF-binding protein-3 (IGFBP-3), and acid-labile subunit (ALS). Less than 1% of total IGFs circulate in the free form, yet even this amount might contribute significantly to circulating insulin-like activity. The ternary binding protein complex appears to inhibit insulin-like activity of bound IGFs by preventing their egress from the circulation. Although the integrity of this complex might be affected by limited proteolysis of IGFBP-3 in pregnancy and catabolic conditions, the evidence that this increases IGF bioavailability, and thus hypoglycemic potential, is as yet unclear. However, in patients with IGF-II-secreting tumors, hypoglycemia may result from a failure of the ternary complex to adequately sequester the IGFs. Improvement in complex formation, by treatment with corticosteroids or growth hormone, alleviates the hypoglycemia, even if (as seen with growth hormone treatment) IGF-II hypersecretion persists. In these patients, blood glucose levels are inversely correlated with IGFBP-2 levels, suggesting that this protein might play a part in transporting IGFs to their target tissues. Conversely, ALS levels correlate positively with blood glucose, emphasizing the importance of the ternary complex in preventing hypoglycemia. Unlike the other IGF-binding proteins, IGFBP-1 is acutely regulated in the circulation, in a manner consistent with its acting as a glucose counterregulator. It might act in this way by inhibiting the activity of free IGFs in the circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗