Effects of fasting on growth hormone, growth hormone receptor, and insulin-like growth factor-I axis in seawater-acclimated tilapia, Oreochromis mossambicus

Effects of fasting on the growth hormone (GH)--growth hormone receptor (GHR)-insulin-like growth factor-I (IGF-I) axis were characterized in seawater-acclimated tilapia (Oreochromis mossambicus). Fasting for 4 weeks resulted in significant reductions in body weight and specific growth rate. Plasma GH and pituitary GH mRNA levels were significantly elevated in fasted fish, whereas significant reductions were observed in plasma IGF-I and hepatic IGF-I mRNA levels. There was a significant negative correlation between plasma levels of GH and IGF-I in the fasted fish. No effect of fasting was observed on hepatic GHR mRNA levels. Plasma glucose levels were reduced significantly in fasted fish. The fact that fasting elicited increases in GH and decreases in IGF-I production without affecting GHR expression indicates a possible development of GH resistance.     

Growth hormone and insulin-like growth factor-I counteracts established steroid catabolism in rats by effects on hepatic amino-N degradation

Background/Aims: Long-term steroid treatment causes protein wasting. Liver contributes towards this by upregulating ureagenesis. Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are anabolic agents with specific hepatic effects. It is unknown whether IGF-I alone and/or in combination with GH have any effect on established hepatic amino-N catabolism during long-term glucocorticoid treatment.Methods: We measured the spontaneous (UNSR) and the substrate standardized rate of urea nitrogen synthesis (STUNSR), N-balance and mRNA levels of urea cycle enzymes in controls (placebo) and four longterm steroid treated groups given (1) prednisolone 4 mg/kg/day during 28 days (St) (2) +GH 1 mg/kg/day from day 21-28 (StGH) (3) +IGF-I 1.5 mg/kg/day 21-28 (StIGF) (4) GH +IGF-I (StGHIGF).Results: Steroid induced weight loss was stepwisely reversed by IGF-I, GH and both. UNSR, STUNSR and mRNA levels of urea cycle enzymes in the liver increased markedly after steroid treatment, and was normalized after co-administration of GH and IGF-I. N-balance improved after GH and IGF-I administration.Conclusions: Our results expands the knowledge of beneficial effects of GH on short-term steroid catabolism to include effects of IGF-I and IGF-I combined with GH on long-term steroid catabolism. Both peptides prevent steroid induced hepatic protein wasting and thereby contribute towards whole body anabolism. The effect in vivo is probably due to an effect of the peptides on urea cycle enzyme mRNA.     

Growth hormone secretion from the Arctic charr (Salvelinus alpinus) pituitary gland in vitro: effects of somatostatin-14, insulin-like growth factor-I, and nutritional status

This study investigated the influence of nutritional status on the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis in Arctic charr (Salvelinus alpinus). The objectives were to study the regulation of GH secretion in vitro by somatostatin-14 (SRIF) and hIGF-I, and to determine whether pituitary sensitivity to these factors is dependent upon nutritional status. Arctic charr were fed at three different ration levels (0, 0.35, and 0.70% BWd(-1)), and pituitary glands were harvested at 1, 2, and 5 weeks for in vitro study. Both SRIF and hIGF-I inhibited GH secretion from Arctic charr pituitary tissue in long-term (18 h) static hemipituitary culture, as well as after acute exposure in a pituitary fragment perifusion system. This response appeared to be dose-dependent for SRIF in static culture over the range of 0.01-1 nM, but not for hIGF-I. The acute inhibitory action of hIGF-I on GH release in the perifusion system suggests an action that is initially independent of any effects on GH gene expression or protein synthesis. Nutritional status did not affect the sensitivity of Arctic charr pituitary tissue to either SRIF or hIGF-I in vitro, indicating that changes in abundance of pituitary SRIF or IGF-I receptors may not explain the alterations in plasma GH levels found during dietary restriction.     

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 (125)I-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 (125)I-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 (125)I-IGF-I binding in skeletal muscle and increased expression of IGFR 1 mRNAs and (125)I-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.     

Cloning of Atlantic halibut growth hormone receptor genes and quantitative gene expression during metamorphosis

To gain insight into the possible regulatory role of the growth hormone (GH)-insulin-like growth factor I (IGF-I) system in flatfish metamorphosis, body GHR gene expression as well as IGF-I protein content was quantified in larval Atlantic halibut throughout metamorphosis (developmental stages 5-10). The cDNA of the full-length GH receptor (hhGHR) was cloned from adult liver and characterized. The hhGHR shows common features of a GHR, including a (Y/F)GEFS motif in the extracellular domain, a single transmembrane region, and an intracellular domain containing a Box 1 and Box 2. Additionally, a truncated GHR (hhGHRtr), similar to turbot and Japanese flounder GHRtr, was cloned and sequenced. These sequences are highly similar to the full-length and truncated GHRs in turbot (89%/86%) and Japanese flounder (93%/91%) with lower identity with other fish type I GHR (81%) and type II GHRs (58%). A quantitative real-time RT-PCR assay was used to measure hhGHR and hhGHRtr mRNA content in normally and abnormally metamorphosed individuals at six developmental stages, from early pre-metamorphosis to post-metamorphosis, when the fish is considered a juvenile. The level of hhGHR gene expression was highest at pre-metamorphic stage 6 and at stage 8 at the onset of metamorphosis, and then decreased during metamorphic climax and post-metamorphosis. Expression of hhGHRtr reached highest levels at stage 6 and then decreased to post-metamorphosis. The ratio of expression between the full-length and the truncated GHR (hhGHR:hhGHRtr) varied among stages and was highest at the onset of metamorphosis and at metamorphic climax. A radioimmunoassay was used to measure halibut IGF-I body content throughout metamorphosis. IGF-I increases from early metamorphosis to the onset of metamorphosis and then decreases towards post-metamorphosis. In comparison between normally and abnormally metamorphosing larvae, IGF-I content, hhGHR and hhGHRtr mRNA levels were reduced in the abnormal fish. These data indicate that the GH-IGF-I system either has a regulatory role in metamorphosis, or is being affected as a consequence of the abnormal metamorphosis.     

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.     

Production and characterization of recombinantly derived peptides and antibodies for accurate determinations of somatolactin, growth hormone and insulin-like growth factor-I in European sea bass (Dicentrarchus labrax)

A specific radioimmunoassay (RIA) for European sea bass (Dicentrarchus labrax) growth hormone (GH) was developed and validated. For this purpose, a stable source of GH was produced by means of recombinant DNA technology in a bacteria system. The identity of the purified protein (ion exchange chromatography) was demonstrated by Western blot and a specific GH antiserum was raised in rabbit. In Western blot and RIA system, this antiserum recognized specifically native and recombinant GH, and it did not cross-react with fish prolactin (PRL) and somatolactin (SL). In a similar way, a specific polyclonal antiserum against the now available recombinant European sea bass SL was raised and used in the RIA system to a sensitivity of 0.3 ng/ml (90% of binding of tracer). Further, European sea bass insulin-like growth factor-I (IGF-I) was cloned and sequenced, and its high degree of identity with IGF-I peptides of barramundi, tuna, and sparid fish allowed the use of a commercial IGF-I RIA based on barramundi IGF-I antiserum. These assay tools assisted for the first time accurate determinations of SL and GH-IGF-I axis activity in a fish species of the Moronidae family. Data values were compared to those found with gilthead sea bream (Sparus aurata), which is currently used as a Mediterranean fish model for growth endocrinology studies. As a characteristic feature, the average concentration year round of circulating GH in growing mature males of European sea bass was higher than in gilthead sea bream. By contrast, the average concentration of circulating SL was lower. Concerning to circulating concentration of IGF-I, the measured plasma values for a given growth rate were also lower in European sea bass. These findings are discussed on the basis of a different energy status that might allowed a reduced but more continuous growth in European sea bass.     

Plasma ghrelin and growth hormone regulation in response to metabolic state in hybrid striped bass: Effects of feeding, ghrelin and insulin-like growth factor-I on in vivo and in vitro GH secretion

The regulation of growth hormone (GH) secretion by ghrelin during variable metabolic states is poorly understood. We examined plasma GH and ghrelin in hybrid striped bass (HSB) undergoing seasonally-based feeding and temperature manipulations. Fasting for 21 days (d) at 24 °C resulted in catabolism and up-regulation of plasma GH and ghrelin relative to fed controls. Continued fasting during cold-banking (14 °C, 90d) resulted in a further 43-fold increase in ghrelin while GH remained elevated. A subsequent 19 day refeeding period at 24 °C elicited hyperphagic and compensatory growth responses, accompanied by declines in ghrelin and GH. We then tested the role of ghrelin in stimulating GH release in vivo and in vitro. Intraperitoneal injections of ghrelin resulted in dose-dependent increases in plasma GH after 6 hours (h). Ghrelin also increased GH release from HSB pituitaries during 6 h incubations. Lastly, we assessed how metabolic state, ghrelin and insulin-like growth factor-I (IGF-I) affect in vitro pituitary GH release. Spontaneous GH release was 5.2-fold higher from pituitaries of fasted compared with fed animals. Ghrelin was equally effective in stimulating GH release from pituitaries of fed and starved animals, while it was ineffective in enhancing GH release from pituitaries of starved (21d) then refed (4d) HSB. Incubation with IGF-I inhibited GH release regardless of metabolic state. These studies are the first to show that seasonally-based periods of feed deprivation and low temperature yield sustained increases in GH secretion that are likely mediated, at least partially, through elevated ghrelin, reduced IGF-I negative feedback and fasting-induced spontaneous GH release.     

Salmon growth hormone receptor: molecular cloning, ligand specificity, and response to fasting

To better understand the role of growth hormone in regulating fish growth, the cDNA of growth hormone receptor (GHR) was cloned from the liver of masu salmon (Oncorhynchus masou) and characterized. The masu salmon GHR (msGHR) sequence revealed common features of a GHR, including a (Y/F)GEFS motif in the extracellular domain, a single transmembrane region, and Box 1 and Box 2 in the intracellular domain. However, the amino acid sequence identity was low (49%) compared to GHRs of other vertebrates including seven teleosts, and the putative msGHR protein lacked one pair of cysteine residues in the extracellular domain. To verify the identity of the msGHR, the recombinant protein of the extracellular domain was expressed with a histidine tag protein (His-msGHR-ECD), refolded and purified for analysis of its ligand specificity. In competition experiments, the specific binding between His-msGHR-ECD and radioiodine-labeled salmon GH was displaced completely by only salmon GH, and not by salmon prolactin or somatolactin. A real-time RT-PCR assay was used to measure salmon GHR mRNA in the liver of fed and fasted coho salmon (Oncorhynchus kisutch). The levels of hepatic GHR mRNA were lower in fasted fish compared to fed fish after 3 weeks, suggesting that GHR gene expression is reduced following a long-term fast. These results confirm the identity of the salmon GHR based on ligand specificity and response to fasting.     

Therapeutic aspects of growth hormone and insulin-like growth factor-I treatment on visceral fat and insulin sensitivity in adults

Growth hormone (GH) is generally considered to exert anti-insulin actions, whereas insulin-like growth factor I (IGF-I) has insulin-like properties. Paradoxically, GH deficient adults and those with acromegaly are both predisposed to insulin resistance, but one cannot extrapolate from these pathological conditions to determine the normal metabolic roles of GH and IGF-I on glucose homeostasis. High doses of GH treatment have major effects on lipolysis, which plays a crucial role in promoting its anti-insulin effects, whereas IGF-I acts as an insulin sensitizer that does not exert any direct effect on lipolysis or lipogenesis. Under physiological conditions, the insulin-sensitizing effect of IGF-I is only evident after feeding when the bioavailability of circulating IGF-I is increased. In contrast, many studies in GH deficient adults have consistently shown that GH replacement improves the body composition profile although these studies differ considerably in terms of age, the presence or absence of multiple pituitary hormone deficiency, and whether GH deficiency was childhood or adult-onset. However, the improvement in body composition does not necessarily translate into improvements in insulin sensitivity presumably due to the anti-insulin effects of high doses of GH therapy. More recently, we have found that a very low dose GH therapy (0.1 mg/day) improved insulin sensitivity without affecting body composition in GH-deficient adults and in subjects with metabolic syndrome, and we postulate that these effects are mediated by its ability to increase free 'bioavailable' IGF-I without the induction of lipolysis. These results raise the possibility that this low GH dose may play a role in preventing the decline of beta-cell function and the development of type 2 diabetes in these "high risk" subjects.     

Dihydrotestosterone inhibits hair growth in mice by inhibiting insulin-like growth factor-I production in dermal papillae

We demonstrated that insulin-like growth factor-I (IGF-I) production in dermal papillae was increased and hair growth was promoted after sensory neuron stimulation in mice. Although the androgen metabolite dihydrotestosterone (DHT) inhibits hair growth by negatively modulating growth-regulatory effects of dermal papillae, relationship between androgen metabolism and IGF-I production in dermal papillae is not fully understood. We examined whether DHT inhibits IGF-I production by inhibiting sensory neuron stimulation, thereby preventing hair growth in mice. Effect of DHT on sensory neuron stimulation was examined using cultured dorsal root ganglion (DRG) neurons isolated from mice. DHT inhibits calcitonin gene-related peptide (CGRP) release from cultured DRG neurons. The non-steroidal androgen-receptor antagonist flutamide reversed DHT-induced inhibition of CGRP release. Dermal levels of IGF-I and IGF-I mRNA, and the number of IGF-I-positive fibroblasts around hair follicles were increased at 6 h after CGRP administration. DHT administration for 3 weeks decreased dermal levels of CGRP, IGF-I, and IGF-I mRNA in mice. Immunohistochemical expression of IGF-I and the number of proliferating cells in hair follicles were decreased and hair re-growth was inhibited in animals administered DHT. Co-administration of flutamide and CGRP reversed these changes induced by DHT administration. These observations suggest that DHT may decrease IGF-I production in dermal papillae by inhibiting sensory neuron stimulation through interaction with the androgen receptor, thereby inhibiting hair growth in mice.     

Treatment with growth hormone and insulin-like growth factor-I in critical illness

The wider availability of recombinant human growth hormone and insulin-like growth factor-I has resulted in an investigation into the potential benefits of the pharmacological administration of these anabolic peptides in a variety of clinical conditions, characterized by an increase in catabolic rate. The initial studies were small, often uncontrolled open investigations, but investigators have more recently concentrated on larger, controlled multi-centre trials. Studies to date have included patients with cardiac failure, sepsis, burns, cancer cachexia, end-stage renal failure, trauma and AIDS, and those prior to or following major surgery. The authors have in general cautiously interpreted positive effects of treatment with growth hormone and insulin-like growth factor-I, either alone or in combination, on net protein balance, body composition, well-being and performance. Two large, randomized, placebo-controlled European multi-centre studies have recently detailed the effects of growth hormone treatment in critically ill intensive care patients. Major increases in mortality and morbidity were associated with growth hormone treatment. The mechanism(s) accounting for the increased mortality remain poorly understood. These negative findings have led to a decrease in the clinical use of growth hormone and in research activity in the area of anabolic treatment in human illness.     

Comparison of serum insulin-like growth factor-1 and growth hormone levels in osteoporotic and non-osteoporotic postmenopausal women

The purpose of this study was to compare the insulin-like growth factor-1 (IGF-1) levels and the growth hormone (GH) levels in osteoporotic and non-osteoporotic postmenopausal women. Eleven non-osteoporotic postmenopausal women and 9 women with untreated postmenopausal osteoporosis were included in the study. Bone mineral density (BMD) was assessed by dual energy X-ray absorbtiometry. Serum was assayed for calcium, phosphorus, alkaline phosphatase, bone-specific alkaline phosphatase, parathyroid hormone, IGF-1 and GH levels. IGF-1 levels were 98.8 ± 43.5 ng/ml for osteoporotic women and 169.8 ± 50.3 ng/ml for the women with normal BMD (p < 0.05). GH levels were 1.3 ± 1.1 ng/ml and 1.3 ± 1.0 ng/ml, respectively. When compared with normal postmenopausal women, IGF-1 levels were found to be lower in women with osteoporosis. IGF-1 seems to play an important role in the development of low bone mass and the present results suggest that IGF-1 is a useful predictor of the presence of osteoporosis. Received: 8 September 1999 / Accepted: 11 May 2000     

原发性高血压赖诺普利治疗前后血清胰岛素样生长因子-I的变化

目的观察原发性高血压(EH)患者服用赖诺普利治疗前后血清胰岛素样生长因子-I(IGF-I)的变化,探讨IGF-I在EH的发生发展过程中所起的可能作用。方法47例EH患者均行超声心动图检查,用放免法测定赖诺普利治疗前、治疗后半年及23例正常对照者血清IGF-I水平。结果EH患者血清IGF-I水平明显高于对照组分别为(22.23±10.06)ng/ml对(15.91±7.59)ng/ml,P<0.01。I~Ⅲ级间比较也有显著性差异(F=3.53,P<0.05),Ⅲ级(28.61±13.10)ng/ml高于Ⅱ级(22.64±9.94)ng/ml,Ⅱ级高于I级(18.09±6.11)ng/ml。EH伴左心室肥厚(LVH)者高于无LVH者(25.95±11.20)ng/ml对(18.68±7.43)ng/ml,P<0.05。IGF-I与左心室重量指数中度相关(r=0.54)。赖诺普利治疗6个月后,血清IGF-I水平由(22.23±10.06)ng/ml降至(16.82±7.93)ng/ml,P<0.05。结论EHLVH患者IGF-I水平升高,赖诺普利治疗后IGF-I水平下降,IGF-I可能参与EHLVH的形成。     

The effect of acute and chronic insulin administration on insulin-like growth factor-I expression in the pituitary-intact and hypophysectomised rat

Summary Although growth hormone is known to be the main regulator of insulin-like growth factor-I, insulin has also been shown to play a role in regulating serum insulin-like growth factor I levels in diabetic animals. While this effect is thought to be due to correction of metabolic perturbations, some studies have suggest that insulin may have a direct effect on growth and/or insulin-like growth factor-I levels. We have examined the effects of acute and chronic insulin administration to non-diabetic, pituitary-intact and hypophysectomised rats. Rats were injected intraperitoneally with insulin as an acute bolus (10 U) or a chronic subcutanious infusion (low dose; 2.4 U/day, high dose; 12 U/day) over 5 days. Insulin-like growth factor-I mRNA was quantitated by Northern and slot blots of RNA from various tissues. A small (less than 2-fold) but significant increase (p<0.05) was seen in hepatic insulin-like growth factor-I mRNA abundance in pituitary-intact rats following acute insulin injection and chronic low dose insulin infusion. An increase in insulin-like growth factor-I mRNA levels was also seen in other tissues including diaphragm, lung, kidney and heart. A significant increase (p<0.05) in serum insulin-like growth factor-I levels was also observed 6 h after insulin injection. In contrast, in pituitary-intact rats which received high dose insulin infusion and were hypoglycaemic at the time of death, tissue levels of insulin-like growth factor-I mRNA were reduced compared to saline-treated control groups. Similarly in the hypophysectomised rats neither acute nor chronic insulin administration had any consistent effect on insulin-like growth factor-I mRNA abundance in any of the tissues examined. This data suggests that insulin has no direct effect in regulating insulin-like growth factor-I gene expression. The small effects demonstrable in pituitary-intact rats may result from a synergistic action of insulin with growth hormone or other pituitary factors.     

Role of growth hormone, insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 in development of non-alcoholic fatty liver disease

Background and aims Pituitary dysfunction including growth hormone (GH) deficiency may be associated with non-alcoholic fatty liver disease (NAFLD). Since the relationships among GH, IGF-1, IGFBP-3, and development of NAFLD without hypopituitarism are unclear, we examined the role of these hormones in the development of NAFLD based on clinical, laboratory and liver histology data. Patients and methods A total of 55 consecutive patients (20 males and 35 females) with NAFLD. Results Aspartate amino transferase (AST), AST/ALT, platelet count and IGF-1, levels were significantly associated with differences in fibrosis, since these variables differed between stage 0–1 and stage 2–3 NAFLD. In multivariate analysis, platelet count (P = 0.0223, relative risk (RR), 5.899; 95% confidence interval (CI), 1.288–27.017), and IGF-1 (P = 0.0363, RR, 4.568; 95% CI, 1.101–18.945) showed significant associations with stage 2–3 NAFLD. Additionally, hyaluronic acid levels had a negative relationship with IGF-1 and the IGF-1/IGFBP-3 ratio. There was no relationship of fibrosis with GH level, but decreased GH (P = 0.0414, RR, 0.199; 95% CI, 0.042–0.989) was significantly associated with steatosis of stage 2–3. Low GH/IGF-1 and GH/IGFBP-3 ratios were found in advanced steatosis. Conclusion GH, IGF-1 and IGFBP-3 are associated with hepatic fibrosis and steatosis in NAFLD. Low levels of IGF-1 might be associated with fibrosis while low level of GH with hepatic steatosis.     

Frailty and the biochemical effects of recombinant human growth hormone in women after surgery for hip fracture

We report a randomised double blind controlled trial investigating the short-term biochemical and adverse clinical responses to recombinant human growth hormone (r-hGH) after surgery for hip fracture. Hip fractures are common, dangerous and expensive, typically affecting frail women with osteoporosis and reduced muscle mass and strength, factors also associated with poor clinical outcomes. Growth hormone therapy increases IGF-I levels, promotes anabolism and increases muscle strength in well older people and selected patient groups and therefore has therapeutic potential to assist recovery of frail patients.Thirty-one women, mean age 86 years, received 14 nightly subcutaneous injections of r-hGH 0.05 mg/kg/day (high dose) or 0.025 mg/kg/day (low dose), or placebo from the 4th post-operative day. There were several serious adverse clinical events but no excess number of adverse events in the r-hGH treatment groups. The r-hGH treatment groups had similar serum IGF-I and IGFBP-3 responses, both significantly different from placebo. The large inter-individual variation of IGF-I responses were inversely correlated with pre-treatment indicators of frailty (body composition and functional abilities).     

Direct effect of insulin and insulin-like growth factor-I on the secretory activity of rat pancreatic beta cells

Summary Purified pancreatic Beta cells were labelled with ³H-tyrosine before studying their secretory activity in perifusion. At 1.4 mmol/l glucose, the cells released similar fractions (0.01% per min) of their contents in preformed and in newly formed insulin. At 20 mmol/l glucose plus 10^–8 mol/l glucagon, these fractional release rates increased by 16 and 40-fold respectively. The preferential release of newly synthesized as compared to stored insulin is attributable to a heterogeneity in individual cell responses. The secretory responsiveness to glucose plus glucagon was completely suppressed by 10^–7 mol/l clonidine. Insulin induced a 20% reduction at 10^–6 mol/l, but remained without effect at 10^–7 mol/l. Insulin-like growth factor-I provoked a 30% decrease at 5.10^–9 mol/l. It is concluded that the type-I insulin-like growth factor receptors on pancreatic Beta cells mediate a suppressive action on the insulin release process. Their high affinity for insulin-like growth factor-I allows physiologic levels of this peptide to participate in the regulation of insulin release. Their low affinity for insulin provides the basis for a minor feedback action by this hormone at concentrations exceeding the normal circulating levels.Part of this study has been presented at the 25th Annual Meeting of the European Association for the Study of Diabetes, Lisbon, Portugal, 1989     

Insulin-like growth factor-I receptor in proliferation and motility of pancreatic cancer

AIM:To develop a molecular therapy for pancreatic cancer, the insulin-like growth factor-I (IGF-I) signaling pathway was analyzed.METHODS: Pancreatic cancer cell lines (MIA-Paca2, NOR-P1, PANC-1, PK-45H, PK-1, PK-59 and KP-4) were cultured in media with 10 mL/L fetal bovine serum. Western blotting analysis was performed to clarify the expression of IGF-I receptor (IGF-IR). Picropodophyllin (PPP), a specific inhibitor of IGF-IR, LY294002, a specific inhibitor of phosphatidylinositol3 kinase (PI3K), and PD980...