Hormone Insulin-like Growth factor-I Research Articles

Heat shock proteins in long-lived worms and mice with insulin/insulin-Like signaling mutations

Heat shock proteins (HSPs) have proven to be effective tools for extending invertebrate lifespan, and in C. elegans daf-2 mutants, longevity resulting from loss of insulin/insulin-like signals is at least partly dependent upon elevated HSP expression. In mice, inhibition of the orthologous growth hormone/insulin-like growth factor I (GH/IGF-I) pathway has similar pro-longevity effects. A recent study, however, suggests that loss of GH/IGF-I signals in long-lived mice does not broadly elevate HSP expression, but in fact decreases HSP expression in many tissue types, such as liver and kidney. The contribution of chaperones to the longevity of long-lived mice with altered GH/IGF-I signals may therefore differ from that described in C. elegans daf-2 mutants. This result, in combination with other recent findings, underscores the possibility that systemic overexpression of chaperones will have dissimilar effects on longevity in vertebrate and invertebrate systems.

The shortness of Pygmies is associated with severe under-expression of the growth hormone receptor

The stature is a highly heritable trait controlled by genetic and environmental factors. The African Pygmies represent a paradigmatic example of non-disease-related idiopathic short stature (ISS), showing a similar endocrine profile of Caucasian individuals with ISS. Pygmy children show normal anthropometric and endocrine parameters until puberty, while adult Pygmies show normal baseline and post-stimulation serum growth hormone (GH) levels but low values of baseline serum GH-binding protein (GHBP) and insulin-like growth factor-I (IGF-I). This discrepancy suggests a defective response to GH occurring in adulthood since Pygmies lack both the pubertal serum IGF-I surge and the growth spurt. However, sequencing of the key genes of the GH–IGF-I axis failed to identify Pygmy specific variants or haplotypes. We therefore aimed at assessing whether the quantitative gene expression profile of two key genes of the GH–IGF-I axis, GH and GHR, was also similar in low-stature and normal stature populations. We showed that the GH gene expression is 1.8-fold reduced and the GH receptor ( GHR) gene expression is 8-fold reduced in adult Pygmies in comparison with sympatric adult Bantu, and that this reduction is not associated with sequence variants of the GHR gene. The marked decrease of the GHR expression in Pygmies is associated with reduced serum levels of the IGF-I and GHBP. Our results, documenting a markedly reduced GHR gene expression in adult Pygmies, could contribute to elucidate the mechanisms involved in ISS in Caucasoid subjects.

Etiopathogenesis of Hepatic Osteodystrophy in Wistar Rats with Cholestatic Liver Disease

The pathophysiology of hepatic osteodystrophy (HO) remains poorly understood. Our aim was to evaluate bone histomorphometry, biomechanical properties, and the role of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) system in the onset of this disorder. Forty-six male Wistar rats were divided into two groups: sham-operated (SO, n = 23) and bile duct-ligated (BDL, n = 23). Rats were killed on day 30 postoperatively. Immunohistochemical expression of IGF-I and GH receptor was determined in liver tissue and in the proximal growth plate cartilage of the left tibia. Histomorphometric analysis was performed in the right tibia, and the right femur was used for biomechanical analysis. The maximal force at fracture and the stiffness of the mid-shaft femur were, respectively, 53% and 24% lower in BDL compared to SO. Histomorphometric measurements showed low cancellous bone volume and decreased cancellous bone connectivity in BDL, compatible with osteoporosis. This group also showed increased mineralization lag time, indicating disturbance in bone mineralization. Serum levels of IGF-I were lower in BDL (basal 1,816 +/- 336 vs. 30 days 1,062 +/- 191 ng/ml, P < 0.0001). BDL also showed higher IGF-I expression in the liver tissue but lower IGF-I and GH receptor expression in growth plate cartilage than SO. Osteoporosis is the most important feature of HO; BDL rats show striking signs of reduced bone volume and decreased bone strength, as early as after 1 month of cholestasis. The endocrine and autocrine-paracrine IGF-I systems are deeply affected by cholestasis. Further studies will be necessary to establish their role in the pathogenesis of HO.

Perspectives on the endocrinology of poultry growth and metabolism

Birds have rapid pre- and post-hatching growth rates. The major hormones required to support normal growth are growth hormone (GH), triiodothyronine (T 3) and insulin-like growth factor-I (IGF-I). Optimal growth requires a “set-point” concentration of both IGF-I and T 3 in the circulation. Pituitary GH plays a role in controlling the circulating concentrations of both IGF-I and T 3. Nutritional restriction (energy, protein) leads to reductions in circulating concentrations of both IGF-I and T 3 with increased GH secretion due removal of negative feedback. Similarly, there is un-coupling of the GH–IGF-I axis in stunting disease. A critical control point is at the level of the liver and GH receptor/signal transduction. The major hormones controlling metabolism include glucagon, insulin, adrenal glucocorticoid hormone, corticosterone and potentially somatostatin. Chickens and turkeys have higher circulating concentrations of glucose than those of livestock mammals. What are not known include the following: the biological basis for the high basal glucose concentrations; the quantitative fluxes of key metabolites in the fed and fasted state through growth and development; the relative contribution of different organs to gluconeogenesis; the relative importance of insulin and somatostatin in controlling lipolysis and the role of gastro-intestinal hormones in the control of metabolism.

Growth hormone and insulin-like growth factor of naked carp ( Gymnocypris przewalskii) in Lake Qinghai: Expression in different water environments

Here, we report the cloning and characterization of growth hormone (GH), insulin-like growth factor-I (IGF-I) and IGF-II from naked carp ( Gymnocypris przewalskii), a native teleost fish of Lake Qinghai in the Qinghai-Tibet Plateau of China. The GH of naked carp encodes for a predicted amino acid sequence showing identities of 63%, 63%, 91% and 94% with cherry salmon, rainbow trout, zebrafish and grass carp, respectively. Compared to common carp and goldfish, evolutionary analysis showed that genome duplication has had less influence on the relaxation of purifying selection in the evolution of naked carp GH. Sequence analysis of naked carp IGF-I (ncIGF-I) and ncIGF-II showed a high degree of homology with known fish IGF-I and IGF-II. To investigate effects of salinity and ionic composition of the aquatic environment on the GH–IGF axis in naked carp, male fish held in river water were assigned randomly to 4 groups: RW (river-water), RW + Na (NaCl in RW), RW + Mg (MgCl 2 in RW) and LW (lake-water) groups. The concentrations of Na + in RW + Na and Mg 2+ in RW + Mg were equal to the concentrations of these ions in lake-water. After 2 days of exposure, the plasma IGF-I levels in the RW + Na and LW groups were significantly higher than the control group (RW), and the plasma GH levels of the LW group were also significantly higher than the RW group. The somatostatin (SS) levels in the hypothalamus significantly increased in the RW + Na group. After 5 days of exposure, these hormone levels did not differ significantly among groups. These results indicate that while the plasma GH and IGF-I levels are osmosensitive, the absence of a change in GH secretion in RW + Na might be partly due to a transiently increased release of hypothalamic SS induced by the stress of neutral-saline water. This is the first report of a salinity-induced increase of GH–IGF-I circulating levels in Cypriniformes.

Insulin-Like Growth Factor I and Growth Responses during the First Year of Growth Hormone Treatment in KIGS Patients with Idiopathic Growth Hormone Deficiency, Acquired Growth Hormone Deficiency, Turner Syndrome and Born Small for Gestational Age

Background and Methods: We assessed the value of in- sulin-like growth factor I (IGF-I) monitoring during growth hormone (GH) treatment by retrospectively examining the relationships between (1) GH dose and IGF-I response, (2) baseline serum IGF-I concentration and growth response and (3) serum IGF-I response and growth response after 1 year of GH treatment among patients in the Pfizer International Growth Study database (KIGS). KIGS patients were eligible for the study if they were classified as having idiopathic GH deficiency, acquired GH deficiency, Turner syndrome or were born small for gestational age. Results: Correlations between GH dose and IGF-I response and between pretreatment IGF-I values and first-year growth response were weak across all groups. Correlations between the IGF-I response and growth response after 1 year of treatment were greater than those between baseline serum IGF-I values and first-year growth response. Pre- and posttreatment clinical characteristics were consistently different across all groups, but the numerous technical factors affecting these relationships are remediable. Conclusions: IGF-I monitoring during GH therapy is a valuable tool to monitor compliance and ensure that IGF-I levels do not exceed the normal range for extended periods. IGF-I monitoring may help clinicians increase GH doses as needed during puberty to achieve normal serum IGF-I values and normal or enhanced growth.

Mecasermin (recombinant human insulin-like growth factor I)

Growth hormone (GH) exercises its growth effects by stimulating insulin-like growth factor I (IGF-I) synthesis in the liver (endocrine IGF-I) and by inducing chondrocyte differentiation/replication and local production of IGF-I (paracrine/autocrine IGF-I). Injectable recombinant human (rh)IGF-I (mecasermin) has been available for nearly 20 years for treatment of the rare instances of GH insensitivity caused by GH receptor defects or GH-inhibiting antibodies. Full restoration of normal growth, as occurs with rhGH replacement of GH deficiency, is not seen, presumably because only the endocrine deficiency is addressed. RhIGF-I has also been effective as an insulin-sensitizing agent in severe insulin-resistant conditions. Although the insulin-sensitizing effect may benefit both type 1 and type 2 diabetes, there are no ongoing clinical trials because of concern about risk of retinopathy and other complications. Promotion of rhIGF-I for treatment of idiopathic short stature has been intensive, with neither data nor rationale suggesting that there might be a better response than has been documented with rhGH. Other applications that have either been considered or are undergoing clinical trial are based on the ubiquitous tissue-building properties of IGF-I and include chronic liver disease, cystic fibrosis, wound healing, AIDS muscle wasting, burns, osteoporosis, Crohn's disease, anorexia nervosa, Werner syndrome, X-linked severe combined immunodeficiency, Alzheimer's disease, muscular dystrophy, amyotrophic lateral sclerosis, hearing loss prevention, spinal cord injury, cardiovascular protection, and prevention of retinopathy of prematurity. The most frequent side effect is hypoglycemia, which is readily controlled by administration with meals. Other common adverse effects involve hyperplasia of lymphoid tissue, which may require tonsillectomy/adenoidectomy, accumulation of body fat, and coarsening of facies. The anti-apoptotic properties of IGF-I are implicated in cancer pathogenesis-a concern for long-term therapy. It is unlikely that mecasermin will be useful beyond the orphan indications of severe insulin resistance and GH insensitivity.

Use of Growth Hormone Secretagogues to Prevent or Treat the Effects of Aging: Not Yet Ready for Prime Time

In this issue, Nass and colleagues report that at 1 year, an oral ghrelin mimetic increased pulsatile growth hormone secretion and morning insulin-like growth factor I concentration to that in heal...

Endocrine effects of growth hormone overexpression in transgenic coho salmon

Non-transgenic (wild-type) coho salmon ( Oncorhynchus kisutch), growth hormone (GH) transgenic salmon (with highly elevated growth rates), and GH transgenic salmon pair fed a non-transgenic ration level (and thus growing at the non-transgenic rate) were examined for plasma hormone concentrations, and liver, muscle, hypothalamus, telencephalon, and pituitary mRNA levels. GH transgenic salmon exhibited increased plasma GH levels, and enhanced liver, muscle and hypothalamic GH mRNA levels. Insulin-like growth factor-I (IGF-I) in plasma, and growth hormone receptor (GHR) and IGF-I mRNA levels in liver and muscle, were higher in fully fed transgenic than non-transgenic fish. GHR mRNA levels in transgenic fish were unaffected by ration-restriction, whereas plasma GH was increased and plasma IGF-I and liver IGF-I mRNA were decreased to wild-type levels. These data reveal that strong nutritional modulation of IGF-I production remains even in the presence of constitutive ectopic GH expression in these transgenic fish. Liver GHR membrane protein levels were not different from controls, whereas, in muscle, GHR levels were elevated approximately 5-fold in transgenic fish. Paracrine stimulation of IGF-I by ectopic GH production in non-pituitary tissues is suggested by increased basal cartilage sulphation observed in the transgenic salmon. Levels of mRNA for growth hormone-releasing hormone (GHRH) and cholecystokinin (CCK) did not differ between groups. Despite its role in appetite stimulation, neuropeptide Y (NPY) mRNA was not found to be elevated in transgenic groups.

Functional Differences in the Growth Hormone and Insulin‐like Growth Factor Axis in Cattle and Pigs: Implications for Post‐partum Nutrition and Reproduction

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) control growth and lactation in cattle and swine. Insulin participates in the endocrinology of growth and lactation because insulin and GH are antagonistic in their actions. Dairy cows experience a period of negative energy balance during the first 4-8 weeks post-partum. During this period, their somatotropic axis (comprised of GH, the GH receptor and IGF-I) becomes uncoupled and there is elevated GH and diminished IGF-I in the circulation. Blood insulin concentrations are low as well. Sows are different from dairy cows because their somatotropic axis remains coupled during lactation and both GH and IGF-I are elevated. Nonetheless, sows that become catabolic during lactation will have reduced IGF-I concentrations. Sows are inseminated after weaning so their metabolic state is different from post-partum beef and dairy cows that are inseminated when they are lactating. Dairy cows are fed ad libitum and naturally have low IGF-I during lactation. Sows have elevated IGF-I when they are well-fed. A threshold of IGF-I protein in follicular fluid may be met by local ovarian (paracrine/autocrine) and endocrine sources of IGF-I. Nutritionally induced changes in insulin and in liver IGF-I secretion that arise from perturbations of the somatotropic axis have a direct effect on the ovary through the endocrine actions of insulin and IGF-I. Sows and cows that are nutritionally compromised have low concentrations of insulin and IGF-I in their blood and this theoretically reduces ovarian responsiveness to gonadotropins. Although sows are inseminated after weaning, there appear to be carry-over effects of the previous lactation on the ovarian follicular populations that develop after the sow is weaned. Understanding the mechanisms through which metabolic hormones control ovarian function may lead to improved reproductive management of both pigs and cattle because lactation and post-partum reproduction are closely tied in both species.

Single gene mutations causing SGA

The growth hormone-insulin-like growth factor-I (GH-IGF-I) axis plays a key role in intra-uterine growth and development. This review will describe the consequences of genetic defects in various components of the GH-IGF-I axis on intra-uterine growth and development. Animal knockout experiments have provided evidence for the GH-independent secretion of IGF-I and its effect in utero. Reports of patients with a deletion or mutation of the IGF-I and IGF1R genes have provided insight into the role of intra-uterine IGF-I in the human. Homozygous defects of the IGF-I gene have dramatic effects on intra-uterine growth and development, whereas heterozygous defects of the IGF1R gene have a more variable clinical presentation. The phenotype in relation to the genotype of the different disorders will be reviewed in this chapter.

Nonalcoholic fatty liver in patients with Laron syndrome and GH gene deletion – Preliminary report

Background There is little information on the relationship between growth hormone/insulin-like growth factor-I (GH/IGF-I) deficiency or IGF-I treatment on nonalcoholic fatty liver disease (NAFLD) a disorder linked to obesity and insulin resistance. Objective To find out whether the markedly obese patients with Laron syndrome (LS) and GH gene deletion have fatty livers. Subjects We studied 11 untreated adult patients with LS (5M, 6F), five girls with LS treated by IGF-I and five adult patients with GH gene deletion (3M, 3F), four previously treated by hGH in childhood. Methods Fatty liver was quantitatively evaluated by ultrasonography using a phase array US system (HITACHI 6500, Japan). Body adiposity was determined by DEXA, and insulin resistance was estimated by HOMA-IR using the fasting serum glucose and insulin values. Results Six out of 11 adult patients with LS, two out of the five IGF-I treated girls with LS and three out of five adult hGH gene deletion patients were found to have NAFLD (nonalcoholic fatty liver disease). Conclusion NAFLD is a frequent complication in untreated and treated congenital IGF-I deficiency. No correlation between NAFLD and age, sex, degree of obesity, blood lipids, or degree of insulin resistance was observed.

Pituitary growth hormone suppression reduces resistin expression and enhances insulin effectiveness: Relationship with caloric restriction

Caloric restriction (CR) retards various age-dependent disorders, increases lifespan, and improves insulin activity in laboratory animals. Recently, adipocytes were found to act together as an active endocrine organ that produces various hormones called adipocytokines. The peripheral and central activities of these adipocytokines have been suggested to mediate the anti-aging effects of CR. Here, we tested this notion by analyzing the effect of CR and suppression of growth hormone/insulin-like growth factor-I (GH/IGF-I) axis on the expression of resistin, adiponectin, and adipsin genes by rat white adipose tissue (WAT). We found that CR and GH/IGF-I suppression markedly downregulated resistin gene expression. We also found plasma resistin levels correlated positively with pituitary GH mRNA expression levels. Our observations suggest that CR reduces resistin expression and increases insulin effectiveness in a GH/IGF-I-dependent manner. The beneficial effects of CR and GH/IGF-I suppression appear to be mediated, at least in part, by changes in glucose metabolism that result from reductions in plasma resistin levels.

Low insulin‐like growth factor I and leukopenia in anorexia nervosa

Considering that leukopenia and anemia are commonly observed in anorexia nervosa (AN) and that growth hormone (GH) and insulin-like growth factor-I (IGF-I) markedly influence the activation, growth and survival of hemopoietic cells, we sought for possible relationships between hematologic parameters and the GH-IGF-I axis in a group of patients with AN. Twenty patients were studied. Leukocyte and erythrocyte counts, as well as baseline serum GH levels and IGF-I standard deviation score (SDS) values, were determined in each participant and correlations between parameters were searched. Leukocyte and erythrocyte counts, as well as IGF-I SDS values, were significantly lower, conversely GH was significantly higher in AN patients than in normal weight participants. In patients, IGF-I SDS values were positively correlated with leukocyte count and BMI, whereas no correlation was found between IGF-I SDS and hemoglobin or erythrocytes. The demonstration of a positive correlation between leukocyte number and circulating IGF-I in AN suggests a likely pathogenetic role of IGF-I deficiency in this hematologic abnormality.

Response of the salmon somatotropic axis to growth hormone administration under two different salinities

We compared the response of plasma insulin-like growth factor-I (IGF-I) to growth hormone (GH) administration under two different salinities to test the hypothesis that environmental salinity alters the “activity” of the GH–IGF-I axis. In July, postsmolt coho salmon reared in fresh water (FW) were transferred to either FW or half seawater (1/2 SW) (15 ppt) tank. During the experiment, water temperature was maintained at 10 °C for both salinities; photoperiod was adjusted to that of Seattle (48°N), and fish were not fed. Two days after transfer, fish were injected once with porcine GH (pGH) at a dose of 2 or 8 μg/g body weight. Liver and blood samples were collected 1, 2 and 3 days after injection. Liver GH receptor (GHR) mRNA expression was analyzed by quantitative real-time RT-PCR, and plasma IGF-I, 41-kDa IGF-binding protein (main carrier of IGF-I) and pGH were quantified by radioimmunoassays. Transfer to 1/2 SW resulted in transient increases in basal levels of liver GHR mRNA and 41 kDa IGF-binding protein (IGFBP) but not IGF-I. The GH injection increased liver GHR mRNA, plasma IGF-I and 41-kDa IGFBP in fish in both FW and 1/2 SW. However, the time course and magnitude of the response differed between salinities. Fish in FW receiving 8 μg/g pGH had the highest IGF-I levels (63.7±6.8 ng/ml) one day after injection, whereas fish in 1/2 SW showed a peak (88.8±14.3 ng/ml) two days after injection of the same dose. It is speculated that the prolonged response to GH by fish in 1/2 SW may be due to slower disappearance of pGH from the circulation in fish in 1/2 SW. The transient increase in basal liver GHR mRNA may also contribute to a greater response for fish in 1/2 SW. These results suggest that salinity is capable of altering the “activity” of the GH–IGF-I axis in salmon.

Anterior Pituitary Function May Predict Functional and Cognitive Outcome in Patients with Traumatic Brain Injury Undergoing Rehabilitation

Traumatic brain injury (TBI) is the leading cause of death and disability in young adults. Growth hormone-insulin-like growth factor I (GH-IGF-I) system has an important role in the recovery of the central nervous system. The aim of the study was to evaluate the relationship between pituitary function (in particular, the GH-IGF-I axis) and outcome from TBI. We studied 72 patients (56 males; mean age 37.2 +/- 1.8 years) receiving rehabilitation after TBI. According to the Glasgow Coma Scale (GCS), 10 patients had moderate and 52 severe TBI. Ten patients had growth hormone GH deficiency (GHD), 10 LH-FSH, three TSH, and three ACTH deficiency. Overall pituitary dysfunction occurred in 22 (30.5%) patients, with anterior hypopituitarism in 19 (26.4%), isolated diabetes insipidus in one, and isolated hyperprolactinemia in two. GH response to GHRH + ARG (arginine) positively correlated with Functional Independence Measure (FIM D; r = 0.267, p < 0.02) and Level of Cognitive Functioning Scale (LCFS D; r = 0.287, p < 0.01) at discharge, and negatively with Disability Rating Score at discharge (DRS D; r = -0.324, p < 0.005). Unfavorable outcome measures (FIM D, LCFS D, and DRS D) occurred in patients with hypopituitarism as compared with normal pituitary function (p < 0.05). Multiple regression analysis identified both GCS (p < 0.005) and GH peak (p < 0.05) as strong independent predictors of outcome. In conclusion, recovery after TBI may be negatively influenced by concomitant pituitary dysfunction. The GH peak value is an independent predictor of outcome, indicating that recovery during an intensive rehabilitation program after TBI may be positively influenced by normal GH secretion.

An audit of treatment outcome in acromegalic patients attending our center at Bergamo, Italy

Acromegaly is a chronic disease impacting on morbidity and mortality. Increased mortality is reverted after the achievement of hormonal targets. The relative role of treatment options is still matter of debate. A retrospective chart review was performed on all the acromegalic patients attending our center along the last 20 years. Data about 159 patients (83 F) were retrieved and analyzed: 18% had been lost to follow-up, while follow-up was >5 years in 79%. Growth hormone (GH) at diagnosis was 24 microg/L (median, range 3-239). Pituitary MRI showed a macro-, micro-adenoma or no lesion in 73.6, 22.9, and 3.5%, respectively. Hyperprolactinemia (hyperPRL) was present in 20.8%. Ninety-six and 29 patients had been treated by neurosurgery (NS) and irradiated (RT), respectively. Drugs had been employed in 149 patients (in 58 as the only treatment). At the last evaluation, 22% of patients were cured (hypopituitarism and GH deficiency in 6.3%), 37.1% were controlled by ongoing pharmacological treatment, 22.6% had discordant GH and Insulin-like growth factor I (IGF-I) values, and 18.2% had still active disease (median follow-up in this last group was 9 months). By evaluating the outcome with a multimodal approach, safe GH and normal IGF-I had been achieved in 78 and 63.5% of the whole series, 80.5 and 59.7% in patients submitted to NS (and adjuvantly treated with drugs), 95.8 and 91.7% in those submitted to NS + RT (and drugs as well), 70.2 and 55.2% in those treated only with drugs (increased to 82.2 and 60.9% if considering only patients treated with modern long-acting drugs). Hypopituitarism had occurred in 25, 66.6, and 13.8% in the three groups, respectively. At multivariate analysis, previous RT and NS were significant positive predictors of cure, whereas previous NS, follow-up, and year of diagnosis were significant positive predictors of control. Diabetes was a negative predictor both of cure and control. Sex, age, baseline GH levels, hyperPRL, tumor size, extrasellar extension, and invasiveness were not independent predictors of either cure or control. This series seems to indicate that a multimodal approach can achieve control of disease in most patients.

Correlation between the components of the insulin-like growth factor I system, nutritional status and visceral leishmaniasis

The role of the insulin-like growth factor I (IGF-I) system and nutritional status was studied in 241 children from a Brazilian area endemic for visceral leishmaniasis (VL). Thirty-nine children had the active form, 20 were oligosymptomatic, 38 were asymptomatic and 144 were not infected. Serum concentrations of growth hormone (GH), total and free IGF-I and IGF binding-protein 3 (IGFBP3) were measured by radioimmunoassay. Nutritional status was evaluated by anthropometric indicators and biochemical measurements. Total and free IGF-I and IGFBP3 were significantly reduced in the active form. Z scores for total and free IGF-I and for IGFBP3 were found to be significantly lower for active VL and oligosymptomatic individuals than for asymptomatic individuals, but never reached values <or=2 SD. Median values of weight-for-age Z and height-for-age Z (HAZ) scores and albumin concentration were significantly different in the active VL group compared with the other groups. Multiple discriminant analysis selected albumin and HAZ score as predictors of active and oligosymptomatic VL. The lack of correlation between auxological data and serum concentrations of the GH/IGF axis components suggested that the primary cause of retarded growth in children with active VL is not dependent on IGF-I or IGFBP3, but rather on VL intrinsic factors that might secondarily involve the GH/IGF axis.

Insulin-like growth factor I (IGF-I) in a growth-enhanced transgenic (GH-overexpressing) bony fish, the tilapia (Oreochromis niloticus): indication for a higher impact of autocrine/paracrine than of endocrine IGF-I

Several lines of growth hormone (GH)-overexpressing fish have been produced and analysed for growth and fertility parameters. However, only few data are available on the growth-promoting hormone insulin-like growth factor I (IGF-I) that mediates most effects of GH, and these are contradictory. Using quantitative real-time RT-PCR, radioimmunoassay, in situ hybridization, immunohistochemistry, and radiochromatography we investigated IGF-I and IGF binding proteins (IGFBPs) in an adult (17 months old) transgenic (GH-overexpressing) tilapia (Oreochromis niloticus). The transgenics showed an around 1.5-fold increase in length and an approximately 2.3-fold higher weight than the non-transgenics. Using radioimmunoassay, the serum IGF-I levels were lower (6.22 +/- 0.75 ng/ml) in transgenic than in wild-type (15.01 +/- 1.49 ng/ml) individuals (P = 0.0012). Radioimmunoassayable IGF-I in transgenic liver was 4.2-times higher than in wild-type (16.0 +/- 2.21 vs. 3.83 +/- 0.71 ng/g, P = 0.0017). No hepatocytes in wild-type but numerous hepatocytes in transgenic liver contained IGF-I-immunoreactivity. RT-PCR revealed a 1.4-times higher IGF-I mRNA expression in the liver of the transgenics (10.51 +/- 0.82 vs. 7.3 +/- 0.49 pg/microg total RNA, P = 0.0032). In correspondence, in situ hybridization showed more IGF-I mRNA containing hepatocytes in the transgenics. A twofold elevated IGF-I mRNA expression was determined in the skeletal muscle of transgenics (0.33 +/- 0.02 vs. 0.16 +/- 0.01 pg/microg total RNA, P < 0.0001). Both liver and serum of transgenics showed increased IGF-I binding. The increased IGFBP content in the liver may lead to retention of IGF-I, and/or the release of IGF-I into the circulation may be slower resulting in accumulation of IGF-I in the hepatocytes. Our results indicate that the enhanced growth of the transgenics likely is due to enhanced autocrine/paracrine action of IGF-I in extrahepatic sites, as shown here for skeletal muscle.

Resolving the growth-promoting and metabolic effects of growth hormone: Differential regulation of GH–IGF-I system components

Growth hormone regulates numerous processes in vertebrates including growth promotion and lipid mobilization. During periods of food deprivation, growth is arrested yet lipid depletion is promoted. In this study, we used rainbow trout on different nutritional regimens to examine the regulation of growth hormone (GH)–insulin-like growth factor-I (IGF-I) system elements in order to resolve the growth-promoting and lipid catabolic actions of GH. Fish fasted for 2 or 6 weeks displayed significantly reduced growth compared to their fed counterparts despite elevated plasma GH, while refeeding for 2 weeks following 4 weeks of fasting partially restored growth and lowered plasma GH. Fish fasted for 6 weeks also exhausted their mesenteric adipose tissue reserves. Sensitivity to GH in the liver was reduced in fasting fish as evidenced by reduced expression of GH receptor type 1 (GHR 1) and GHR 2 mRNAs and by reduced 125I-GH binding capacity. Expression of GHR 1 and GHR 2 mRNAs also was reduced in the gill of fasted fish. In adipose tissue, however, sensitivity to GH, as indicated by GHR 1 expression and by 125I-GH binding capacity, increased after 6 weeks of fasting in concert with the observed lipid depletion. Fasting-associated growth retardation was accompanied by reduced expression of total IGF-I mRNA in the liver, adipose and gill, and by reduced plasma levels of IGF-I. Sensitivity to IGF-I was reduced in the gill of fasted fish as indicated by reduced expression of type 1 IGF-I receptor (IGFR 1A and IGFR 1B) mRNAs. By contrast, fasting did not affect expression of IGFR 1 mRNAs or 125I-IGF-I binding in skeletal muscle and increased expression of IGFR 1 mRNAs and 125I-IGF-I binding in cardiac muscle. These results indicate that nutritional state differentially regulates GH–IGF-I system components in a tissue-specific manner and that such alterations disable the growth-promoting actions of GH and promote the lipid-mobilizing actions of the hormone.