Serum Insulin-like Growth factor-I Values Research Articles

A longitudinal study of serum insulin-like growth factor-I levels over 6 years in a large cohort of children and adolescents with type 1 diabetes mellitus: A marker reflecting diabetic retinopathy.

To evaluate longitudinal serum insulin-like growth factor-I (IGF-I) in a large cohort of children and adolescents with type 1 diabetes in relation to hemoglobin A1c (HbA1c), age, diabetes duration, and body mass index (BMI), its association to height and retinopathy, and in comparison with healthy subject references. A total of 2683 serum IGF-I values were obtained from 806 children and adolescents with T1DM, from annual blood samples for up to 6 consecutive years. In a multiple regression analysis IGF-I values were negatively correlated to HbA1c and diabetes duration, and positively correlated to BMI (P < .001, P < .001, and P < .001, respectively, adjusted r2 = 0.102). Children and adolescents with T1DM had lower mean IGF-I levels and reference interval limits compared to healthy subjects. In boys, mean (SD) IGF-I SD score (SDS) levels were -1.04 (±1.3) calculated from the healthy reference. IGF-I peaked at 15 years of age, similarly to healthy controls, but with markedly lower levels in late puberty. Girls were more affected at later stages of puberty but with a slightly less depressed overall mean IGF-I SDS of -0.69 (±1.2). In a subgroup of 746 subjects with fundus photography, a negative correlation was seen between individual mean IGF-I SDS and preproliferative retinopathy (P = .004, adjusted r2 = 0.021). In another subgroup of 84 adolescents, no correlation was seen between individual mean IGF-I SDS and target height SDS or distance to target height SDS. Poor metabolic control and diabetes duration impact negatively on serum IGF-I levels. A low individual mean IGF-I level was associated with progression of retinopathy independently of HbA1c, age, gender, and diabetes duration. Disease, sex and age related IGF-I SDS may become clinical helpful as a supplement to HbA1c in predicting the long-term outcome for children and adolescents with T1DM.

Prevalence of morphometric vertebral fractures in "difficult" patients with acromegaly with different biochemical outcomes after multimodal treatment.

Skeletal fragility with high risk of vertebral fractures is an emerging complication of acromegaly in close relationship with duration of active disease. The aim of this cross-sectional study was to evaluate the prevalence and determinants of vertebral fractures in males and females with a history of long-standing active acromegaly undergoing treatment with Pegvisomant. Thirty-eight patients (25 females, 13 males) with acromegaly under Pegvisomant therapy were evaluated for vertebral fractures and bone mineral density at lumbar spine and femoral neck. Gonadal status, serum IGF1 levels and growth hormone receptor genotype were also assessed. Vertebral fractures were detected in 12 patients (31.6%). Fractured patients had longer duration of active disease (p = 0.01) with higher frequency of active acromegaly (p = 0.04), received higher dose of Pegvisomant (p = 0.008), and were more frequently hypogonadic (p = 0.02) as compared to patients who did not fracture. Stratifying the patients for gender, vertebral fractures were significantly associated with Pegvisomant dose (p = 0.02) and untreated hypogonadism (p = 0.02) in males and with activity of disease (p = 0.03), serum insulin-like growth factor-I values (p = 0.01) and d3GHR polymorphism (p = 0.005) in females. No significant association was found between vertebral fractures and bone mineral density at either skeletal site. Vertebral fractures are a frequent complication of long-standing active acromegaly. When patients are treated with Pegvisomant, vertebral fractures may occur in close relationship with active acromegaly and coexistent untreated hypogonadism.

Alterations of growth plate and abnormal insulin-like growth factor I metabolism in growth-retarded hypokalemic rats: effect of growth hormone treatment

Hypokalemic tubular disorders may lead to growth retardation which is resistant to growth hormone (GH) treatment. The mechanism of these alterations is unknown. Weaning female rats were grouped (n = 10) in control, potassium-depleted (KD), KD treated with intraperitoneal GH at 3.3 mg x kg(-1) x day(-1) during the last week (KDGH), and control pair-fed with KD (CPF). After 2 wk, KD rats were growth retarded compared with CPF rats, the osseous front advance (+/-SD) being 67.07 +/- 10.44 and 81.56 +/- 12.70 microm/day, respectively. GH treatment did not accelerate growth rate. The tibial growth plate of KD rats had marked morphological alterations: lower heights of growth cartilage (228.26 +/- 23.58 microm), hypertrophic zone (123.68 +/- 13.49 microm), and terminal chondrocytes (20.8 +/- 2.39 microm) than normokalemic CPF (264.21 +/- 21.77, 153.18 +/- 15.80, and 24.21 +/- 5.86 microm). GH administration normalized these changes except for the distal chondrocyte height. Quantitative PCR of insulin-like growth factor I (IGF-I), IGF-I receptor, and GH receptor genes in KD growth plates showed downregulation of IGF-I and upregulation of IGF-I receptor mRNAs, without changes in their distribution as analyzed by immunohistochemistry and in situ hybridization. GH did not further modify IGF-I mRNA expression. KD rats had normal hepatic IGF-I mRNA levels and low serum IGF-I values. GH increased liver IGF-I mRNA, but circulating IGF-I levels remained reduced. This study discloses the structural and molecular alterations induced by potassium depletion on the growth plate and shows that the lack of response to GH administration is associated with persistence of the disturbed process of chondrocyte hypertrophy and depressed mRNA expression of local IGF-I in the growth plate.

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.

Minimally Invasive Sampling of Transdermal Body Fluid for the Purpose of Measuring Insulin-Like Growth Factor-I During Exercise Training

Insulin-like growth factor-I (IGF-I) is a ubiquitous hormone that is secreted in both an endocrine and an autocrine/paracrine manner. IGF-I has conventionally been measured in serum; however, transdermal body fluid (TDF) remains as an unexplored biocompartment in which IGF-I also resides and may be more biologically relevant because of its proximity to tissues and cells. The purpose of this study was to compare IGF-I in serum versus IGF-I in TDF before and after 8 weeks of physical training. Twenty-eight healthy men (28 +/- 5 years old, 176 +/- 8 cm tall, weighing 83 +/- 11 kg) had TDF obtained by a novel, minimally invasive method that included the application of continuous vacuum pressure on forearm skin perforated with tiny micropores created by a focused beam from a laser system and also had blood obtained by venipuncture. An enzyme-linked immunosorbent assay measured total IGF-I concentrations. A repeated-measures analysis of variance (biocompartment x time) and Pearson Product Moment Correlation coefficients (P < or = 0.05) were used for statistical analyses. Data are presented as mean +/- SE. Total TDF IGF-I was significantly lower than serum IGF-I both before (TDF, 91 +/- 6 ng/mL; serum, 375 +/- 17 ng/mL) and after (TDF, 83 +/- 5 ng/mL; serum, 363 +/- 19 ng/mL) the exercise training. Serum and TDF IGF-I values were not significantly different pre- to post-training. Serum and TDF IGF-I levels were significantly correlated pre-training (r = 0.41), but not post-training (r = 0.34). The percent change between serum and TDF was not correlated (r = 0.09). This study has demonstrated that total IGF-I can be sampled and measured in TDF via a minimally invasive manner and is appreciably (approximately 76%) less than total IGF-I measured in serum. Additionally, the IGF-I measurements in these two biocompartments were not closely associated, possibly indicating an uncoupled, rather than a linked, regulation of IGF-I among the body's biocompartments.

Body mass index, waist circumference and waist–hip ratio and serum levels of IGF-I and IGFBP-3 in European women

To examine the relationship between body mass index (BMI) and waist-hip ratio (WHR) with serum levels of insulin-like growth factor-I (IGF-I), and its binding protein (IGFBP)-3. Cross-sectional study on 2139 women participating in a case-control study on breast cancer and endogenous hormones. Data on lifestyle and reproductive factors were collected by means of questionnaires. Body height, weight, waist and hip circumferences were measured. Serum levels of IGF-I and insulin-like binding protein (IGFBP)-3 were measured by enzyme-linked immunosorbent assays. Adjusted mean levels of IGF-I and IGFBP-3 across quintiles of BMI, waist circumference, and WHR were calculated by linear regression. Results were adjusted for potential confounders associated with IGF-I and IGFBP-3. Adjusted mean serum IGF-I values were lower in women with BMI<22.5 kg/m(2) or BMI>29.2 kg/m(2) compared to women with BMI within this range (P(heterogeneity)<0.0001, P(trend)=0.35). Insulin-like growth factor-I was not related to WHR after adjustment for BMI. IGF-binding protein-3 was linearly positively related to waist and WHR after mutual adjustment. The molar ratio IGF-I/IGFBP-3 had a non-linear relation with BMI and a linear inverse relationship with WHR (P (trend)=0.005). Our data confirm the nonlinear relationship of circulating IGF-I to total adiposity in women. Serum IGFBP-3 was positively related to central adiposity. These suggest that bioavailable IGF-I levels could be lower in obese compared to non-obese women and inversely related to central adiposity.

Postnatal serum insulin-like growth factor I deficiency is associated with retinopathy of prematurity and other complications of premature birth.

Insulin-like growth factor I (IGF-I) is necessary for normal development of retinal blood vessels in mice and humans. Because retinopathy of prematurity (ROP) is initiated by abnormal postnatal retinal development, we hypothesized that prolonged low IGF-I in premature infants might be a risk factor for ROP. We conducted a prospective, longitudinal study measuring serum IGF-I concentrations weekly in 84 premature infants from birth (postmenstrual ages: 24-32 weeks) until discharge from the hospital. Infants were evaluated for ROP and other morbidity of prematurity: bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC). Low serum IGF-I values correlated with later development of ROP. The mean IGF-I +/- SEM level during postmenstrual ages 30-33 weeks was lowest with severe ROP (25 +/- 2.41 micro g/L), 29 +/- 1.76 micro g/L with moderate ROP, and 33 +/- 1.72 micro g/L with no ROP. The duration of low IGF-I also correlated strongly with the severity of ROP. The interval from birth until serum IGF-I levels reached >33 micro g/L was 23 +/- 2.6 days for no ROP, 44 +/- 4.8 days for moderate ROP, and 52 +/- 7.5 days for severe ROP. Each adjusted stepwise increase of 5 micro g/L in mean IGF-I during postmenstrual ages 30 to 33 weeks decreased the risk of proliferative ROP by 45%. Other complications (NEC, BPD, IVH) were correlated with ROP and with low IGF-I levels. The relative risk for any morbidity (ROP, BPD, IVH, or NEC) was increased 2.2-fold (95% confidence interval: 1.41-3.43) if IGF-I was <or=33 micro g/L at 33 weeks' postmenstrual age. These results indicate that persistent low serum concentrations of IGF-I after premature birth are associated with later development of ROP and other complications of prematurity. IGF-I is at least as strong a determinant of risk for ROP as postmenstrual age at birth and birth weight.

The hypothalamus–pituitary function after pituitary stereotactic radiosurgery: evaluation of growth hormone deficiency

Radiation therapy to the pituitary gland means a considerable risk of developing hypopituitarism. The aim of the study was to investigate the growth hormone releasing hormone (GHRH)-growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis after treatment with stereotactic radiosurgery to the pituitary because of Cushing's disease. Inpatient ward in university clinic. Eleven adult patients (eight women, three men), 20-65 years of age were studied 2.5-11.3 years after stereotactic radiosurgery (isocentre dose 50-100 Gy lesion-1) and compared with healthy controls. Spontaneous GH secretion was evaluated as 12-h night GH profiles. Stimulated GH responses were evaluated in seven of 11 patients using arginine-insulin and GHRH tests. Serum IGF-I levels were measured in fasting serum morning samples. All patients except one displayed blunted nocturnal GH profiles. After arginine-insulin challenge, six of seven patients displayed low GH release. GH response was higher after GHRH injection compared with both the response to arginine-insulin and to the maximum GH levels in the nocturnal profiles. Seven patients had an IGF-I standard deviation score (SDS) within the normal range for age. Serum IGF-I values were correlated to mean GH values in the 12-h night profile (r = 0.67, P < 0.05) and both these variables were negatively correlated to time elapse since last radiation treatment (r = -0.64, P < 0.05 and r = -0.78, P < 0.05, respectively). Our patients with Cushing's disease evaluated several years after stereotactic radiosurgery as the primary and only treatment, demonstrated severely blunted spontaneous GH secretion and GH response to arginine-insulin. A disturbed regulation at the hypothalamic level was suggested as mechanism for this. Noteworthy is that serum IGF-I values correlated to the mean values of the 12-h GH profile.

Leptin binding activity (LBA) in plasma of nondiabetic and diabetic adolescents and obese children: relation to auxologic and hormonal data.

Leptin circulates in serum bound to high molecular weight proteins. Hypothesizing that leptin binding proteins may regulate the functional efficiency of leptin, we characterized auxologic and hormonal factors that influence leptin binding in three disparate groups: normal adolescents, obese children, and teenagers with type I diabetes mellitus (IDDM). Specific leptin binding activity (sLBA) was assessed by column chromatography after incubation of serum with 125I-leptin in the presence and absence of excess unlabeled leptin. Mean sLBA was 17.0 +/- 7% (SD) in the healthy adolescents (n=41), 6.6 +/-4.3% in the obese children (n=26), and 14.9 +/-7.3% in the diabetic teenagers (n=17). At any value of sLBA, obese children had higher serum leptin levels than non-obese adolescents or diabetic teenagers, consistent with "leptin resistance" in the obese group. sLBA was higher in males than in females only in those with diabetes (18.6 +/- 7.3 vs 10.9 +/- 5.1%, p<0.05). sLBA correlated inversely with serum insulin-like growth factor-I values in the normal group (r= -0.45, p<0.01) and with insulin in the obese children (r= -0.53, p<0.01). There was no correlation between sLBA or serum leptin values and HbA1c, in the diabetic group. The serum leptin concentration was the principal determinant explaining the total variability of sLBA in all three cohorts. However, body mass index (BMI = weight/ height2) accounted for more of the total variability of percent specific binding in the healthy adolescents than in the other groups. We conclude that sLBA reflects circulating leptin levels, body composition, and hormonal milieu. Thus, in addition to leptin, qualitative and quantitative characteristics of leptin binding may play a physiological role in the regulation of appetite and in the "leptin resistance" of obesity.

Insulin-like growth factor-I and binding protein-3 in relation to childhood leukaemia.

The aetiology of most cases of childhood leukaemia remains unknown, but several studies have indicated that increased birthweight and height are risk factors for the disease. Since insulin-like growth factor-I (IGF-I) mediates the effect of growth hormone and has been positively associated with prostate cancer, we have evaluated the role of this hormone and its principal binding protein, IGFBP-3, in the aetiology of childhood leukaemia. Incident cases of childhood leukaemia from those recorded by a national network of childhood oncologists were enrolled in our study. Controls were children hospitalised for acute conditions of no more than moderate severity with matching for gender, age and maternal place of residence. Blood measurements of IGF-I and IGFBP-3 were undertaken using commercially available radioimmunoassays. Serum IGF-I values decreased by about 1.7% per month, and the rate of decline was higher, though not significantly so, among cases (2.1% per month) than among controls (1.4%). There was no significant association between IGF-I and the likelihood of childhood leukaemia, but an increment of 1 microg/ml of IGFBP-3 was associated with a substantial and statistically significant reduction of childhood leukaemia by 28% (95% confidence interval 7% to 45%). Because IGFBP-3 is essentially a binding protein, we interpret our findings as indicating that bioavailable IGF-I may play an important role in the aetiology of childhood leukaemia. The much smaller quantities and the inherent instability of IGF-I in the blood in comparison to those of IGFBP-3 are likely to hinder documentation of an underlying positive association of IGF-I with the disease.

Growth hormone--insulin-like growth factor-I (IGF-I) axis in prepubertal children with chronic renal failure.

The hypothalamic-pituitary insulin-like growth factor I (IGF-I) axis was evaluated in 12 children with chronic renal failure (CRF) aged 3.2 to 16.5 yr (mean 9.5) on chronic dialysis, and in 13 renal transplantation patients aged 7.5 to 15.0 yr (mean 11.1). Height standard deviation score (SDS) was -2.8 +/- 0.5 (mean +/- SE) and -3.0 +/- 0.3 SDS (p = NS), and growth velocity was 3.7 +/- 0.4 and 1.5 +/- 0.3 cm/year (p < 0.01), respectively. Mean nocturnal growth hormone (mean GH) and number of pulses > 5 ng/ml in CRF and transplantation children were 4.2 +/- 0.8 vs 2.4 +/- 0.3 ng/ml, p = 0.08 and 1.7 +/- 0.2 vs 1.0 +/- 0.2, p < 0.05, respectively. In transplant children there was a positive correlation between mean GH and growth velocity (p < 0.02). GH peak response and the area under the curve post GH releasing hormone test were significantly higher in CRF and transplant children treated with deflazacort (new steroid derived from prednisolone) vs transplant children treated with methylprednisone. Mean serum IGF-I levels were -0.5 +/- 0.2 SDS for chronological age (CA) in CRF patients and +0.8 +/- 0.2 SDS(CA) in transplant patients, p = NS. In the latter, serum IGF-I values were positively correlated with growth velocity (p < 0.02) and negatively correlated with methylprednisone dose (p < 0.05). Patients with CRF and growth retardation have a higher number of GH peaks and slightly elevated mean GH levels compared to transplant patients. After renal transplantation GH secretion may be influenced by glucocorticoids as shown by the lower GH response to GHRH which improved with deflazacort and the inverse correlation between methylprednisone dose and IGF-I levels.

Postnatal Variations of Growth Hormone Bioactivity and of Growth Hormone-Dependent Factors

To evaluate whether the low insulinlike growth factor I (IGF-I) levels that are observed in the neonate depend on the biological inactivity of the molecular forms of growth hormone (GH) or on the immaturity of the hepatic GH receptors during the early postnatal period. Serum samples were collected from 60 normal full-term neonates on day 5 and at 1 and 4 months of age to evaluate the GH concentrations by using both an immunofluorometric assay and Nb2 cell bioassay, as well as the GH-binding protein, IGF-I, and IGF-binding protein 3 values by radioimmunoassay. Five-day-old neonates showed significantly higher (P < .001) mean +/- SEM GH levels that were measured by using the immunofluorometric assay (27.22 +/- 1.62 micrograms/L) and Nb2 cell bioassay (3.56 +/- 0.14 U/mL) compared with those levels in 11 prepubertal children who were studied as control subjects (1.26 +/- 0.28 micrograms/L and 0.74 +/- 0.08 U/mL, respectively). At 1 and 4 months of age, GH values that were measured by using both the immunofluorometric assay (9.15 +/- 0.89 and 2.58 +/- 0.32 micrograms/L, respectively) and Nb2 cell bioassay (2.52 +/- 0.11 and 1.71 +/- 0.15 U/mL, respectively) were decreased significantly (P < .001). In 5-day-old neonates, we observed significantly lower (P < .001) serum GH-binding protein (9.73% +/- 0.42%), IGF-I (67.63 +/- 5.20 ng/mL), and IGF-binding protein 3 (1.46 +/- 0.17 mg/L) concentrations compared with those in the prepubertal children (30.74% +/- 2.01%, 210 +/- 25 ng/mL, and 3.08 +/- 0.22 mg/L, respectively). At 1 month of age, serum GH-binding protein (16.00% +/- 0.70%) and IGF-binding protein 3 (2.96 +/- 0.30 mg/L) values were increased significantly (P < .001), while IGF-I levels (72.55 +/- 7.6 ng/mL, P = .09) were not increased. Serum IGF-I values were increased significantly (P < .005) at 4 months of age (97.94 +/- 9.68 ng/mL). The interaction of bioactive molecular forms of GH with the increased hepatic GH receptors induces the rise in postnatal IGF-I levels in early infancy.

The ontogeny of serum insulin-like growth factor-I concentration in foals: Effects of dam parity, diet, and age at weaning

The effects of dam parity, age at weaning, and preweaning diet were examined in the ontogeny of serum insulin-like growth factor-I (IGF-I) concentrations in foals. Foals born to 13 primiparous and 19 multiparous draft-cross mares were weighed and bled near birth. About one-half of the foals in each group were weaned early (about 13 wk old); the remaining foals were weaned late (about 16 wk of age). Pooled values for serum IGF-I concentrations between birth and 17 wk of age were higher (P < 0.065) for foals born to multiparous (386 ng/ml) than to primiparous mares (237.5 ng/ml). Colts (378 ng/ml) had higher (P < 0.05) serum IGF-I concentrations than fillies (254.5 ng/ml), regardless of dam parity. Colts (173.5 kg) also tended (P = 0.12) to be heavier than fillies (159.2 kg). Weaning, whether at 13 or 16 wk of age, reduced (P < 0.05) growth rates and serum IGF-I concentrations. Serum IGF-I values recovered to preweaning values within 1–3 wk postweaning concurrent to an improved weight gain. Fifteen 1-d-old foals in a second study were fed milk replacer for 7 wk and were compared with five foals that nursed their mares for 8 wk. During the first 2 wk, replacer-fed foals (0.46 kg/d) did not gain as rapidly (P < 0.03) as mare-nursed foals (1.73 kg/d). The associated serum IGF-I values for replacer foals (139.4 ng/ml) were lower (P < 0.0001) than values for mare-nursed foals (317.4 ng/ml). Despite similarity in gains for both groups thereafter, serum IGF-I concentrations of replacer-fed foals were only 36 and 60% of values obtained for mare-nursed foals at 8 (weaning) and 18 wk of age, respectively. The intrinsic differences between mare-nursed and milk-replacer foals in serum IGF-I concentrations persisted to 1 yr of age despite similarities in dietary management and body weight of the foals. At 1 yr of age, the serum IGF-I concentration of mare-nursed foals (1,203 ng/ml) was 48% higher than that of replacer-fed foals (815 ng/ml). These data indicate that dam parity, sex of foal, and preweaning nutrition affect the ontogeny of serum IGF-I concentration in the foal. The chronic, persistent difference in serum IGF-I values created by the early nutritional management of growing animals has implications in the interpretation of longitudinal serum IGF-I studies in all species.

Decreased serum levels of nutritional biochemical indices in healthy children with marginally delayed physical growth.

Biochemical markers of nutritional status (albumin, transthyretin, insulin-like growth factor-I and zinc) were measured in slowly growing two- to five-year-old, low-income Parisian children whose weight-for-height or height-for-age z scores (WHZ or HAZ) were between -1 and -2 SD of the NCHS median. The results were compared to controls who were matched for age, sex, and ethnic origin with WHZ and HAZ between -1 and +2 SD. Mean serum levels of transthyretin, albumin and insulin-like growth factor-I and mean plasma zinc concentrations were significantly lower in the growth-impaired children than in the controls (p = 0.002, p = 0.006, p = 0.015, and p = 0.035, respectively). While the height-retarded children had low mean serum insulin-like growth factor-I values, the weight-retarded subjects had decreased levels of albumin, transthyretin and zinc when compared to controls. Lower mean levels of nutritional markers in healthy, slowly growing children suggest that inadequate dietary intakes of zinc, protein and/or energy may result in marginal delays in weight and height gains.

Chromatin changes accompany the developmental activation of insulin-like growth factor I gene transcription.

Insulin-like growth factor I (IGF-I) is a potent regulator of postnatal growth in mammals, yet little is known about the developmental control of IGF-I synthesis. We have investigated the regulation of IGF-I expression in the rat in order to gain insight into the mechanisms of growth factor induction during early postnatal life. Steady-state levels of liver IGF-I mRNA increased by more than 15-fold during the period from fetal day 18 to postnatal day 7 and reached 50% of adult values by day 14. Transcription run-on experiments using isolated hepatic nuclei and direct analysis of nuclear RNA each demonstrated a comparable rise in nascent IGF-I mRNA over the same time period. Over 90% of transcripts were directed by promoter 1, the more 5' of the two IGF-I gene promoters. By contrast IGF-II gene transcription rates and mRNA levels fell during the first 3 weeks after birth, and albumin expression rose slightly. Analysis of chromatin structure around the IGF-I gene revealed 15 DNase I-hypersensitive sites in adult rat liver in the 120 kilobases (kb) comprising the 6 exon gene and its flanking regions (8 sites within 10 kb at the 5'-end including exons 1-3, 5 sites in the 50-kb third intron, and 2 sites in the 15-kb fifth intron). During development there was a progressive appearance of DNase I-hypersensitive sites that coincided with activation of IGF-I gene expression. One site that became fully hypersensitive by postnatal day 7 was mapped by in vivo DNAse I footprinting to the proximal 200 nucleotides of promoter 1. Since serum IGF-I values rose from 10 to 120 micrograms/liter during the initial postnatal week, these results indicate that transcriptional mechanisms are principally responsible for the stimulation of IGF-I synthesis that occurs shortly after birth. Because discrete changes in chromatin organization coincided with induction of IGF-I gene transcription, it is likely that a series of developmentally modulated transcription factors are involved the activation process.

Expression of Insulin-Like Growth Factor-I during Chicken Development*

We have investigated the expression of insulin-like growth factor-I (IGF-I) during ontogeny in the chick. IGF-I mRNA was first detectable in whole embryos on day 6, while serum IGF-I could be measured on day 9, the earliest time point examined. Serum IGF-I values rose 10-fold from about 3 ng/ml on day 10 to a prehatch peak of 30-35 ng/ml during days 15-17, and then declined to about 10 ng/ml at the time of hatching. On days 17 and 20 of incubation, IGF-I mRNA was detected in eye, skeletal muscle, and brain, but could not be found in liver or heart until after hatching. During the posthatch period, serum IGF-I rose from 10 ng/ml in the first week to 35-40 ng/ml during weeks 3-6, and liver IGF-I mRNA increased nearly 5-fold from weeks 1-7. The increases observed during weeks 1-3 correlated with a posthatch rise in serum GH from 21 to 37 ng/ml, although GH levels declined over the subsequent 4 weeks without an appreciable change in serum IGF-I values. By contrast, before embryonic day 12 no GH could be detected in the circulation, while IGF-I was 19 ng/ml on day 11. These observations suggest that there is both GH-dependent and GH-independent regulation of IGF-I gene expression in the chick, as has been found in mammals, and support the idea that IGF-I plays a role in chicken embryonic development.

Effect of Maternal Fasting on Fetal Growth, Serum Insulin-Like Growth Factors (IGFs), and Tissue IGF Messenger Ribonucleic Acids*

Pregnant rats were fasted or allowed access to ad libitum feeds for the last 3 days of gestation to determine if the fetal growth retardation that results from maternal nutrient deprivation correlates with reductions in serum insulin-like growth factor-I (IGF-I) and IGF-II. In addition, IGF-I and IGF-II mRNA concentrations in liver and lung were measured by specific solution hybridization assays to determine if changes in steady state levels of mRNA correlate with changes in serum values. Fetal serum IGF-I concentrations were 30% lower in fasted than in control fetuses, although fasting did not significantly reduce the abundance of IGF-I mRNA in their livers or lungs. Serum IGF-I concentrations in the fasted dams were 34% lower than those in controls. IGF-I mRNA concentrations in the livers and lungs of the fasted dams were also lower than those in controls and correlated with serum IGF-I values (liver: r = 0.833; P less than 0.001; lung: r = 0.610; P less than 0.05). Therefore, whereas IGF-I appears to be transcriptionally regulated by fasting in dams, regulation of circulating IGF-I in fetuses may occur at a post-transcriptional step. Serum IGF-II and liver IGF-II mRNA concentrations were much higher than IGF-I levels in the fetuses and were not influenced by maternal fasting. Dam serum IGF-II concentrations were low compared to those in fetal serum and also were not reduced by fasting. We conclude that one mechanism by which maternal malnutrition causes intrauterine growth retardation is through decreased expression of IGF-I. On the other hand, short term nutrient restriction does not appear to be a regulator of IGF-II during either fetal or adult life.