Growth Hormone (GH) Hypersecretion and GH Receptor Resistance in Streptozotocin Diabetic Mice in Response to a GH Secretagogue

The growth hormone (GH) and insulin-like growth factor I (IGF-I) axis were studied in streptozotocin (STZ) diabetic and nondiabetic female mice following intravenous (IV) injection of the GH secretagogue (GHS) ipamorelin or saline. On day 14, blood samples were obtained before and 10 minutes after the injection. Livers were removed and frozen for determination of the mRNA expressions of the GH receptor, GH-binding protein, and IGF-I, and hepatic IGF-I peptide. Serum samples were analyzed for GH and IGF-I. Following ipamorelin injection, the GH levels were found to be 150 ± 35 μg/L and 62 ± 11 μg/L in the diabetic compared to the nondiabetic mice (P < .05). Serum IGF-I levels were lower in diabetic than in nondiabetic animals, and rose after stimulation only in the nondiabetic animals. Furthermore, hepatic GH resistance and IGF-I mRNA levels and IGF-I peptide were increased in nondiabetic animals in response to GH stimulation, whereas the low levels per se of all these parameters in diabetic mice were unaffected. The study shows that STZ diabetic mice demonstrate a substantial part of the clinical features of type 1 diabetes in humans, including GH hypersecretion and GH resistance. Accordingly, it is proposed that STZ diabetic mice may be a better model of the perturbations of the GH/IGF-I axis in diabetes than STZ diabetic rats.     

Differential expression of insulin-like growth factor-I and insulin-like growth factor binding protein-1 in the diabetic rat

Summary Multiple factors contribute to the growth retardation which is a characteristic feature of uncontrolled diabetes. In this report we have examined the effects of streptozotocin-induced (STZ) diabetes on expression of insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-1 (IGFBP-1) in various tissues. As early as 7 days after STZ administration there was a modest reduction in IGF-I mRNA abundance. The reduction (10–30%) was of similar magnitude in each of the 7 tissues examined; liver, kidney, lung, diaphragm, quadraceps, heart and adipose tissue. However, the reduction achieved statistical significance only in the lung (p < 0.05) and diaphragm (p < 0.01). A further reduction in IGF-I mRNA abundance was seen in many tissues, 32 and 91 days after STZ administration. In contrast to the decrease in IGF-I mRNA, IGFBP-1 mRNA was significantly increased in the liver and kidney of diabetic rats. IGFBP-1 mRNA was detectable at only very low levels in other tissues but was increased in diabetic rats compared non-diabetic rats. In diabetic rats, a highly significant correlation (R = 0.75, p < 0.001) between hepatic IGFBP-1 mRNA and glucose was observed whereas there was no significant correlation between serum glucose and hepatic IGF-I mRNA abundance (R = 0.24, p = NS). Treatment of diabetic rats with insulin resulted in a small, non significant increase in hepatic and renal IGF-I mRNA and a significant decrease in renal IGFBP-1 mRNA abundance. The observations reported here are consistent with the hypothesis that diminished IGF-I expression and inhibition of available IGF-1 by increased levels of IGFBP-1 may explain the impaired growth seen in diabetic animals.     

Effect of pulsatile growth hormone administration to the growth-restricted fetal sheep on somatotrophic axis gene expression in fetal and placental tissues

We have previously reported (Bauer MK, Breier BH, Bloomfield FH, Jensen EC, Gluckman PD, and Harding JE. J Endocrinol 177: 83-92, 2003) that a chronic pulsatile infusion of growth hormone (GH) to intrauterine growth-restricted (IUGR) ovine fetuses increased fetal circulating IGF-I levels without increasing fetal growth. We hypothesized a cortisol-induced upregulation of fetal hepatic GH receptor (GH-R) mRNA levels, secondary increases in IGF-I mRNA levels, and circulating IGF-I levels, but a downregulation of the type I IGF receptor (IGF-IR) as an explanation. We, therefore, measured mRNA levels of genes of the somatotrophic axis by real-time RT-PCR in fetal and placental tissues of fetuses with IUGR (induced by uteroplacental embolization from 110- to 116-days gestation) that received either a pulsatile infusion of GH (total dose 3.5 mg/day) or vehicle from 117-126 days and in control fetuses (n = 5 per group). Tissues were collected at 127 days (term, 145 days). Fetal cortisol concentrations were significantly increased in IUGR fetuses. However, in liver, GH-R, but not IGF-I or IGF-IR, mRNA levels were decreased in both IUGR groups. In contrast, in placenta, GH-R, IGF-I, and IGF-IR expression were increased in IUGR vehicle-infused fetuses. GH infusion further increased placental GH-R and IGF-IR, but abolished the increase in IGF-I mRNA levels. GH infusion reduced IGF-I expression in muscle and increased GH-R but decreased IGF-IR expression in kidney. IUGR increased hepatic IGF-binding protein (IGFBP)-1 and placental IGFBP-2 and -3 mRNA levels with no further effect of GH infusion. In conclusion, the modest increases in circulating cortisol concentrations in IUGR fetuses did not increase hepatic GH-R mRNA expression and, therefore, do not explain the increased circulating IGF-I levels that we found with GH infusion, which are likely due to reduced clearance rather than increased production. We demonstrate tissue-specific regulation of the somatotrophic axis in IUGR fetuses and a discontinuity between GH-R and IGF-I gene expression in GH-infused fetuses that is not explained by alterations in phosphorylated STAT5b.     

Kidney growth in normal and diabetic mice is not affected by human insulin-like growth factor binding protein-1 administration

Insulin-like growth factor I (IGF-I) accumulates in the kidney following the onset of diabetes, initiating diabetic renal hypertrophy. Increased renal IGF-I protein content, which is not reflected in messenger RNA (mRNA) levels, suggests that renal IGF-I accumulation is due to sequestration of circulating IGF-I rather than to local synthesis. It has been suggested that IGF-I is trapped in the kidney by IGF binding protein 1 (IGFBP-1). We administered purified human IGFBP-1 (hIGFBP-1) to nondiabetic and diabetic mice as three daily sc injections for 14 days, starting 6 days after induction of streptozotocin diabetes when the animals were overtly diabetic. Markers of early diabetic renal changes (i.e., increased kidney weight, glomerular volume, and albuminuria) coincided with accumulation of renal cortical IGF-I despite decreased mRNA levels in 20-day diabetic mice. Human IGFBP-1 administration had no effect on increased kidney weight or albuminuria in early diabetes, although it abolished renal cortical IGF-I accumulation and glomerular hypertrophy in diabetic mice. Increased IGF-I levels in kidneys of normal mice receiving hIGFBP-1 were not reflected on kidney parameters. IGFBP-1 administration in diabetic mice had only minor effects on diabetic renal changes. Accordingly, these results did not support the hypothesis that IGFBP-1 plays a major role in early renal changes in diabetes.     

Insulin resistance (HOMA) in relation to plasma cortisol,IGF-I and IGFBP-3. A study in normal short-statured and GH-deficient children

OBJECTIVE: To investigate the possible contribution of plasma cortisol and growth hormone (GH) as reflected by insulin-like growth factor-I (IGF-I)/insulin-like growth factor-binding protein-3 (IGFBP-3) on insulin action in short-statured children. METHODS: In this study, insulin resistance (HOMA) was determined in 34 normal short-statured (age 9.4 +/- 3.5 years) and in 19 GH-deficient children (age 10.4 +/- 2.2 years). HOMA was examined in relation to fasting plasma cortisol, IGF-I, IGFBP-3 and in addition to birthweight and body mass index (BMI). RESULTS: Birthweight was not correlated to insulin resistance. In GH-deficient children, BMI was significantly augmented and was associated with HOMA (p < 0.02). In both groups of patients, fasting plasma cortisol was related to HOMA (normal: r = 0.295, p < 0.05, GH-deficient: r = 0.495, p < 0.02). Only in normal short-statured children IGF-I (r = 0.338, p < 0.03) and IGFBP-3 (r = 0.493, p < 0.002) were associated with insulin resistance. CONCLUSION: The results indicated that at a young age cortisol contributed to insulin resistance in short-statured children. In normal short-statured children HOMA was associated with IGF-I and IGFBP-3. Possibly GH, a known cause of insulin resistance, contributed to HOMA as IGF-I and IGFBP-3 do not mediate insulin resistance but reflect growth hormone secretion. The results in GH-deficient children supported this conclusion as in the absence of GH insulin resistance was not associated with IGF-I/IGFBP-3.     

Insulin-like growth factors and their binding proteins in children born small for gestational age: implication for growth hormone therapy

The insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are important regulators of growth and metabolism and are the key mediators of the actions of growth hormone (GH). Children born small for gestational age (SGA) have a host of medical problems including an increased risk of poor growth later in life, a tendency to develop metabolic abnormalities and a high incidence of learning disabilities. IGFs and related molecules may be linked to all of these concerns. Mouse models of IGF-I and IGF-II deficiencies have phenotypes reminiscent of human SGA, including slow growth, insulin resistance, and mental dysfunction. Humans with IGF-I mutations are born SGA and exhibit very poor subsequent growth, metabolic syndrome and mental retardation. Current management of children born SGA who present with growth failure during childhood includes treatment with GH. SGA children usually have growth factor levels within the normal range; however, as a group, they display lower IGFBP-3 levels in relation to their IGF-I levels. GH is effective in improving growth in children born SGA, but higher doses of GH are required to achieve optimal outcome, suggesting a component of GH insensitivity in SGA children. As in other indications for GH, a rational monitoring approach (focusing on maintaining IGF levels in the high normal range) is prudent.     

Seasonal regulation of the growth hormone-insulin-like growth factor-I axis in the American black bear (Ursus americanus)

The American black bear maintains lean body mass for months without food during winter denning. We asked whether changes in the growth hormone/insulin-like growth factor-I (GH-IGF-I) axis may contribute to this remarkable adaptation to starvation. Serum IGF-I levels were measured by radioimmunoassay, and IGF-binding proteins (IGFBPs) were analyzed by ligand blotting. Initial studies in bears living in the wild showed that IGF-I levels are highest in summer and lowest in early winter denning. Detailed studies in captive bears showed that IGF-I levels decline in autumn when bears are hyperphagic, continue to decline in early denning, and later rise above predenning levels despite continued starvation in the den. IGFBP-2 increased and IGFBP-3 decreased in early denning, and these changes were also reversed in later denning. Treatment with GH (0.1 mg·kg(-1)·day(-1) × 6 days) during early denning increased serum levels of IGF-I and IGFBP-3 and lowered levels of IGFBP-2, indicating that denning bears remain responsive to GH. GH treatment lowered blood urea nitrogen levels, reflecting effects on protein metabolism. GH also accelerated weight loss and markedly increased serum levels of free fatty acids and β-hydroxybutyrate, resulting in a ketoacidosis (bicarbonate decreased to 15 meq/l), which was reversed when GH was withdrawn. These results demonstrate seasonal regulation of GH/IGF-I axis activity in black bears. Diminished GH activity may promote fat storage in autumn in preparation for denning and prevent excessive mobilization and premature exhaustion of fat stores in early denning, whereas restoration of GH/IGF activity in later denning may prepare the bear for normal activity outside the den.     

Cell-specific localization of insulin-like growth factor binding protein mRNAs in rat liver

The liver is a major source of circulating insulin-like growth factor I (IGF-I), and it also synthesizes several classes of IGF binding proteins (IGFBPs). Synthesis of IGF-I and IGFBPs is regulated by hormones, growth factors, and cytokines. They are nutritionally regulated and expressed in developmentally specific patterns. To gain insight into cellular regulatory mechanisms that determine hepatic synthesis of IGF-I and IGFBPs and to identify potential target cells for IGF-I within the liver, we studied the cellular sites of synthesis of IGF-I, IGF receptor, growth hormone (GH) receptor, and IGFBPs in freshly isolated rat hepatocytes, endothelial cells, and Kupffer cells. We also localized cellular sites of IGFBP synthesis by in situ hybridization histochemistry. Western ligand and immunoblot analyses were used to determine IGFBP secretion by isolated cells. Two IGF-I mRNA subtypes with different 5' ends (class 1 and class 2) were detected in all isolated liver cell preparations. Type 1 IGF receptor mRNA was detected in endothelial cells, indicating that these cells are a local target for IGF actions in liver. GH receptor was expressed in all cell preparations, consistent with GH regulation of IGF-I and IGFBP synthesis in multiple liver cell types. The IGFBPs expressed striking cell-specific expression. IGFBP-1 was synthesized only in hepatocytes, and IGFBP-3 was expressed in Kupffer and endothelial cells. IGFBP-4 was expressed at high levels in hepatocytes and at low levels in Kupffer and endothelial cells. Cell-specific expression of distinct IGFBPs in the liver provides the potential for cell-specific regulation of hepatic and endocrine actions of IGF-I.     

The effect of cyclosporine administration on growth hormone release and serum concentrations of insulin-like growth factor-I in male rats.

The aim of this work was to study the effect of cyclosporine on the somatotropic axis. Accordingly, growth hormone (GH) secretion, circulating insulin-like growth factor I (IGF-I) and IGF binding proteins (IGFBPs) in response to cyclosporin A (CsA) treatment were examined in adult male Wistar rats. Cyclosporine administration (5, 10 or 20 mg/Kg daily) over 8 days did not modify the body weight, but it did decrease serum concentration of corticosterone and increased serum IGF-I and GH levels. Rats treated with 5 and 10 mg/Kg of cyclosporine had similar levels of serum IGFBPs to control rats, but there was an increase in circulating IGFBP-3 and IGFPB-1,2 in the group treated with 20 mg/Kg of CsA. The increase in circulating GH correlates with a decrease in pituitary GH content in CsA treated rats, with no modification in hypothalamic somatostatin content, suggesting an increase in pituitary GH release. In order to test this hypothesis, anterior pituitary cell cultures were exposed to different CsA concentrations during a 4 h incubation period. Cyclosporine increased GH secretion in cultured pituitary cells (p<0.05). These data suggest that cyclosporine increases circulating IGF-I and GH by stimulating pituitary GH release.     

Serum leptin, insulin-like growth factor-I components and sex-hormone binding globulin. Relationship with sex, age and body composition in healthy population

Leptin plays an important role in the regulation of food intake and thermogenesis, regulates long term energy balance and reproductive function and its concentrations are closely linked to body mass index. Leptin secretion is influenced by many factors and the age-related changes in different hormones might modify circulating leptin concentrations. Sex dimorphism in leptin concentrations has been clearly shown in previous studies and its concentrations were lower in men than in women in all decades of life. Insulin growth factor-I (IGF-I) is a peptide growth factor that is present in all types of physiologic fluids and is also produced by connective tissue cell types and its autocrine/paracrine secretion is nearly always present within tissues. There is a physiological decline of the growth hormone (GH)/IGF-I axis with ageing and in addition, insulin, thyroid hormones and the supply of dietary energy may directly regulate the circulating levels of the IGFs and growth hormone binding protein (GHBP). Furthermore, there is no doubt that GH participates in the regulation of body composition, and with advanced age there is a decrease in muscle and an increase in adiposity associated with a decline in GH and total IGF-I. The biological activities of the IGF ligands are modulated by the family of high affinity GHBP. Sex hormone binding globulin (SHBG) concentrations are thought to be regulated primarily through opposing actions of sex steroids on hepatic SHBG production, with oestrogen stimulating and androgen inhibiting SHBG production, and thyroid hormones are also a potent stimulator of SHBG production concentrations. Some studies support an independent IGFBP3 contribution to SHBG variability and these findings are compatible with the hypothesis that some of the anabolic effects ascribed to the GH/IGF axis may be caused by SHBG-mediated changes in testosterone activity or SHBG/total testosterone index.     

Normal growth spurt and final height despite low levels of all forms of circulating insulin-like growth factor-I in a patient with acid-labile subunit deficiency

BACKGROUND: In a recently described patient with acid-labile subunit (ALS) deficiency, the inability to form ternary complexes resulted in a marked reduction in circulating total insulin-like growth factor (IGF)-I, whereas skeletal growth was only marginally affected. To further study the role of circulating versus locally produced IGF-I in skeletal growth in this patient, we now describe in detail growth changes and their relationship with several components of the circulating IGF system. DESIGN AND METHODS: We followed growth and development up to the final height in a patient with complete ALS deficiency and determined both spontaneous and growth hormone (GH)-stimulated changes in the IGF system, including measurements of total, free and bioactive IGF-I, total IGF-II and insulin-like growth factor binding protein (IGFBP)-1, IGFBP-2 and IGFBP-3. RESULTS: The patient had a delayed growth and pubertal onset. Six months of GH treatment had no effect on growth. At the age of 19.3 years, he spontaneously completed puberty and had a normal growth spurt for a late adolescent (peak height velocity of 8.4 cm/year). A normal final height was attained at 21.3 years (167.5 cm; -0.78 SDS). During as well as after puberty, basal levels of total, free and bioactive IGF-I were low, as were total IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3. GH treatment for 6 months normalized free IGF-I and increased bioactive IGF-I, but had no effect on growth velocity. CONCLUSIONS: This case story shows that in the presence of complete ALS deficiency, a height within normal limits can be obtained despite low levels of all forms of circulating IGF-I. Furthermore, the patient presented a delayed but normal growth spurt without any marked increment of circulating IGF-I.     

NO plays a role in LPS-induced decreases in circulating IGF-I and IGFBP-3 and their gene expression in the liver

In this study, we administered aminoguanidine, a relatively selective inducible nitric oxide synthase (iNOS) inhibitor, to study the role of nitric oxide (NO) in LPS-induced decrease in IGF-I and IGFBP-3. Adult male Wistar rats were injected intraperitoneally with LPS (100 microg/kg), aminoguanidine (100 mg/kg), LPS plus aminoguanidine, or saline. Rats were injected at 1730 and 0830 the next day and killed 4 h after the last injection. LPS administration induced an increase in serum concentrations of nitrite/nitrate (P < 0.01) and a decrease in serum concentrations of growth hormone (GH; P < 0.05) and IGF-I (P < 0.01) as well as in liver IGF-I mRNA levels (P < 0.05). The LPS-induced decrease in serum concentrations of IGF-I and liver IGF-I gene expression seems to be secondary to iNOS activation, since aminoguanidine administration prevented the effect of LPS on circulating IGF-I and its gene expression in the liver. In contrast, LPS-induced decrease in serum GH was not prevented by aminoguanidine administration. LPS injection decreased IGFBP-3 circulating levels (P < 0.05) and its hepatic gene expression (P < 0.01), but endotoxin did not modify the serum IGFBP-3 proteolysis rate. Aminoguanidine administration blocked the inhibitory effect of LPS on both IGFBP-3 serum levels and its hepatic mRNA levels. When aminoguanidine was administered alone, IGFBP-3 serum levels were increased (P < 0.05), whereas its hepatic mRNA levels were decreased. This contrast can be explained by the decrease (P < 0.05) in serum proteolysis of this binding protein caused by aminoguanidine. These data suggest that iNOS plays an important role in LPS-induced decrease in circulating IGF-I and IGFBP-3 by reducing IGF-I and IGFBP-3 gene expression in the liver.     

Factors regulating insulin-like growth factor binding protein-3 secretion from human hepatoma (HepG2) cells

Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) is a growth hormone (GH) dependent carrier of the IGFs in human serum. Apart from GH regulation the hormonal control of IGFBP-3 production is not well established and although the liver is considered to be the main source of circulating IGFBP-3, there are no in vitro studies of the effect of both insulin and IGFs on the IGFBP-3 produced in human hepatoma cells. The effect of sex hormones as well as cortisol has not been studied. To elucidate this we performed cell culture studies on HepG2 cells in the presence of various effectors. Insulin, IGF-I and IGF-II brought about a 1.5-2-fold enhancement of IGFBP-3 release at 7.5-30 nM concentrations. In contrast, cortisol decreased IGFBP-3 secretion by 30-40% whereas estradiol, tamoxifen and testosterone had no effect at physiological concentrations. We conclude that, in addition to GH, also insulin, IGF-I and IGF-II and glucocorticoids can modulate IGFBP-3 secretion by human hepatoma cells.     

Sex steroids and the growth hormone/insulin-like growth factor-I axis in adults

In healthy adults insulin-like growth factor (IGF)-I levels do not differ between males and females, whereas spontaneous growth hormone (GH) secretion is approximately twofold higher in females. Untreated GH-deficient (GHD) women exhibit lower IGF-I levels compared with men and the increase in serum IGF-I during GH replacement is also significantly less. These data suggest a resistance to GH in women, which in healthy subjects is compensated for by increased GH secretion. Administration of oral oestrogen in healthy postmenopausal women suppresses hepatic IGF-I production and increases pituitary GH release, and oral oestrogen replacement in women with GHD lowers IGF-I concentrations and increases the amount of GH necessary to achieve IGF-I target levels during treatment. These data clearly suggest that hepatic suppression of IGF-I production by oestrogen subserves the gender difference in GH sensitivity, but it is also likely that sex steroids may interact with the GH/IGF axis at other levels. There is also circumstantial evidence to indicate that testosterone stimulates IGF-I production and it is speculated that a certain threshold level of androgens is essential to ensure hepatic IGF-I production. Whether these data should translate into earlier discontinuation of oestrogen replacement therapy in women with hypopituitarism merits consideration.     

Role of interleukin-6 in growth failure: an animal model

Indirect evidence suggests a link between factors produced during the inflammatory response and stunted growth. The demonstration of this link was provided by the observation that mice transgenic for the inflammatory cytokine interleukin-6 (IL-6), expressing high circulating levels of IL-6 since birth, show a marked decrease in growth rate leading to adult mice 50-70% the size of wild-type littermates. The growth defect is completely abolished by neutralization of IL-6. In these mice the production of GH is normal, while circulating levels of IGF-I are markedly decreased. Administration of IL-6 to wild-type mice results in a marked decrease in IGF-I levels. These observations show that in vivo high levels of IL-6 are associated with low levels of IGF-I. However, IL-6 does not directly affect IGF-I production both in vitro and in vivo. In contrast, markedly decreased levels of IGFBP-3 are present in the IL-6 transgenic mice and administration of IL-6 to wild-type mice results in a marked decrease in IGFBP-3 levels. In these mice the decrease in IGFBP-3 levels is associated with impaired formation of the 150 kD ternary complex, even in the presence of normally functional ALS. As a consequence, IL-6 transgenic mice show increased clearance of circulating IGF-I, suggesting that IL-6 decreases IGF-I levels by increased clearance. Proteolytic degradation of IGFBP-3 occurs in the IL-6 transgenic mice, suggesting that the decrease in IGFBP-3 could be at least in part due to proteolysis. The abnormalities of the IGF-I system observed in the IL-6 transgenic mice are similar to those found in patients with systemic juvenile idiopathic arthritis, one of the chronic inflammatory diseases characterized by stunted growth and prominent production of IL-6. The IL-6 transgenic mice represent a faithful animal model of the growth impairment associated with chronic inflammation and may therefore provide information relevant to the understanding and treatment of this complication of inflammatory diseases.     

Effect of Mild Hypoinsulinemia on Renal Hypertrophy: Growth Hormone/Insulin-Like Growth Factor I System in Mild Streptozotocin Diabetes

The metabolic aberrations associated with diabetes mellitus profoundly alter the growth hormone/insulin-like growth factor I (GH/IGF-I) system. In severe experimental diabetes, serum IGF-I level is reduced, reflecting altered hepatic expression. On the other hand, increased levels of kidney IGF-I have been implicated in the development of diabetic kidney disease. This study aimed to examine the effect of mild experimental diabetes with hypoinsulinemia on both the systemic and renal GH/IGF-I systems in a low-dose streptozotocin (STZ)-induced diabetic rat. Diabetic animals with mild hypoinsulinemia developed renal hyperfiltration within 3 days of diabetes, whereas the renal size increased significantly only between 30 and 48 days of diabetes. Plasma GHlevels were unchanged during the entire course of the study, but a decrease in serum IGF-I, IGF-binding protein 3 (IGFBP-3), and IGF-binding protein 4 (IGFBP-4) occurred after 10, 30, and 48 days. Kidney IGF-I and IGF-binding protein 1 (IGFBP-1) mRNA expression increased after 10 and 30 days of diabetes. A significant increase in kidney IGFBP-1/2, IGFBP-3, and IGFBP-4 proteins was seen after 48 days of diabetes.Apositive correlations was found between renal growth and insulin/glucose ratio (r = .57), kidney IGF-I (r = .57), IGFBP-1 mRNA(r = .43), IGFBP-1/2 (r = .41), and IGFBP-4 levels (r = .40). These results demonstrate hyperfiltration within 3 days of diabetes and a similar response in the IGF-I system in mildly and severely hypoinsulinemic rats; however, renomegaly develops slower in mildly diabetic rats at least partly due to delayed changes in the renal IGF and IGF BPs.     

Growth hormone secretagogues in critical illness

Alterations within the somatotropic axis occurring during the course of critical illness follow a biphasic pattern. The initial stress response consists of activated growth hormone (GH) release whereas circulating levels of GH-dependent insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-3 fall and IGFBP-1 concentrations rise. In contrast, in the chronic intensive care-dependent phase of severe illness, pulsatile GH secretion substantially decreases whereas the non-pulsatile fraction remains relatively elevated, resulting in an abnormally flat GH secretory pattern and low-normal mean nocturnal GH serum concentrations. Specifically the reduced amount of GH released in pulses is found to be related to low circulating levels of IGF-I, IGFBP-3 and acid-labile subunit (ALS), which suggests that a relative hyposomatotropism may participate in the pathogenesis of the wasting syndrome distinctively in the chronic phase of critical illness. The relative hyposomatotropism seems at least in part of hypothalamic origin since the whole somatotropic axis has been found to be very responsive to continuous infusion of GH releasing peptide (GHRP), administered alone or in combination with GH releasing hormone (GHRH), as evidenced by reactivated pulsatile GH secretion followed by substantial increases in circulating levels of IGF-I, IGFBP-3 and ALS. GHRH alone, however, is unable to exert the same effect, which may point to an underlying reduced availability of the endogenous ligand for the GHRP receptor. The presence of considerable responsiveness to restored endogenous pulsatile GH secretion using GHRPs not only further delineates the distinct pathophysiological paradigm of the chronic phase of critical illness, as opposed to the acute phase, which is thought to be primarily a condition of GH resistance, but may also have important therapeutic consequences. Recent data revealed that this novel strategy evokes metabolic improvement related to the balanced endocrine responses. Whether GH secretagogues also enhance clinical recovery of protracted critically ill patients remains to be elucidated.     

Serum insulin-like growth factor I levels in growth hormone-deficient adults: influence of sex steroids

Measurement of serum insulin-like growth factor I (IGF-I) concentrations remains the single most important tool in the evaluation of growth hormone (GH) replacement in GH-deficient adults, and the therapeutic goal is to maintain the level within the age-adjusted normal range. In healthy adults, IGF-I levels do not differ between males and females, whereas spontaneous GH secretion is approximately twofold higher in females. Untreated GH-deficient women exhibit lower IGF-I levels compared with men, and the increase in serum IGF-I during GH replacement is also significantly less. Put together, these data suggest resistance to GH in women, which in healthy individuals is compensated for by increased GH secretion. Administration of oral oestrogen in healthy post-menopausal women suppresses hepatic IGF-I production and increases pituitary GH release, and oral oestrogen replacement in women with GH deficiency lowers IGF-I concentrations and increases the amount of GH necessary to obtain IGF-I target levels during treatment. These data clearly suggest that hepatic suppression of IGF-I production by oestrogen subserves the gender difference in GH sensitivity, but it is also likely that sex steroids may interact with the GH/IGF axis at further levels. There is also circumstantial evidence to indicate that testosterone stimulates IGF-I production, and it is speculated that a certain threshold level of androgens is essential to ensure hepatic IGF-I production. Whether these data should translate into earlier discontinuation of oestrogen replacement therapy in adult women with hypopituitarism merits consideration.     

Chronic upper airway resistive loading induces growth retardation via the GH/IGF-I axis in prepubescent rats.

The effect of upper airway loading on longitudinal bone growth and various components of the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis has not been fully elucidated. In the present study, the effect of chronic resistive airway loading (CAL) in a prepubescent rat model on linear bone growth and weight gain was investigated. We hypothesize that CAL induced in prepubescent rats will lead to impaired longitudinal growth due to impairment in circulating and liver GH/IGF-I parameters. The tracheae of 22-day-old rats were obstructed by tracheal banding to increase inspiratory esophageal pressure. The GH/IGF-I markers were analyzed using ELISA, RT-PCR, and Western immunoblot analysis 14 days after surgery. Animals exhibited impaired longitudinal growth as demonstrated by reduction of tibia and tail length gains by 40% (P < 0.0001) and body weight gain by 24% (P < 0.0001). No differences were seen in total body energy balance, i.e., oxygen consumption, daily food intake, or arterial blood gases. Circulating GH, IGF-I, and IGF binding protein-3 (IGFBP-3) levels were reduced by 40% (P = 0.037), 30% (P < 0.006), and 27% (P = 0.02), respectively, in the CAL group. Liver IGF-I mRNA level decreased by 20% (P < 0.0002), whereas GH receptor mRNA and protein expression were unchanged. We conclude that impaired longitudinal growth in prepubescent CAL rats is related to a decrease in GH, IGF-I, and IGFBP-3 levels.     

No influence of prednisolone on IGFBP-3 proteolysis in healthy young men

AIMS: The impact of growth hormone (GH) and prednisolone on the GH/insulin-like growth factor (IGF) axis with special emphasis on IGF binding protein-3 (IGFBP-3) proteolysis was studied in 8 healthy adults in a double-blind cross-over study with four periods: (1) placebo; (2) s.c. GH 0.1 IU/kg/day; (3) oral prednisolone 50 mg/day, and (4) co-administration of GH and prednisolone. METHODS: Each treatment period lasted for 4 days followed by a washout period of 10 days. We measured IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3 by immunoassays, IGFBP-3 by Western ligand blotting (WLB) and finally in vitro IGFBP-3 proteolysis by a (125)I-IGFBP-3 degradation assay. RESULTS: IGF-I levels increased by 99% during GH administration and 67% during co-administration of GH and prednisolone (p < 0.0005), whereas no significant change was seen during prednisolone alone. IGFBP-1 levels decreased 55% during the prednisolone period (p < 0.002), but the between period changes were not significant (p < 0.1). IGFBP-2 decreased 33% during co-administration of GH and prednisolone (p < 0.002). IGFBP-3 increased 12% during GH and 7% during co-administration of GH and prednisolone (p < 0.003 and p < 0.03 compared to placebo, respectively), whereas prednisolone alone induced no significant changes. IGFBP-3 measured by WLB did not change significantly, neither did IGFBP-3 proteolysis. CONCLUSIONS: Prednisolone administration induces only minimal changes in circulating components of the IGF axis and is not accompanied by alterations in IGFBP-3 proteolysis. This indicates that the metabolic effects of glucocorticoids do not depend on serum IGF-I.