Increased Serum IGF-I Research Articles

Impact of dehydroepianrosterone (DHEA) supplementation on serum levels of insulin-like growth factor 1 (IGF-1): A dose-response meta-analysis of randomized controlled trials.

Inconsistencies exist with regard to the influence of dehydroepiandrosterone (DHEA) supplementation on insulin-like growth factor 1 (IGF-1) levels. The inconsistencies could be attributed to several factors, such as dosage, gender, and duration of intervention, among others. To address these inconsistencies, we conducted a systematic review and meta-analysis to combine findings from randomized controlled trials (RCTs) on this topic. Electronic databases (Scopus, PubMed/Medline, Web of Science, Embase and Google Scholar) were searched for relevant literature published up to February 2020. Twenty-four qualified trials were included in this meta-analysis. It was found that serum IGF-1 levels were significantly increased in the DHEA group compared to the control (weighted mean differences (WMD): 16.36ng/ml, 95% CI: 8.99, 23.74; p=.000). Subgroup analysis revealed that a statistically significant increase in serum IGF-1 levels was found only in women (WMD: 23.30ng/ml, 95% CI: 13.75, 32.87); in participants who supplemented 50mg/d DHEA (WMD: 15.75ng/ml, 95% CI: 7.61, 23.89); in participants undergoing DHEA intervention for >12weeks (WMD: 17.2ng/ml, 95% CI: 8.02, 26.22); in participants without an underlying comorbidity (WMD: 19.11ng/ml, 95% CI: 10.69, 27.53); and in participants over the age of 60years (WMD: 19.79ng/ml, 95% CI: 9.86, 29.72). DHEA supplementation may increase serum IGF-I levels especially in women and older subjects. However, further studies are warranted before DHEA can be recommended for clinical use.

Growth Hormone Effects on Bone Loss-Induced by Mild Traumatic Brain Injury and/or Hind Limb Unloading

Growth hormone (GH) deficiency and loss of physical activity are common features in traumatic brain injury (TBI) patients that may contribute to bone loss. Therefore, we tested the hypothesis that GH treatment will rescue the hind limb unloading (UL)-induced skeletal deficit in TBI mice. Mild TBI was induced once per day for four consecutive days. UL (right hind limb) and treatment (3 mg/day GH or vehicle) began two weeks after the first TBI episode and lasted for four weeks. GH treatment increased femur BMD and lean body mass but decreased the % fat measured by DXA in the Control group. Micro-CT analysis revealed that the TBI, UL and TBI-UL groups showed reduced tibia trabecular (Tb) bone mass by 15%, 70%, and 75%, respectively compared to Control mice and that GH treatment significantly increased Tb. bone mass in all four groups. Vertebra also showed reduced Tb. bone mass in TBI, UL and TBI-UL groups. GH treatment increased vertebral Tb. bone mass in Control and UL groups but not in the TBI or TBI-UL group. GH treatment increased serum IGF-I levels similarly in TBI, UL and TBI-UL groups at day 14, suggesting the GH effect on liver IGF-I production was unaffected by skeletal UL. In contrast, GH effect on expression of ALP, IGFBP5 and axin2 in bone were compromised by UL. In conclusion, skeletal UL caused a greater Tb. bone deficit than mild TBI alone and that GH anabolic effects in the TBI and UL groups vary depending on the skeletal site.

Influence of a fermented protein-fortified dairy product on serum insulin-like growth factor-I in women with anorexia nervosa: A randomized controlled trial

Patients with anorexia nervosa (AN) have low serum IGF-I levels that may contribute to a lower bone mineral mass. We investigated the effects of a fermented, protein-fortified, dairy product on serum IGF-I levels in patients with AN during an in-hospital refeeding program. In this multicenter, randomized, double-blind, placebo-controlled, clinical trial conducted at 3 university hospitals and 3 private clinics in France and Switzerland, 62 women recently admitted with confirmed AN and with a baseline low serum IGF-I level were randomized to 2 daily isocaloric fresh cheese pots containing either 15g/150g or 3g/150g (controls) of protein for 4 weeks. The primary outcome was the change in IGF-I levels. In the primary intention-to-treat analysis, mean serum IGF-I levels increased during the intervention phase from 22.9±1.5 to 28.6±1.3nmol/L (means±SEM) (+20.2%) in the intervention group and from 20.2±1.2 to 25.7±1.5nmol/L (+16.8%) in controls. In a preplanned analysis of covariance with repeated measures, the between-group difference was close to statistical significance (P=0.071). In a post-hoc mixed-regression model analysis, the difference was statistically significant (4.9nmol/l increase; P=0.003), as was the change of the ratio IGF-I/IGF-BP3 (P=0.004). There was no between-group difference in biochemical markers of bone turnover (osteocalcin, P1NP, CTX) or in serum parathyroid hormone level. Serum calcium levels slightly increased during the intervention phase in the higher protein group (P=0.02). IGF-BP2 decreased significantly more in the intervention group during the follow up period at week 4 after supplements cessation (P=0.019). Intake of a fermented, protein-fortified, isocaloric dairy product during 4 weeks may slightly increase serum IGF-I levels in women with AN, without significant changes in bone turnover markers. NCT01823822 (www.clinicaltrials.gov).

Profiles of circulating insulin-like growth factor-I during smoltification of masu salmon reared under different conditions

We compared profiles of serum insulin-like growth factor (IGF)-I levels during smoltification of masu salmon reared under different environments, hatcheries and growth histories. Masu salmon from the Kenichi River in Hokkaido showed a sharp increase in serum IGF-I from April to May, followed by a peak of gill Na+,K+-ATPase (NKA) activity. Fish at Kumaishi Hatchery had an IGF-I profile similar to that of the river fish, while the increase in gill NKA was lower. At Shimamaki Hatchery, interval feeding during winter appeared to suppress the spring IGF-I peak. At Kumaishi Hatchery, a difference in size during smoltification affected IGF-I levels at release, but the numbers of adults that returned to the release site were not significantly different. In the following year, three release groups differing in winter size and/or spring growth (Large-High, Large-Low and Small-High) were created. Large-High and Small-High fish showed a higher IGF-I peak than Large-Low fish in April, while smolt-to-adult return of Large-High fish was highest. These results suggest that in smolting masu salmon in freshwater, circulating IGF-I level alone is not a predictor of long-term survival in seawater. However, since growth history in freshwater affected the smolt-to-adult return, optimizing rearing conditions is a critical component of hatchery releases for masu salmon.

The Relation between Concentric and Eccentric EXERCISE and the Carbohydrate Metabolism in Healthy Individuals

The purpose of the present study was to determine the response of glucose (G), insulin (In) and insulin like growth factor (IGF)-I to eccentric (ECC) vs. concentric (CON) resistance exercise in healthy trained and untrained subjects. Venous blood samples were drawn before and immediately after the test, and during 1-hour recovery for the determinations of hormonal and somatomedin concentrations. As compared to resting values, the maximal eccentric (ECC) resistance exercise test caused a significant decrease in G level (p<0.05). Significant differences were observed in post-exercise G level during ECC exercise (p<0.05). Different types of muscle contractions (ECC vs. CON) and resistance training had a significant effect on serum IGF-I concentration at maximal exercise intensity. A significant increase in IGF-I concentration was observed in response to eccentric muscle contraction in trained subjects compared to the control. Conclusions: These results seem to have demonstrated that in healthy subjects increased serum IGF-I concentration might be responsible for better glucose transport during resistance exercise, and this predominantly in eccentric muscle contraction.

A critical pathway for the management of elderly inpatients with malnutrition: effects on serum insulin-like growth factor-I

Several guidelines recommend systematic screening for malnutrition in elderly inpatients for early dietary intakes assessment and treatment, but data demonstrating the efficacy of such interventions are scarce. The aim of this study was to evaluate a critical medical pathway for the detection and management of malnutrition in elderly inpatients. In a 3-month prospective controlled study, 694 recently admitted inpatients were assigned to an intervention group (critical medical pathway; n=465) or a standard care control group (n=229). Nutritional status was assessed at the time of admission with a Mini Nutritional Assessment. A renutrition program tailored to the initial dietary assessment results was applied in the intervention group. The efficacy of the program was verified by measuring the evolution of serum insulin-like growth factor 1 (IGF-I) between admission and 3 weeks later. In the intervention group at baseline, 23% were malnourished, 51% were at risk and 26% were eunourished. Serum IGF-I increased in the intervention group (from 84±45 μg/l to 95±50 μg/l, P<0.0001; mean±s.d., n=209), but remained stable in the controls (from 79±43 μg/l to 81±35 μg/l, P=0.4; n=99), with a statistically significant between group difference (P<0.01). Early malnutrition assessment and targeted renutrition program in elderly inpatients were associated with an increase in serum IGF-I. It remains to be determined whether such variations are clinically relevant.

Associations of serum insulin-like growth factor-I and insulin-like growth factor-binding protein 3 levels with biomarker-calibrated protein, dairy product and milk intake in the Women's Health Initiative

It is well established that protein-energy malnutrition decreases serum insulin-like growth factor (IGF)-I levels, and supplementation of 30 g of whey protein daily has been shown to increase serum IGF-I levels by 8 % after 2 years in a clinical trial. Cohort studies provide the opportunity to assess associations between dietary protein intake and IGF axis protein levels under more typical eating conditions. In the present study, we assessed the associations of circulating IGF axis protein levels (ELISA, Diagnostic Systems Laboratories) with total biomarker-calibrated protein intake, as well as with dairy product and milk intake, among postmenopausal women enrolled in the Women's Health Initiative (n 747). Analyses were carried out using multivariate linear regression models that adjusted for age, BMI, race/ethnicity, education, biomarker-calibrated energy intake, alcohol intake, smoking, physical activity and hormone therapy use. There was a positive association between milk intake and free IGF-I levels. A three-serving increase in milk intake per d (approximately 30 g of protein) was associated with an estimated average 18·6 % higher increase in free IGF-I levels (95 % CI 0·9, 39·3 %). However, total IGF-I and insulin-like growth factor-binding protein 3 (IGFBP-3) levels were not associated with milk consumption and nor were there associations between biomarker-calibrated protein intake, biomarker-calibrated energy intake, and free IGF-I, total IGF-I or IGFBP-3 levels. The findings of the present study carried out in postmenopausal women are consistent with clinical trial data suggesting a specific relationship between milk consumption and serum IGF-I levels, although in the present study this association was only statistically significant for free, but not total, IGF-I or IGFBP-3 levels.

Effects of dietary glutathione on growth performance,tissue biochemical indexes and non-specific immune related enzymes of GIFT Oreochromis niloticus

This study was conducted to investigate the effects of dietary glutathione(GSH)on growth performance,tissue biochemical indexes and non-specific immune related enzymes of GIFT Oreochromis niloticus.720 fish with initial weight of(3.27±0.04)g were randomly allocated into 6 groups.The fish in control group were fed the basal diet(G0),while those in the other five groups were fed the basal diet added with 80,160,240,320,400 mg/kg GSH.After 7 weeks' feeding,weight gain rate(WGR),specific growth rate(SGR),protein efficiency ratio(PER)and RNA/DNA ratio of liver in 320 mg/kg group were significantly higher than those in the control group(P0.05),and feed coefficient(FC)was significantly lower(P0.05).Hepatosomatic index(HSI)was higher in GSH added groups than the control,showing no significant difference(P0.05).Among all groups,no significant difference was found in condition factor(CF)(P0.05).The whole-body crude protein content and crude lipid content were significantly affected by dietary GSH levels(P0.05),while the ash and dry matter content showed no significant difference(P0.05).Serum UN content was significantly lower in 320 mg/kg group compared with the control(P0.05).The IGF-Ⅰlevel in G160-G400 mg/kg groups was significantly higher than the control and 80 mg/kg groups.The serum lysozyme(LZM)activities increased significantly in 240,320 and 400 mg/kg groups compared with the others(P0.05),and liver LZM activities were significantly higher in 320 and 400 mg/kg groups(P0.05).Dietary GSH increased serum alkaline phosphatase(AKP),phenoloxidase(PO)and liver AKP,acid phosphatase(ACP)activities,but no significant difference was shown(P0.05).Serum nitric oxide synthase(NOS)activities in 320 mg/kg group were significantly higher than the control(P0.05),but those in liver showed no significant difference(P0.05).The result suggested that dietary GSH could significantly improve growth performance,raise whole-body crude protein and crude lipid content,increase serum and liver IGF-Ⅰ level,and enhance activities of non-specific immune related enzymes in GIFT Oreochromis niloticus.The optimum level of dietary GSH was 355.13 mg/kg on the basis of WGR.

Blood Erythrocyte and Hemoglobin Concentrations in Premature Adrenarche

Premature adrenarche (PA) is characterized by an earlier than normal increase in adrenocortical androgen production, and it is associated with increased serum IGF-I concentrations. Both the GH-IGF system and androgens, particularly testosterone, are known to enhance erythropoiesis. Our objective was to test the hypothesis that blood erythrocyte count and blood hemoglobin (B-Hb) concentration are increased in PA. Sixty-four prepubertal children (10 boys) with clinically and biochemically defined PA and 62 healthy prepubertal controls (10 boys) participating in our Premature Adrenarche study were examined, and a fasting blood sample was drawn at a university hospital. We evaluated B-Hb and erythrocyte, thrombocyte, and leukocyte counts and their association with serum dehydroepiandrosterone sulfate (DHEAS), testosterone and IGF-I concentrations. Children with PA had higher mean blood erythrocyte count (4.74 vs. 4.64 × 10(12)/liter, P = 0.04; significant difference in girls but not in boys) and a tendency toward higher B-Hb (130 vs. 128 g/liter, P = 0.06) than their controls. No difference was observed in leukocyte or thrombocyte counts between the study groups. In linear regression models including age, sex, body mass index SD score, IGF-I, and DHEAS or testosterone, B-Hb was associated with serum DHEAS (P = 0.04), testosterone (P = 0.01), and IGF-I (P ≤ 0.003) concentrations in the entire study cohort and with IGF-I separately in girls (P ≤ 0.02). Similar models showed a significant association of blood erythrocyte count with serum IGF-I concentration (P = 0.003-0.049) but not with DHEAS or testosterone. Increased erythrocyte count in PA girls suggests that relatively small increases in serum androgen or IGF-I concentrations during adrenarche may associate with enhanced erythropoiesis.

OR06-1 Physiological low-oxygen tension mediates the Insulin-Like Growth Factor (IGFs) induced signal transduction in Placental Mesenchymal Stem Cell (PMSC) towards enhanced multipotency via polycomb group proteins

of the GH signaling pathway impact on the serum levels of IGF-I after 12 months of GHRT. Patients and methods: 313 consecutive GHD subjects (89.8 % adult onset, 58.1 % men; mean age 49.7 yrs, mean BMI 28.1 kg/m) were studied before and after 12 months of GHRT. GH dose was individually tailored to normalize serum IGF-I and body composition. Using a candidate-gene approach, 6 single-nucleotide polymorphisms (SNPs) in 5 genes within or downstream of the GH signaling pathway were genotyped using either Sequenom or TaqMan SNP genotyping. Results: Minor allele frequencies (MAF) are presented in Table 1. At baseline, in linear regression analysis adjusted for sex, SNPs rs6503691 and rs361072 were associated with height (p =0.016 and p =0.032 respectively). In multiple regression analyses adjusted for sex, age and the GH dose at 12 months of GHRT, SNP rs11107116 was significantly associated with serum levels of IGF-I (p=0.028; for each added T-allele there was a 20.8 mg/L increase in serum IGF-I).

Short-term growth hormone or IGF-I administration improves the IGF-IGFBP system in arthritic rats

ObjectiveAdjuvant-induced arthritis is an experimental model of rheumatoid arthritis that inhibits the GH-IGF-I axis and decreases body weight gain and muscle mass. Although chronic GH or IGF-I treatment increases body weight gain in arthritic rats, muscle resistance to GH and IGF-I is a very common complication in inflammatory diseases. In this study we examine the effect of short-term administration of rhGH and rhIGF-I on liver and muscle IGF-I, IGFBP-3 and −5 as well as on the ubiquitin-ligases MuRF1 and atrogin-1 in the muscle of arthritic rats. DesignArthritis was induced in adult male Wistar rats by an intradermal injection of 4mg of Freund's adjuvant. Fifteen days after adjuvant injection, 300μg/kg of rhGH or 200μg/kg of rhIGF or saline was administrated 18 and 3h before decapitation. A pair-fed group injected with saline was included in order to discard a possible effect of decreased food intake. Gene expression of IGF-I, GHR, IGFBP-3, IGFBP-5, atrogin-1 and MuRF1 were quantified using RT-PCR. In serum, IGF-I was measured by radioimmunoassay (RIA) and IGFBP-3 by ligand blot. ResultsArthritis decreased serum IGF-I and IGF mRNA in liver (P<0.05), but not in skeletal muscle. In arthritic rats, rhGH increased serum IGF-I and liver IGF-I mRNA similar to the levels of pair-fed rats. Arthritis increased atrogin-1, MuRF1, IGFBP-3 and IGFBP-5 mRNA in muscle (P<0.01). IGFBP-3 mRNA was downregulated by rhIGF-I, but not by rhGH, administration in control and arthritic rats (P<0.05). Administration of rhGH and rhIGF-I increased IGFBP-5 in the gastrocnemius of arthritic rats. ConclusionsShort-term rhGH and rhIGF-I administration was found to increase muscle IGFBP-5 mRNA, whereas only rhIGF-I administration decreased muscle IGFBP-3 mRNA in control and arthritic rats. These data suggest that arthritis does not induce GH or IGF-I resistance in skeletal muscle.

Effects of intensive glycemic control on serum levels of insulin-like growth factor-I and dehydroepiandrosterone sulfate in Type 2 diabetes mellitus.

Although accumulating evidence shows that aging hormones are involved in glucose metabolism, effects of glycemic control on serum IGF-I and DHEAS levels are still unclear. To investigate the effects of glycemic control on these hormone levels, we conducted a 1-month longitudinal study of 49 Japanese patients with Type 2 diabetes mellitus. We measured serum levels of IGF-I and DHEA-S before and after 1-month glycemic control and analyzed the association of changes in IGF-I and DHEA-S with glycated hemoglobin (HbA1c). HbA1c was decreased at 1 month with mean changes of -1.2% (p<0.001). Serum IGF-I was increased with mean changes of 11 ng/ml (p<0.05), while serum DHEA-S was decreased with mean changes of -19 μg/dl (p<0.05). Multiple regression analysis showed that changes in DHEA-S were inversely associated with changes in fasting plasma glucose (β=-0.36, p=0.027) and HbA1c (β=-0.33, p=0.028), while changes in IGF-I were not. The present longitudinal study showed that intensive glycemic control for 1 month increased serum IGF-I level and decreased serum DHEA-S level in Japanese patients with poorly controlled Type 2 diabetes. Further studies are needed to clarify the hormonal changes in IGF-I and DHEA-S after intensive glycemic control would affect diabetic complications.

Serum IGF-I Is Not a Reliable Pharmacodynamic Marker of Exogenous Growth Hormone Activity in Mice

Serum IGF-I is a well-established pharmacodynamic marker of GH administration in humans and has been used for this purpose in animal studies. However, its general suitability in wild-type laboratory mice has not been demonstrated. Here we show that treatment with recombinant human GH (rhGH) in four different strains of laboratory mice increases body weight, lean body mass, and liver weight but does not increase hepatic expression and release of IGF-I. In contrast and as expected, hypophysectomized rats show a rapid increase in serum IGF-I after rhGH administration. The lack of IGF-I up-regulation in mice occurs despite hepatic activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and is not explained by GH dose, route of administration, origin of GH (i.e. recombinant human, bovine, and murine GH), treatment duration, genetic background, sex, or formation of neutralizing antibodies. Effects on other components of the GH/IGF pathway were highly influenced by genetic background and sex but not consistently affected by rhGH treatment. We conclude that IGF-I is not a reliable indicator of the biological effects of exogenous GH treatment in genetically and pharmacologically unmodified mice. We speculate that IGF-I release is already maximal in these animals and cannot be further increased by exogenous GH treatment. This is also suggested by the observation of restored IGF-I up-regulation in isolated murine hepatocytes after rhGH treatment. Total body weight, lean body mass, and liver weight may be more reliable phenotypic indicators in these models.

Targeted Deletion of Somatotroph Insulin-Like Growth Factor-I Signaling in a Cell-Specific Knockout Mouse Model

The role of IGF-I in the negative regulation of GH expression and release is demonstrated by in vitro and in vivo models; however, the targets and mechanisms of IGF-I remain unclear. We have developed a cell-specific knockout mouse in which the IGF-I receptor was ablated from the somatotroph in order to validate and characterize IGF-I negative regulation; we termed this the somatotroph IGF-I receptor knockout (SIGFRKO) mouse. The SIGFRKO mice demonstrated increased GH gene expression and secretion as well as increased serum IGF-I. Compensatory changes were noted with decreased GHRH and increased somatostatin mRNA expression levels. SIGFRKO mice had normal linear growth, but by 14 wk of age weighed significantly less than controls. Furthermore, metabolic studies revealed SIGFRKO mice had significantly less fat mass and body percent fat. These data support somatotroph IGF-I negative regulation and suggest that hypothalamic feedback limits the extent of GH release. The SIGFRKO mouse is a model delineating the mechanisms of IGF-I regulation in the hypothalamic-pituitary axis and demonstrates compensatory mechanisms that mediate growth and metabolic function in mammals.

Effects of ractopamine and sex on serum metabolites and skeletal muscle gene expression in finishing steers and heifers

We evaluated growth-related responses to ractopamine in steers and heifers. Sixteen Angus steers (512 kg) and 16 Angus heifers (473 kg) housed in individual pens were used in a complete block design. At 90 to 97 d before the experiment, steers were implanted with 120 mg of trenbolone acetate and 24 mg of estradiol-17beta (Component TE-S) and heifers were implanted with 140 mg of trenbolone acetate and 14 mg of estradiol-17beta (Component TE-H). Treatments were arranged as a 2 x 2 factorial and included sex (steer vs. heifer) and ractopamine-HCl (0 or 200 mg/d). Cattle were fed a diet based on steam-flaked corn once daily. Blood and LM and biceps femoris (BF) biopsy samples were collected on d 0 (before ractopamine feeding) and after 14 and 28 d of ractopamine feeding. Serum insulin concentrations were not affected by ractopamine or sex. Serum IGF-I concentrations were greater in steers than heifers (P < 0.001), and steers demonstrated greater IGF-I mRNA expression in BF than heifers (P = 0.05). Ractopamine decreased serum IGF-I concentrations in heifers on d 14, but increased serum IGF-I concentrations in steers on d 28 (sex x ractopamine x day interaction; P = 0.03). Ractopamine did not affect (P >or= 0.19) mRNA expression of IGF-I, IGFBP-3, or calpastatin in BF or LM. However, ractopamine led to increases in LM expression of IGFBP-5 in heifers, but to decreases in expression in steers (ractopamine x sex interaction; P = 0.04). Ractopamine decreased myosin heavy chain IIA mRNA expression in BF (P = 0.04) but not in LM (P = 0.99). Ractopamine decreased beta(2)-receptor mRNA expression in LM of steers on d 14, but not on d 28; in contrast, expression of beta(2)-receptor mRNA in LM of heifers was not affected by ractopamine (sex x ractopamine x day interaction; P = 0.03). Although there were a few criteria for which ractopamine led to differences in response between steers and heifers, there were no striking disparities to suggest that the effectiveness of ractopamine would markedly differ between sexes.

The effect of different patterns of growth hormone administration on the IGF axis and somatic and skeletal growth of the dwarf rat

Normal childhood growth is determined by ultradian and infradian variations in GH secretion, yet GH treatment of children with short stature is restricted to daily fixed doses. We have used GH-deficient dwarf rats to determine whether variable GH dose regimens promote growth more effectively than fixed doses. Animals were treated with saline or 4.2 mg of recombinant bovine GH given as 1) 700 microg/wk in 100 microg/day doses, 2) alternating weekly doses of 966 (138 microg/day) or 434 microg (62 microg/day), or 3) 700 microg/wk in randomized daily doses (5-250 microg/day). Body weight and length were measured weekly. Femur and tibia lengths and internal organ, fat pad, and muscle weights were recorded at the end of the study (6 wk); blood was collected for IGF axis measurements. GH promoted femur [F(3,60) = 14.67, P < 0.05], tibia [F(3,60) = 14.90, P < 0.05], muscle [F(3,60) = 10.37, P < 0.05], and organ growth [liver: F(3,60) = 9.30, P < 0.05; kidney: F(3,60) = 2.82, P < 0.05] and an increase in serum IGF-I [F(3,60) = 9.18, P < 0.05] and IGFBP-3 [F(3,60) = 6.70, P < 0.05] levels. IGF-I levels correlated with final weight (r = 0.45, P < 0.05) and length (r = 0.284, P < 0.05) in the whole cohort, but within each group, growth parameters correlated with serum IGF-I only in animals treated with random GH doses. The variable regimens promoted femur length (P < 0.05) and muscle (P < 0.05) and kidney (P < 0.05) weight more effectively than treatment with the fixed regimen. This study demonstrates that aspects of growth are improved following introduction of infradian variation to GH treatment in a GH-deficient model. The data suggest that varying the pattern of GH doses administered to children may enhance growth performance without increasing the overall GH dose.

Hormonal influences of early postnatal indomethacin and ibuprofen in neonatal rats

Objective Indomethacin and ibuprofen are administered to preterm neonates for symptomatic patent ductus arteriosus. The drugs suppress prostaglandins (PGs) which modulate growth and secretion of various hormones. We examined the hypothesis that early postnatal indomethacin and ibuprofen influence growth and GH-IGF-I-insulin and HPA axes in neonatal rats. Design Rat pups received IP injections of saline (Sal) on P1, P2, and P3; 10 mg/kg ibuprofen on P1 followed by 5 mg/kg on P2 and P3; or 0.2 mg/kg indomethacin on P1 followed by 0.1 mg/kg on P2 and P3. Serum and hepatic GH, GHBP and IGF-I; and serum corticosterone and insulin levels were determined. Results Ibuprofen suppressed somatic growth in the sucking rats, but the effect was transient, resolving by P14. Indomethacin had an opposite, latent effect on body weight and liver to body weight ratios in weanling rats. Both indomethacin and ibuprofen had profound hormonal effects that differed in magnitude and timing. Indomethacin resulted in a sustained elevation in corticosterone levels at P21, while ibuprofen increased serum and hepatic GH levels. Both drugs suppressed GHBP in serum at P7 and P14; and liver at P4 and P7, but a rebound increase in serum GHBP was noted at P21 with Ibuprofen only. Both drugs increased serum IGF-I at P7. The effect remained sustained with indomethacin. Conclusions These results provide evidence for an involvement of PGs in the regulation of growth as well as the GH-IGF and HPA axes. Therefore, early postnatal exposure to PG inhibitors may further exacerbate postnatal growth restriction and ability to cope with stress.

A Pharmacokinetic and Dosing Study of Intravenous Insulin-Like Growth Factor-I and IGF-Binding Protein-3 Complex to Preterm Infants

In preterm infants, low levels of insulin like growth factor 1 (IGF-I) have been associated with impaired growth and retinopathy of prematurity. Our objective was to study safety and pharmacokinetics of i.v. administered rhIGF-I with its binding protein 3 (rhIGFBP-3) to preterm infants. At 3 d chronological age, an i.v. 3 h infusion of rhIGF-I/rhIGFBP-3 was administered followed by serial measurements of IGF-I and IGFBP-3. Infants were evaluated for physiologic safety measurements. The individual dose of rhIGF-I ranged from 1 to 12 microg/kg. The study was conducted at Queen Silvia Children's Hospital, Gothenburg, Sweden, between January and November 2007. Five patients (3 F) with mean (range) post menstrual age 27 wk (26-29) and birth weight 1022 g (810-1310) participated. IGF-I and IGFBP-3 levels before infusion were median (range) 18 (12-28) and 771 (651-1047) ng/mL, respectively. Immediately after study drug infusion, serum IGF-I and IGFBP-3 levels were 38 (25-59) and 838 (754-1182) ng/mL, respectively. Median (range) half-life for IGF-I and IGFBP-3 was 0.79 (0.59-1.42) and 0.87 (0.85-0.94) hours, respectively. Blood glucose, insulin, sodium, potassium, and physiologic safety measures were within normal ranges. The rhIGF-I/rhIGFBP-3 equimolar proportion was effective in increasing serum IGF-I levels and administration under these study conditions was safe and well tolerated.

Dietary Supplementation with Dried Plum Prevents Ovariectomy‐Induced Bone Loss in C57BL/6 Mice and Modulates the Immune Response

Due to recent evidence demonstrating the link between the immune system and skeletal health, this study was designed to determine the osteoprotective effects of dried plum (DP) on bone metabolism and the immune response. Twelve‐week old female mice (n=59) were assigned to 5 treatment groups for a duration of 4 wks: sham‐operated (Sham) control diet (AIN‐96M), ovariectomized (OVX)‐control diet and OVX animals receiving diet supplemented with 5%, 15%, or 25% DP (w/w). Bone mineral density and content of the spine was decreased (8%) by OVX, which was totally prevented by 25% DP. µCT analyses revealed the OVX compromise in spine and proximal tibial bone volume was prevented by higher doses of DP. Similar results were also observed in the trabecular number and thickness of the spine. Simulated biomechanical tests (finite element analyses) showed the improved structural properties observed with DP (15% &amp; 25%) resulted in enhanced bone strength and stiffness. These alterations in bone mass and architecture coincided with increased serum IGF‐I and reduced bone turnover (i.e. serum PINP) in OVX mice consuming DP. Following ex vivo Con A stimulation, splenocyte TNF‐α production was suppressed by DP, but no change in IL‐6 occurred. This study supports DP's positive effects on bone in the OVX mouse model; however the role of the immune system in this response warrants further investigation. (Supported by California Dried Plum Board)Grant Funding SourceCalifornia Dried Plum Board

Abstract ED04-02: The role of genes in protecting against age-related disease in cancer

Abstract ED04-02 Despite evidence for a substantial genetic component, the inherited biological factors that promote extended life span (longevity) in humans remain unknown. We have comprehensively characterized over 450 Ashkenazi Jewish families with exceptional longevity (survival in good health to at least age 95) and have identified several biological markers that may be causative in their longevity. These subjects and their offspring have 2-3 fold increases in rates of polymorphism in 3 genes all validated by other in other studies. Two genes are regulating lipoprotein--cholesterol ester transfer protein (CETP) and apolipoprotein C-3 (APOC-3)--and decrease in plasma levels CETP and APOC-3. Another gene is Adiponectin (ADIPOQ) regulating insulin action and inflammation. We have also demonstrated that these genotypes and phenotypes are associated with less hypertension (HTN), cardiovascular disease (CVD) and metabolic syndrome (MS), and improved cognitive function. However, these genes have not been shown yet to protect against cancer. Modulation of GH/IGF-1 axis is conferring longevity in mamalians and low IGF-1 levels is associated with decreased rates of cancers in humans. We demonstrated a gender-specific increase in serum IGFI associated with a smaller stature in female offspring of centenarians. Sequence analysis of the IGF1 and IGF1 receptor (IGF1R) genes of female centenarians showed overrepresentation of heterozygous mutations in the IGF1R gene among centenarians relative to controls that are associated with high serum IGFI levels and reduced activity of the IGFIR as measured in transformed lymphocytes. Thus, genetic alterations in the human IGF1R that result in altered IGF signaling pathway confer an increase in susceptibility to human longevity, suggesting a role of this pathway in modulation of human lifespan, possibly by protecting against cancer. Citation Information: Cancer Prev Res 2008;1(7 Suppl):ED04-02.