Effect of aging on the sensitivity of growth hormone secretion to insulin-like growth factor-I negative feedback

To determine the effect of aging on the suppression of GH secretion by insulin-like growth factor (IGF)-I, we studied 11 healthy young adults (6 men, 5 women, mean +/- SD: 25.2 +/- 4.6 yr old; body mass index 23.7 +/- 1.8 kg/m2) and 11 older adults (6 men, 5 women, 69.5 +/- 5.8 yr old; body mass index 24.2 +/- 2.5 kg/m2). Saline (control) or recombinant human IGF-I (rhIGF-I) (2 h baseline then, in sequence, 2.5 h each of 1, 3, and 10 micrograms/kg.h) was infused iv during the last 9.5 h of a 40.5-h fast; serum glucose was clamped within 15% of baseline. Baseline serum GH concentrations (mean +/- SE: 3.3 +/- 0.7 vs. 1.9 +/- 0.5 micrograms/L, P = 0.02) and total IGF-I concentrations (219 +/- 15 vs. 103 +/- 19 micrograms/L, P < 0.01) were higher in the younger subjects. In both age groups, GH concentrations were significantly decreased by 3 and 10 micrograms/kg.h, but not by 1 microgram/kg.h rhIGF-I. The absolute decrease in GH concentrations was greater in young than in older subjects during the 3 and 10 micrograms/kg.h rhIGF-I infusion periods, but both young and older subjects suppressed to a similar GH level during the last hour of the rhIGF-I infusion (0.78 +/- 0.24 microgram/L and 0.61 +/- 0.16 microgram/L, respectively). The older subjects had a greater increase above baseline in serum concentrations of both total (306 +/- 24 vs. 244 +/- 14 micrograms/L, P = 0.04) and free IGF-I (8.5 +/- 1.4 vs. 4.2 +/- 0.6 micrograms/L, P = 0.01) than the young subjects during rhIGF-I infusion, and their GH suppression expressed in relation to increases in both total and free serum IGF-I concentrations was significantly less than in the young subjects. We conclude that the ability of exogenous rhIGF-I to suppress serum GH concentrations declines with increasing age. This suggests that increased sensitivity to endogenous IGF-I negative feedback is not a cause of the decline in GH secretion that occurs with aging.     

Role of growth hormone and insulin-like growth factor-I in mammary development

Mammary glands from 3- to 4-week-old mice were incubated in whole organ culture to determine the effects of GH, PRL, and insulin-like growth factor-I (IGF-I) on lobulo-alveolar development and milk protein expression. Virgin mice were implanted with pellets of estrogen and progesterone (1:1000). After 9 days, abdominal no. 4 glands were removed and place on siliconized lens paper in Waymouths' medium supplemented with insulin (Ins), aldosterone, hydrocortisone, and epidermal growth factor. Concentrations of bovine GH, ovine GH, rat GH, or ovine PRL added to the medium varied from 0-1 micrograms/ml. IGF-I was added to replace either Ins or PRL up to 1 microgram/ml. When glands were incubated with Ins, aldosterone, hydrocortisone, and 250 ng/ml PRL, they exhibited lobulo-alveolar development and expressed the milk protein beta-casein. When GH was substituted for PRL, little lobulo-alveolar development occurred, although beta-casein mRNA was expressed at low levels. Either PRL or GH at 1 microgram/ml induced lobulo-alveolar development and beta-casein mRNA. Addition of epidermal growth factor to whole organ culture with GH or PRL (1 microgram/ml) was equally effective in stimulating lobulo-alveolar development. IGF-I did not substitute for PRL, GH, or insulin in tissue maintenance. It is clear that GH at high concentrations can act directly on mouse mammary tissue to induce both lobulo-alveolar development and casein expression.     

Growth hormone secretion and circulating insulin-like growth factor-I (IGF-I) and IGF binding protein-3 concentrations in children with sickle cell disease

Impaired growth involving both height and weight accompanying sickle cell disease (SCD) poses diagnostic and therapeutic problems. We undertook this study to test the hypothesis that this impaired growth is associated with abnormalities of the growth hormone (GH)/insulin-like growth factor-I (IGF-I)/IGF binding protein-3 (IGFBP-3) axis in 21 children with SCD and that SCD is associated with GH resistance. Nine of 21 children with SCD had a defective GH response to both clonidine and glucagon provocation (peak < 10 micrograms/L); these children differed from the 12 others in having slower linear growth velocity (GV and GVSDS), lower circulating concentrations of IGF-I and IGFBP-3, and either partial or complete empty sellae in computed tomographic scans of the hypothalamic-pituitary area. In this group of patients with SCD, it appears that defective GH secretion and consequent low IGF-I production are the major etiological factors causing the slow growth. The two groups with SCD did not differ significantly in dietary intake, body mass index (BMI), midarm circumferences, skinfold thickness, serum albumin concentration, or intestinal absorption of D-xylose. A single injection of GH produced a smaller increase in circulating IGF-I in children with SCD with or without defective GH secretion versus 10 age-matched children with idiopathic short stature (ISS) and 11 children with isolated GH deficiency (GHD), suggesting partial GH resistance in the SCD group. The presence of defective GH secretion, decreased IGF-I synthesis, and partial resistance to GH in short children with SCD suggests that treatment with IGF-I may be superior to GH therapy for improving growth.     

Correlation between longitudinal bone growth, growth hormone, and insulin-like growth factor-I in prepubertal dogs

OBJECTIVE: To determine the association between longitudinal bone growth and concentrations of growth hormone (GH) and insulin-like growth factor-I (IGF-I) in serum from prepubertal dogs. Animals-6 male 14-week-old German Shepherd Dogs. PROCEDURE: Blood was obtained every 30 minutes for 14 consecutive days. Concentrations of GH and IGF-I in serum were determined, using a canine-specific radioimmunoassay and conventional radioimmunoassay after acid-ethanol extraction, respectively. Simultaneous biplanar radiography was performed daily to measure bone growth. Spectral analysis was used to estimate specific features of GH secretion during an extended period. Multiple linear regression with different lag times between independent and dependent variables was used to determine the strongest predictors of bone growth. RESULTS: The power spectra of GH concentrations in serum had a primary peak at a frequency of 0.02 cycles/h or a periodicity of 50 h/cycle. A significant determinant of longitudinal bone growth was a lag time of 1 day in concentration of GH in serum. The relationship between IGF-I concentration in serum and bone growth was not significant. CONCLUSIONS: The primary frequency of GH secretion is outside the time frame of a single day and the concentration of GH in serum is a primary determinant of bone growth. CLINICAL RELEVANCE: A better understanding of the components of bone growth provide discernment to improved diagnosis and treatment of abnormal bone growth.     

Experimental diabetic renal growth: role of growth hormone and insulin-like growth factor-I

We have compared the kidneys of two inbred strains of rats (Lewis and Lewis-Dwarf) 7 days after the induction of diabetes mellitus with streptozotocin, in order to examine the influence of a selective growth hormone (GH) deficiency on diabetic renal growth and insulin-like growth factor-I (IGF-I) content of the kidneys. Insulin-like growth factor-I (IGF-I) content of the kidneys. Insulin-like growth factor-I was measured by radioimmunoassay and its distribution within the kidney by immunohistochemical staining. We detected a significant increase in both the wet weight (32.9 +/- 5.3%, P = 0.0085) and dry weight (16.3 +/- 6.3%, P = 0.046) of the kidneys of diabetic Lewis rats but dwarf rats, selectively deficient in GH, did not show a significant increase in either parameter. Extractable IGF-I increased within the kidneys of diabetic rats of both strains but to a lesser extent in the dwarf rats (+105 +/- 28% and +65 +/- 21% respectively, P < 0.01). In diabetic Lewis rats a positive correlation was noted between the severity of glycaemia and kidney IGF-I content (r = 0.604, P < 0.05) but no such correlation was noted in dwarf rats. Inulin-like growth factor-I immunostaining increased in diabetic rats of both strains, mainly within cells of the thick ascending limb of the loop of Henle including damaged and vacuolated cells. However, morphometric analysis of the staining showed that it was significantly less widespread in the diabetic dwarf rats (P = 0.026).(ABSTRACT TRUNCATED AT 250 WORDS)     

Growth promoting peptides in osteoarthritis and diffuse idiopathic skeletal hyperostosis--insulin, insulin-like growth factor-I, growth hormone

OBJECTIVE: To investigate growth factors influencing bone and cartilage in patients with diffuse idiopathic skeletal hyperostosis (DISH). METHODS: Standard radioimmunoassays (INCSTAR, Stillwater, MN) quantified serum levels of insulin, insulin-like growth factor-I (IGF-I) and growth hormone (GH) in patients with DISH, in patients with osteoarthritis (OA) and in controls. Patients with DISH with comorbidity with obesity, hypertension, diabetes and coronary artery disease, also were studied. RESULTS: Patients with DISH demonstrated normal IGF-I levels; patients with OA had reduced IGF-I levels. Subjects with DISH or OA had elevated insulin and GH values. Patients with DISH with comorbidity had changes in growth factors similar to those found in patients with DISH only. There is frequent association of DISH with obesity, hypertension, coronary artery disease and diabetes mellitus suggesting that these associations are not random. CONCLUSION: Specific associations of skeletal abnormalities with clinical features in which skeletal change and clinical features combine with disturbances of insulin, IGF-I and GH exist in DISH that are distinct from OA. DISH is considered a multisystemic hormonal disorder with protean presentations.     

Growth hormone, insulin-like growth factor-I and insulin-like growth factor binding protein-3 are regulated differently in small-for-gestational-age and appropriate-for-gestational-age neonates

BACKGROUND: TBP-associated factors contain a variety of structural motifs and their related in vivo significance has remained unclear. We have attempted to identify specific biological phenomena linked to a particular domain of a TAF by analysing domain-exchanged chimeric mutants between Schizosaccharomyces pombe (Sp) and Saccharomyces cerevisiae (Sc) counterparts. RESULTS: Contrary to the case of TBP, Sp TAF containing the WD40 repeat cannot be exchanged for its Sc counterpart, despite their highly conserved primary structures. This 'species-specific' function locates in the N-terminal region. The C-terminal region, largely consisting of the WD40 repeat, is exchangeable for the corresponding region of its Sc counterpart. Growth of the strain harbouring this C-terminal chimeric mutant is temperature-sensitive. The chimeric gene product did not disappear at a restrictive temperature, a finding which strongly suggests that the growth defect is caused by an aberration in the interactions through the WD40 repeat structural motif. With temperature elevation, the chimeric mutants underwent drastic morphological changes due to a defect in cytokinesis. CONCLUSIONS: The WD40 repeat of TAF is primarily involved in reactions which might regulate cytokinesis in Sp.     

Effects of growth hormone, insulin-like growth factor-I, and cortisol on periparturient antibody response profiles of dairy cattle

The objectives of this study were to determine hormone and antibody response profiles from the prepartum period to peak lactation, and evaluate potential immunomodulatory effects of the classic endocrine hormones, growth hormone (GH), insulin-like growth factor-I (IGF-I) and cortisol. Specifically, 33 Holstein cows were immunized with ovalbumin (OVA) and Escherichia coli J5 at weeks -8 and -3 prior to parturition. At parturition (week 0), cows received an additional immunization of OVA. Blood was collected at weeks -8, -3, 0, 3 and 6 relative to parturition and various samples were used to determine plasma hormone concentration, serum immunoglobulin (Ig), and specific antibody response to OVA and E. coli. Colostrum and milk samples were also collected post-parturition to monitor local immunoglobulin and antibody responses. Results indicated that not all periparturient cows exhibited depressed immune response, and that antibody response to OVA could be used to partition cows into 3 groups recognizing animals with sustained measurable antibody response before and after parturition (Group 1), animals which responded poorly to immunization at parturition (Group 2), and animals which did not respond to immunizations at week -3 or parturition (Group 3). Cows with the highest antibody response to OVA (Group 1) also tended (P < or = 0.10) to have the highest response to E. coli J5 at parturition and had the lowest incidence of disease, particularly mastitis. Antibody response to OVA measured in milk tended to be higher in Group 1 cows, particularly at week 0 (P < or = 0.06) compared to cows of Group 3. IGF-I was higher (P < or = 0.05) in cows of Group 1 than Group 3 at peak lactation (week 6).     

Long [R3] insulin-like growth factor-I reduces growth, plasma growth hormone, IGF binding protein-3 and endogenous IGF-I concentrations in pigs

Growth hormone (GH) improves growth performance in the pig. Analogues of insulin-like growth factor-I (IGF-I) that bind poorly to IGF binding proteins (IGFBP) stimulate growth in the rat but, in contrast, inhibit growth in the pig. This study was designed to determine the effect of IGF peptides alone or in combination with porcine GH (pGH) on growth characteristics and plasma hormone concentrations in finisher pigs. A four-day infusion of Long [R3] IGF-I (LR3IGF-I; 180 micrograms/kg/day) decreased the average daily gain, food intake, and plasma IGFBP-3, IGF-I and insulin concentrations. The mean plasma GH concentration was decreased by 23% and the area under the GH peaks was reduced by 60%. Co-administration of pGH (30 micrograms/kg/day) with LR3IGF-I had no interactive effect on growth performance, and plasma insulin, IGFBP-3 and IGF-I concentrations remained suppressed. The area under the GH peaks was not restored with this combination treatment although mean plasma GH concentrations were elevated in all animals receiving pGH. Infusion of IGF-I (180 micrograms/kg/day) decreased plasma insulin and mean GH concentrations but had no significant effect on IGFBP-3 concentrations. Average daily gain and feed intake were not changed by IGF-I treatment. A combination of IGF-I and pGH injection (30 micrograms/kg/day) increased plasma IGFBP-3 concentrations but plasma insulin levels remained suppressed. Plasma glucose levels were unaffected by any treatment. The study demonstrates that both IGF-I and LR3IGF-I suppress plasma GH concentrations in finisher pigs. This, in turn, may be responsible for the reduction in the plasma concentration of IGF-I, IGFBP-3 and insulin seen in LR3IGF-I-treated animals. The decrease in these parameters may contribute to the inhibitory effect of LR3IGF-I on growth performance in the pig.     

Effects of growth hormone and pregnancy on expression of growth hormone receptor, insulin-like growth factor-I, and insulin-like growth factor binding protein-2 and -3 genes in bovine uterus, ovary, and oviduct

The effects of growth hormone (GH) and pregnancy on insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-2, and IGFBP-3 mRNA in reproductive tissues were studied in cattle. Lactating dairy cows were inseminated at estrus and treated with 25 mg/day GH (n = 8) or saline (n = 8) for 16 days. Corpus luteum (CL), ovary (CL removed), oviduct, endometrium, and myometrium were collected at the end of treatment. Messenger RNA for GH receptor, IGF-I, IGFBP-2, IGFBP-3, and actin were measured by nuclease protection assays. The CL contained more GH receptor mRNA than the other reproductive tissues examined. Expression of IGF-I mRNA was highest in myometrium, with lower amounts found in endometrium; the CL expressed the least amount of IGF-I mRNA. The IGFBP-2 mRNA was most abundant in endometrium and least abundant in CL. Expression of IGFBP-3 mRNA was detected in all reproductive tissues examined. However, endometrium, a tissue that expressed the most IGFBP-2 mRNA, had the lowest amount of IGFBP-3 mRNA. The GH receptor mRNA was decreased in cows treated with GH whereas the mRNA for IGF-I, IGFBP-2, or IGFBP-3 was not changed. In the reproductive tissues evaluated, cows that contained a conceptus at tissue collection (pregnant) had higher amounts of IGF-I mRNA than did nonpregnant cows. In summary, the level of mRNA encoding GH receptor, IGF-I, IGFBP-2, and IGFBP-3 varied within the tissues examined, suggesting that these genes may play a variety of roles in the bovine female reproductive tract. Supplemental GH failed to change the expression of IGF-I, IGFBP-2, and IGFBP-3 mRNA, possibly because of low GH receptor mRNA levels in tissues other than CL. A direct action of GH on IGF-I, IGFBP-2, or IGFBP-3 gene expression within cow reproductive tissues was not supported because the amount of IGF-I, IGFBP-2, or IGFBP-3 mRNA was not altered by GH.     

The immune-endocrine loop during aging: role of growth hormone and insulin-like growth factor-I

Why a primary lymphoid organ such as the thymus involutes during aging remains a fundamental question in immunology. Aging is associated with a decrease in plasma growth hormone (somatotropin) and IGF-I, and this somatopause of aging suggests a connection between the neuroendocrine and immune systems. Several investigators have demonstrated that treatment with either growth hormone or IGF-I restores architecture of the involuted thymus gland by reversing the loss of immature cortical thymocytes and preventing the decline in thymulin synthesis that occurs in old or GH-deficient animals and humans. The proliferation, differentiation and functions of other components of the immune system, including T and B cells, macrophages and neutrophils, also demonstrate age-associated decrements that can be restored by IGF-I. Knowledge of the mechanism by which cytokines and hormones influence hematopoietic cells is critical to improving the health of aged individuals. Our laboratory has recently demonstrated that IGF-I prevents apoptosis in promyeloid cells, which subsequently permits these cells to differentiate into neutrophils. We also demonstrated that IL-4 acts much like IGF-I to promote survival of promyeloid cells and to activate the enzyme phosphatidylinositol 3'-kinase (PI 3-kinase). However, the receptors for IGF-I and IL-4 are completely different, with the intracellular beta chains of the IGF receptor possessing intrinsic tyrosine kinase activity and the alpha and gammac subunit of the heterodimeric IL-4 receptor utilizing the Janus kinase family of nonreceptor protein kinases to tyrosine phosphorylate downstream targets. Both receptors share many of the components of the PI 3-kinase signal transduction pathway, converging at the level of insulin receptor substrate-1 or insulin receptor subtrate-2 (formally known as 4PS, or IL-4 Phosphorylated Substrate). Our investigations with IGF-I and IL-4 suggest that PI 3-kinase inhibits apoptosis by maintaining high levels of the anti-apoptotic protein Bcl-2. The sharing of common activation molecules, despite vastly different protein structures of their receptors, forms a molecular explanation for the possibility of cross talk between IL-4 and IGF-I in regulating many of the events associated with hematopoietic differentiation, proliferation and survival.     

Normal growth hormone secretory reserve in men with idiopathic osteoporosis and reduced circulating levels of insulin-like growth factor-I

Many men with idiopathic osteoporosis have reduced circulating insulin-like growth factor-I (IGF-I) levels. The major source of circulating IGF-I is GH-mediated production by the liver. The known anabolic effects of GH on the skeleton raised the possibility of GH deficiency in these men. We sought to test this hypothesis in this study. Fourteen men (mean age, 52.1 +/- 3.2 yr, range 31-68) with idiopathic osteoporosis were studied. Mean lumbar spine bone mineral density (BMD) was 0.723 g/cm2, T score -3.5; femoral neck BMD was 0.642 g/cm2, T score, -3.07; distal (1/3) radius BMD was 0.708 g/cm2, T score, -2.05. Eleven of 14 (79%) had frank reductions in serum IGF-I levels compared with age and sex-matched values (158.5 +/- 50 SD vs. 180 +/- 45 SD). GH secretion was stimulated by iv arginine infusion (30 g) over 30 min followed 1 h later by oral L-dopa (500 mg). Serum GH was measured at time (t) = -15, 0, 30, 45, 60, 90, 120, 150, and 180 min. All patients responded to at least one stimulus with the majority (n = 9) responding to both. Five patients responded either to arginine or to L-dopa but not to both. Baseline GH for the entire group was 0.77 + 0.08 ng/mL (SEM). Peak GH following arginine (t = 45-60 min) was 14.0 +/- 2.8 ng/mL, a 17.7 +/- 2.8-fold rise. Peak GH following L-dopa (t = 120-180 min) was 5.7 +/- 1.0 ng/mL, a 9.2 +/- 2.2-fold rise. No difference in maximal secretion was observed between those with low or normal IGF-I levels. Neither IGF-I nor IGF binding protein-3 concentrations changed significantly during the short period of GH stimulation. These data suggest that men with osteoporosis and reduced IGF-I levels do not appear to have a deficiency in the GH axis. Other hormonal or local factors may be important in regulating IGF-I expression. Deficiencies of IGF-I production at skeletal sites may be important in the pathogenesis of this syndrome.     

A multicenter study on insulin-like growth factor-I serum levels in children with chronic inflammatory diseases

OBJECTIVE: To study insulin-like factor-I (IGF-I) levels in children and adolescents with connective tissue diseases (CTDs), compare them with values obtained in normal controls, and correlate them with age, sex, steroid treatment, and inflammatory parameters. METHODS: A multicenter, cross-sectional study was performed in 3 Italian pediatric rheumatology centers. The subjects studied comprised 117 patients with juvenile arthritis (53 systemic, 25 pauciarticular and 17 polyarticular) and other CTDs (22), and 78 children without inflammatory conditions. IGF-I levels were measured by radioimmunoassay after acid-ethanol extraction. RESULTS: Mean IGF-I serum levels were 167.6 ng/ml (+/- 132.5) in patients and 214.4 (+/- 142.8) in controls. A significant correlation was found between IGF-I levels and age in the controls (P = 0.001), but not in the patients. Covariance analysis with age as the covariate showed significantly lower IGF-I levels in the patient group (P = 0.001). No significant correlation was found between IGF-I levels and the total quantity of steroid taken. Multiple regression analysis showed that IGF-I levels were inversely correlated with the ESR (P = 0.0001) and positively correlated with age (P = 0.0002) and sex (P = 0.021) in the patient group. CONCLUSION: IGF-I serum levels are decreased in patients with CTDs; inflammation could play a major role.     

Growth hormone (GH) secretion from human lymphocytes is up-regulated by GH, but not affected by insulin-like growth factor-I

Regulation of GH secretion from phytohemagglutinin (PHA)-stimulated lymphocytes was investigated in six normal subjects. Peripheral blood mononuclear cells were incubated with PHA (10 micrograms/mL) in the presence of various amounts of recombinant human GH (0-100 ng/L) and/or recombinant human insulin-like growth factor-I (0-1000 micrograms/L), and the secreted GH was measured by a highly sensitive enzyme immunoassay. PHA-stimulated lymphocytes secreted immunoreactive GH in all subjects (13.6 +/- 2.4 ng/L). Exogenous GH up-regulated the GH secretion in a dose-dependent manner, while IGF-I did not affect either basal GH secretion or the up-regulation by exogenous GH. These findings suggest a difference in the regulation of GH secretion between endocrine and immune systems.     

Comparison of the effects of growth hormone, insulin-like growth factor-I and fetal calf serum on mouse molar odontogenesis in vitro

The effects of growth hormone, its mediator insulin-like growth factor-I (IGF-I), and fetal calf serum on odontogenesis were compared to those of serum-free medium. Explanted, 16-day, fetal mouse first molar tooth germs in early bell stage were grown on semisolid, serum-free medium supplemented with ascorbic and retinoic acids. Recombinant human growth hormone at 50 or 100 ng/ml, IGF-I at 100 or 200 ng/ml, or fatal calf serum at 20% concentration were added to the media. Volumetric changes in serial sections of six tooth germs per treatment over 3 days of treatment (4, 5, 6 days in vitro) were compared by digitized morphometry. Mitotic indices were also compared and the cell densities of the dental papillae recorded. Qualitative ratings of differentiation were ascribed to each tooth germ by light microscopy. Differences in volume, mitotic activity and cell densities were found. The growth hormone-treated tooth germs were not larger than the serum-free ones but had increased mitotic indices and higher cell densities in the dental papillae. IGF-I-treated tooth germs had larger volumes than with all other treatments, e.g. germs treated with 200 ng/ml of IGF-I, after 6 days in culture, were significantly larger than with all other treatments (p<0.01-<0.001). Whilst IGF-I-treated germs displayed the greatest extent of differentiation, growth hormone-treated germs also showed advanced differentiation compared to those on serum-free medium. These results suggest that growth hormone and IGF-I are involved in odontogenesis of murine teeth in vitro by affecting mitotic activity, tissue volume and cell differentiation. In conjunction with previous immunohistochemical studies that show expression of growth hormone receptor and IGF-I in developing teeth, these results provide evidence that both growth hormones and its mediator play a part in odontogenesis.     

Effects of insulin-like growth factor-1 on luteinizing hormone secretion in sheep

Liver dysfunction often occurs during chemotherapy for AML, but the etiologies are many and varied. To determine liver dysfunction that is not related to HCV, liver function during intense therapy for one week after complete remission was studied in eight patients not infected with HCV (38 courses) and six HCV-infected patients (19 courses) with AML. There were remarkable differences in changes of ALT levels among HCV-infected patients. ALT level changes among patients not infected with HCV were similar. Changes in mean serum ALT levels in HCV-infected patients occurred at higher serum levels as compared with those in patients not infected with HCV. The mean serum ALT levels in patients not infected with HCV significantly increased at one week (45 +/- 5 IU/l) and further increased at two (58 +/- 8 IU/l) and three weeks (57 +/- 5 IU/l) as compared with pretreatment levels (24 +/- 21 IU/l) (p < 0.001, p < 0.001, p < 0.0001, respectively). ALT levels returned to normal at four weeks. During 31 of 38 courses (81.6%) in patients not infected with HCV, febrile episodes occurred at three weeks. The mean serum ALT levels in patients with febrile episodes were significantly higher than those in patients without febrile episodes at three weeks, and serum ALT levels at three weeks showed a significant positive correlation with CRP levels at three weeks. These findings indicate that liver dysfunction during chemotherapy for AML is due to hepatocellular injury, and infection or inflammatory cytokine induced by infection results in the worsening of the liver dysfunction.     

Differential effect of insulin-like growth factor-1 and growth hormone on hypothalamic regulation of growth hormone secretion in the rat

Pharmacological administration of either growth hormone (GH) or insulin-like growth factor 1 (IGF-1) were reported to inhibit endogenous GH release in humans and in the laboratory animal. We have evaluated the short-term differential mechanisms whereby the two hormones affect hypothalamic regulation of GH secretion. Wistar male rats (90 days old) were injected i.p. with either GH (recombinant GH NIAMDD, Baltimore, MD, USA), rIGF-1 (Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan) or saline. Animals were sacrificed at 15, 30, 60 and 120 minutes following injection. Hypothalami were dissected and extracted immediately and the levels of growth hormone-releasing hormone (GHRH) and somatostatin were determined using specific antisera. Trunk blood was collected for GH and IGF-1 determination by RIA. Administration of IGF-1 or GH markedly decreased hypothalamic somatostatin stores by 77% and 54% respectively, within 15 minutes. Concomitantly, the wide range of GH levels found in the control group was reduced in the IGF-1 treated group suggesting that the pulsatile pattern of GH secretion was suppressed. Growth hormone administration induced an increase in hypothalamic GHRH stores (60% at 120 minutes). During this period serum IGF-1 levels were not altered. It is suggested that short term modulation of hypothalamic neurohormones by GH and IGF-1 is mediated by rapid stimulation of somatostatin release by both hormones, and inhibition of GHRH release is induced only by GH.     

Effects of low-dose recombinant human insulin-like growth factor-I on insulin sensitivity, growth hormone and glucagon levels in young adults with insulin-dependent diabetes mellitus

Despite recent interest in the therapeutic potential of recombinant human insulin-like growth factor-I (rhIGF-I) in the treatment of diabetes mellitus, its mechanism of action is still not defined. We have studied the effects of low-dose bolus subcutaneous rhIGF-I (40 microg/kg and 20 microg/kg) on insulin sensitivity, growth hormone (GH) and glucagon levels in seven young adults with insulin-dependent diabetes mellitus (IDDM) using a randomized double-blind placebo-controlled crossover study design. Each was subjected to a euglycemic clamp (5 mmol/L) protocol consisting of a variable-rate insulin infusion clamp (6:00 PM to 8:00 AM) followed by a two-dose hyperinsulinemic clamp (insulin infusion of 0.75 mU x kg(-1) x min(-1) from 8 to 10 AM and 1.5 mU x kg(-1) x min(-1) from 10 AM to 12 noon) incorporating [6,6 2H2]glucose tracer for determination of glucose production/utilization rates. Following rhIGF-I administration, the serum IGF-I level (mean +/- SEM) increased (40 microg/kg, 655 +/- 90 ng/mL, P < .001; 20 microg/kg, 472 +/- 67 ng/mL, P < .001; placebo, 258 +/- 51 ng/mL). Dose-related reductions in insulin were observed during the period of steady-state euglycemia (1 AM to 8 AM) (40 microg/kg, 48 +/- 5 pmol/L, P = .01; 20 microg/kg, 58 +/- 8 pmol/L, P = .03; placebo, 72 +/- 8 pmol/L). The mean overnight GH level (40 microg/kg, 9.1 +/- 1.4 mU/L, P = .04; 20 microg/kg, 9.6 +/- 2.0 mU/L, P = .12; placebo, 11.3 +/- 1.7 mU/L) and GH pulse amplitude (40 microg/kg, 18.8 +/- 2.9 mU/L, P = .04; 20 microg/kg, 17.0 +/- 3.4 mU/L, P > .05; placebo, 23.0 +/- 3.7 mU/L) were also reduced. No differences in glucagon, IGF binding protein-1 (IGFBP-1), acetoacetate, or beta-hydroxybutyrate levels were found. During the hyperinsulinemic clamp conditions, no differences in glucose utilization were noted, whereas hepatic glucose production was reduced by rhIGF-I 40 microg/kg (P = .05). Our data demonstrate that in subjects with IDDM, low-dose subcutaneous rhIGF-I leads to a dose-dependent reduction in the insulin level for euglycemia overnight that parallels the decrease in overnight GH levels, but glucagon and IGFBP-1 levels remain unchanged. The decreases in hepatic glucose production during the hyperinsulinemic clamp study observed the following day are likely related to GH suppression, although a direct effect by rhIGF-I cannot be entirely discounted.     

Postnatal catch-up growth induced by growth hormone and insulin-like growth factor-I in rats with intrauterine growth retardation caused by maternal protein malnutrition

In an earlier study, we found that yellow-rumped warblers had in vitro active uptake rates of D-glucose that were only a few percent of the glucose absorption rate achieved at the whole-animal level. Here we used a pharmacokinetic technique to test whether a substantial amount of sugar can be absorbed passively. We used yellow-rumped warblers (Dendroica coronata), known for their seasonal frugivory, freely feeding on a synthetic mash formulated with naturally occurring concentrations of D-glucose. Birds absorbed 89.8% +/- 1.0% (SE) of the D-glucose in the mash. When fed the same mash with trace-labeled 3H L-glucose, the stereoisomer that does not interact with the intestinal Na(+)-glucose cotransporter, 3H appeared in plasma, an indication that this stereoisomer of glucose was absorbed. We used 3H levels in plasma and excreta in a pharmacokinetic model to calculate L-glucose extraction efficiency (i.e., the percent absorbed). Calculated mean extraction efficiency for the passively absorbed L-glucose averaged 91% +/- 23%. Our finding of considerable passive absorption reconciles the in vitro and in vivo results for D-glucose absorption and is in concert with results from five other avian species. The passive pathway appears to provide birds with an absorptive process that can respond quickly to changing luminal concentration and that is energetically inexpensive to maintain and modulate in real time but that may bear a cost. Less discriminate passive absorption might increase vulnerability to toxins and thus constrain foraging behavior and limit the breadth of the dietary niche.