Plasma Insulin-like Growth factor-I Concentrations Research Articles

Regulation of insulin-like growth factor-I (IGF-I) and IGF-binding proteins by tumor necrosis factor.

The purpose of the present study was to determine 1) whether exogenous administration of tumor necrosis factor-alpha (TNF-alpha) alters insulin-like growth factor-I (IGF-I) and IGF-binding proteins (BPs) and 2) whether the enhanced endogenous production of TNF mediates the lipopolysaccharide (LPS)-induced changes in the IGF system. The overnight infusion of murine TNF-alpha reduced circulating concentrations of both growth hormone (GH) and IGF-I in fasted rats. Furthermore, TNF-alpha decreased IGF-I content in liver, gastrocnemius muscle, and pituitary. In contrast, TNF-alpha increased IGF-I content in kidney and brain. IGFBP-1 was increased in plasma, liver, and muscle in response to TNF-alpha. In a second study, rats were injected with LPS after treatment with a neutralizing anti-TNF antibody (Ab), and blood and tissues were collected 4 h later. In LPS-treated rats, plasma concentrations of GH and IGF-I were reduced. LPS also decreased the IGF-I content in liver and skeletal muscle and increased plasma, liver, and muscle concentrations of IGFBP-1. Pretreatment with anti-TNF Ab attenuated the LPS-induced reduction in IGF-I and the increased IGFBP-1 in plasma and liver and completely prevented the decrease in IGF-I observed in muscle. In contrast, the LPS-induced decrease in plasma GH and the increased IGFBP-1 observed in muscle were unaltered by the anti-TNF Ab.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin-like growth factor binding proteins in prepubertal children with insulin-dependent diabetes mellitus

To study the possible role of insulin-like growth factor binding proteins (IGFBPs) in the discrepancy between normal or only slightly retarded growth and substantially reduced concentrations of insulin-like growth factor I (IGF-I) in prepubertal children with insulin-dependent diabetes mellitus (IDDM), we measured the plasma concentrations of IGF-I, IGFBP-1, IGFBP-2 and IGFBP-3 and free insulin in 24 prepubertal diabetic subjects and 12 control children. In addition, the growth hormone response to exercise was evaluated. The diabetic children had significantly decreased peripheral IGF-I levels (8.2 + 1.1 (SEM) vs 16.7 + 2.5 nmol/l; p < 0.001), whereas the concentrations of free insulin were increased (217 + 14 vs 103 + 21 pmol/l; p < 0.001). The concentrations of IGFBP-1 and IGFBP-3 were of the same magnitude in both groups. The diabetic children had significantly increased levels of IGFBP-2 (465 + 13 vs 416 + 14 micrograms/l; p = 0.029), which were inversely related to the circulating IGF-I levels (r = -0.35; p = 0.034). The diabetic and control children had comparable growth hormone responses to exercise. Diabetic children with poor glucose control had even lower IGF-I levels than those with moderate metabolic control (6.0 + 0.8 vs 10.3 + 1.7 nmol/l; p = 0.037). No differences could be observed in the plasma concentrations of various IGFBPs between these two groups of diabetic subjects. The absence in prepubertal diabetic children of increased IGFBP-1 levels observed in adolescent and adult patients with IDDM may contribute to their maintained linear growth, despite definitely decreased IGF-I concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Safety and efficacy of long-term octreotide therapy of acromegaly: results of a multicenter trial in 103 patients--a clinical research center study.

One hundred and three acromegalic patients from 14 medical centers were enrolled in this study to determine the efficacy and safety of the somatostatin analog, octreotide acetate, during long term treatment. Seventy percent of the patients had undergone previous surgery or radiation treatment. Octreotide was initiated at a dose of 100 micrograms, sc, every 8 h and gradually increased to a maximum of 1500 micrograms daily depending upon the individual patient's clinical and biochemical response [GH and insulin-like growth factor I (IGF-I) reduction]. The mean duration of treatment was 24 months (range, 3-30 months). However, most patients were treated for a mean of 30 months, because this study took place after an initial 6-month study previously reported. Mean serum GH fell from 30.9 micrograms/L (range, 2.7-350) to 5.7 micrograms/L (range, 0.6-59) at the 3 months visit and remained suppressed (P < 0.001). Plasma IGF-I concentrations were also significantly reduced and remained in the normal range for at least half of the treatment visits in 56 of 87 patients (64%) treated for 12-30 months. Patients with higher initial GH concentrations were less likely to normalize IGF-I concentrations during treatment (P < 0.001). There was no evidence of drug tachyphylaxis in those patients who continued taking stable doses of medication. With some exceptions, dose increments above 800 micrograms daily in 31 patients did not provide additional benefit in terms of GH and IGF-I reduction. Headache, excessive perspiration, fatigue, and joint pain were ameliorated in 83-95% of patients. Mean finger circumference was decreased significantly at the 12 month visit (P < 0.05). The most common adverse events reported were diarrhea, abdominal discomfort, loose stools, and nausea; these symptoms usually disappeared within 3 months of treatment. Five patients discontinued octreotide because of adverse events. Of 102 patients with normal baseline ultrasound examinations of the gallbladder, 24 patients (23.5%) developed gallstones (usually during the first year of treatment), and 21 patients developed sludge alone. Gallstone formation was not related to the dose of octreotide. Most patients with cholelithiasis were asymptomatic, and none developed cholecystitis. These observations suggest that octreotide is a valuable long term medical treatment for acromegaly.

Subcutaneous octreotide treatment of a growth hormone-releasing hormone-secreting bronchial carcinoid: superiority of continuous versus intermittent administration to control hormonal secretion

Diagnosis of ectopic acromegaly was made in a 21-year-old female patient who 3 years before had undergone a right pneumectomy for a disseminated bronchial carcinoid. Plasma growth hormone-releasing hormone (GHRH) concentrations were markedly elevated (6440 ng/l; normal value < 100 ng/l), as were serum GH (187 micrograms/l; normal < 5 micrograms/l) and plasma insulin-like growth factor I (IGF-I) levels (6.7 U/ml; normal < 2 U/ml). Retrospective immunohistochemical examination of the carcinoid tumor was positive for GHRH and the tumoral content of GHRH was 2130 ng/g wet weight. Subcutaneous treatment with octreotide was begun and first resulted in a profound inhibition of GH hypersecretion, normalization of plasma IGF-I and only partial reduction of GHRH concentrations. However, the initial dose of 3 x 100 micrograms had to be increased gradually to 4 x 750 micrograms because of a progressive deterioration of the hormonal control. After 15 months of intermittent therapy, octreotide was administered by continuous sc infusion. This treatment improved compliance, allowed the daily dose of octreotide to be reduced to 1500 micrograms and normalized serum GH levels. A near-normalization of the plasma IGF-I concentrations was also obtained, whereas the suppression of plasma GHRH concentrations remained incomplete. Despite favorable evolution of the endocrine parameters, intramedullar metastases were diagnosed and required radiation therapy. This observation emphasizes the superiority of continuous over intermittent administration of octreotide in the treatment of ectopic acromegaly. It also shows that the somatostatin analog acts more at the pituitary level to inhibit GH secretion than at the site of the neuroendocrine tumor.

Long R3 insulin-like growth factor-I (IGF-I) infusion stimulates organ growth but reduces plasma IGF-I, IGF-II and IGF binding protein concentrations in the guinea pig

We have tested whether an animal with substantial amounts of both IGF-I and IGF-II in circulation, such as the guinea pig, would respond to chronic IGF infusion in the same manner as the adult rat, which has negligible amounts of IGF-II in blood. Female guinea pigs of 350 g body weight were continuously infused for 7 days with recombinant guinea pig IGF-I or -II (120 or 360 micrograms/day) or long R3 IGF-I (LR3IGF-I) (120 micrograms/day), an analogue which has much reduced affinities for IGF binding proteins. IGF-I or IGF-II infusion led to substantial increases in plasma IGF-I or IGF-II respectively in comparison with vehicle-infused animals. Nevertheless, body weight gain, feed intake, feed conversion efficiency and carcass composition were not significantly affected by any treatment (significance was deemed to be P < 0.05). Amongst the tissues examined only the fractional weight (g/kg body weight) of the adrenals was increased, and that only by the higher dose (360 micrograms/day) of IGF-I. However, the fractional weight of adrenals, gut, kidneys and spleen were significantly increased by LR3IGF-I, but again overall growth was not stimulated. A possible explanation for the lack of IGF-I effects is that total circulating IGF concentrations were not increased by these treatments. IGF-II significantly raised total IGF concentrations at the higher dose only. Plasma IGF-I was reduced by IGF-II infusion, as was plasma IGF-II by IGF-I infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Dietary Acid or Aluminum on Growth and Growth-Related Hormones in Young Chickens

The effect of two concentrations of dietary acid (sulfuric acid) or aluminum (aluminum sulfate) on growth and growth-related hormones was examined in a heavy (broiler) strain of chicken between 4 and 18 days old. Growth (body weight, average daily gain, and tibial length) in chicks receiving either dietary acid or aluminum-containing diets were compared to chicks fed a control diet and to chicks fed diets containing sodium sulfate. Despite the reduced growth in acid-fed chicks, there were no changes in the plasma concentrations of growth hormone, insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding proteins (IGF-BP). However, in chicks receiving the high aluminum diet where growth was markedly depressed (by 57%), plasma concentrations of IGF-I were depressed, while those of the 36-kDa IGF-BP were elevated. The effects of acid and aluminum on growth were mediated at least partially by reductions in feed intake. Pair feeding depressed growth and tended to decrease plasma concentrations of IGF-I. Some differences were observed between acid or aluminum groups and their respective pair-fed controls. For the groups receiving the low-aluminum and both the high- and low-acid diets, values were increased compared to corresponding pair-fed controls for average daily gain, the level of the 36-kDa IGF-BP, and skeletal growth. On the other hand, high aluminum had a toxic effect in addition to reducing feed intake, with skeletal growth being reduced more in chicks receiving the aluminum diet than in the pair-fed controls.

Responses to exogenous pulsatile turkey growth hormone by growing 8-week-old female turkeys

A study was conducted in turkeys to determine the effects of pulsatile infusion of turkey growth hormone (tGH) on growth, feed conversion, carcass component parts, carcass composition, plasma metabolite concentrations, and other hormones associated with growth. Female turkeys, 8 weeks of age, were dually cannulated via the right jugular for intermittent (10 min every 2 hr) infusion of tGH at a low dosage (4.5 μg tGH/infusion or 54μg/day), a high dosage (18μg tGH/infusion or 216 μg/day) or vehicle infused controls (vehicle, 0.025 M NaHCO 3, 0.025 M Na 2CO 3+5 mg/ml NaCitrate, pH 9.4). Treatment was for 18 days. The second cannula was used to serially bleed the turkeys (5 or 10 min between samples) at 4 and 16 days of treatment to determine concentrations of GH, glucose, triacylglycerides (TG) non-esterified fatty acids (NEFA), and uric acid (UA). Overall GH was increased 74% above the control group in the low and 195% in the high treatment group. Baseline GH was increased 52% in the high group above the control group. The amplitude of GH peaks increased 292% in the low, and 574% in the high group above the amplitude of naturally occurring peaks in the control group. Infusion of tGH for 18 days did not affect overall daily gain, feed conversion, final body weight, tibiotarsus length, weights of pectoralis major, pectoralis minor, gastrocnemius or biceps femoris muscles, or weights of liver and offal. Abdominal fat pad weight (70% decrease), and percentages of carcass fat (4.9% decline) and carcass dry matter (2.3% decline) were lower in the high treatment group. Plasma TG and glucose were unaffected by treatment. Overall plasma NEFA concentration was increased in the high treatment group, and this increase was associated with an increase in the baseline concentration and incidence of pulses of NEFA, but not with the amplitude concentration of NEFA pulses. The dynamic nature of plasma NEFA concentration observed in this study suggests single time point measurements of this metabolite may not appropriately detect treatment effects. Plasma overall uric acid (UA) was decreased in the high treatment group in comparison to the control group, and this decrease was associated with a decrease in the baseline concentration of UA but not in the amplitude concentration not incidence of UA pulses. Plasma insulin-like growth factor-I (IGF-I) concentrations were increased in the low treatment group at 4 but not at 16 days of treatment. Plasma triiodothyronine (T 3) was increased in both the high and low treatment groups at 16 days of treatment, while tetraiodothyronine (T 4) was depressed in the high treatment group in comparison to the control group. It was concluded that tGH infused in a pulsatile pattern in growing female turkeys does not affect body weight gain, feed conversion, or weight of muscles, but does affect carcass fat content and plasma concentrations of NEFA and UA, and concentrations of the growth hormone associated hormones, IGF-I, T 3, and T 4.

Alterations in hepatic production and peripheral clearance of IGF-I after endotoxin.

Lipopolysaccharide (LPS) produces a rapid and sustained reduction in the circulating concentration of insulin-like growth factor I (IGF-I), which may be responsible, in part, for the alterations in protein metabolism observed in these animals. The purpose of the present study was to determine whether this drop was due to a decreased hepatic production of IGF-I and/or an increased clearance of the peptide from the blood. Four hours after intravenous injection of LPS the plasma IGF-I concentration was decreased 50%. IGF-I release by in situ perfused livers from control rats was constant throughout the 60-min perfusion period and averaged 111 +/- 3 ng/min. In contrast, hepatic IGF-I output was decreased 46% by in vivo LPS. In contrast, livers from LPS-injected rats released more IGF binding proteins-1, -2 and -4 than did control livers. Hepatic cell isolation indicated that LPS decreased the IGF-I content in Kupffer and parenchymal cells, but not endothelial cells, by approximately 45%. Pharmacokinetic analysis of blood 125I-IGF-I decay curves indicated that the half-life for whole body clearance of 125I-IGF-I from the circulation was not altered by LPS. However, LPS increased 125I-IGF-I uptake by spleen, liver, lung, and kidney while decreasing uptake by the pancreas and gastrointestinal tract. These results indicate that the LPS-induced decrease in blood IGF-I concentration is primarily due to a reduction in hepatic production, not a change in whole body peptide clearance, and that a decreased production by both parenchymal and Kupffer cells contributes to this alteration.

Size-Dependent, Sex-Dependent, and Seasonal Changes in Insulin-like Growth Factor I in the Loggerhead Sea Turtle (Caretta caretta)

This study examines size-dependent, sex-dependent, and seasonal fluctuations in plasma insulin-like growth factor-I (IGF-I) concentrations in loggerhead sea turtles (Caretta caretta). Loggerhead turtles (n = 158) were captured in shrimp trawler nets during a 12-month survey in Cape Canaveral Channel, Florida. Plasma samples were analyzed using a validated heterologous radioimmunoassay. Large turtles (>75 cm straight-line carapace length) had significantly higher plasma IGF-I concentrations than small turtles (⩽75 cm; P < 0.0001). Plasma IGF-I concentrations did not vary seasonally in small turtles, but large turtles had significantly higher plasma IGF-I concentrations during the spring and summer months (P < 0.005). Within the large turtles, adult males had significantly lower IGF-I concentrations than females and subadult males (P < 0.05). These results and a review of loggerhead turtle natural history suggest that the seasonal fluctuations in plasma IGF-I of adult turtles are due to elevated IGF-I levels in reproductively active female turtles. Further research is needed to examine correlations between reproductive activities and plasma IGF-I concentrations in reptiles.

Insulin-like Growth Factor-I in the Plasma of Two Reptiles: Assay Development and Validations

Radioimmunoassays (RIAs) of insulin-like growth factor-I (IGF-I) in nonmammals are complicated by two problems: decreased specificity due to heterologous assays and assay interference from IGF binding proteins. We have developed and validated an RIA fo the detection of IGF-1 in reptilian plasma that circumvents these problems. Biochemical validations show parallelism between standard curves, plasma dilutions, and internal standards. Further, biological validations indicate that (1) plasma IGF-I levels are significantly reduced in nonreproductive, female American alligators ( Alligator mississippiensis) with high plasma estradiol-17β concentrations and (2) plasma IGF-I concentrations are elevated in juvenile Trachemys scripta elegans turtles fed higher quality diets (defined by protein and energy content). These results provide impelus for future studies of IGF-I in reptiles.

Insulin-like growth factor I (IGF-I) and IGF binding proteins in seminal plasma before and after vasectomy in normal men

To examine the levels and origins of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding proteins (IGFBPs) in the human male genital tract. Examining seminal plasma before and 3 months after vasectomy. Fifteen men who were candidates for vasectomy were included in the study. Seminal plasma and serum levels of IGF-I, IGFBP-1, and IGFBP-3 were determined by commercially available assays, furthermore, samples were subjected to Western ligand blotting. Seminal plasma concentrations of IGF-I were significantly lower after vasectomy: 18.0 +/- 2.4 micrograms/L (before) and 12.5 +/- 1.2 micrograms/L (after). When the total ejaculate content of IGF-I was calculated, the figures were reduced by 50% after vasectomy: 45.64 +/- 7.8 ng (before) and 23.45 +/- 3.8 ng (after). The patterns observed for seminal plasma IGFBP-3 concentrations were 844.9 +/- 59 micrograms/L (before) and 816.5 +/- 65 micrograms/L (after). When the total ejaculate IGFBP-3 content was calculated there was a 36% reduction after vasectomy: 2,300 +/- 251 ng (before) and 1,474 +/- 217 ng (after). A considerable amount of seminal plasma IGF-I and IGFBP-3 may be of testicular origin. Although the physiological significance of IGF-I and IGFBPs in the male reproductive system still remains uncertain, the demonstration of their presence in the testes add support to a functional role in the regulation of gonadal function.

Insulin-like growth factor-I prevents gut atrophy and maintains intestinal integrity in septic rats.

The effects of insulin-like growth factor-I (IGF-I) on gut metabolism, structure, and barrier function as well as its general anabolic effects were investigated in septic rats. Thirty-three male Wistar rats that underwent cecal ligation were randomly divided into one of the following two groups: (1) received only total parenteral nutrition (control group) or (2) received total parenteral nutrition with IGF-I (IGF group) at a dose of 4 mg/kg/d for 3 days. During the 3-day period, the body weight of rats in the IGF group increased significantly over that of rats in the control group (17.1 +/- 2.6 vs 5.8 +/- 4.6 g, p < .01). The total and free IGF-I plasma concentrations were significantly higher in the IGF group than in the control group. The cumulative nitrogen balance was significantly more positive for the IGF group (423.9 +/- 24.3 mg of nitrogen) than for the control group (290.8 +/- 26.0 mg of nitrogen). The weights of thymus, spleen, and kidneys were significantly increased in the IGF group compared with weights in the control group. Treatment with IGF-I improved the gut mucosal weight in all regions of the gut examined, including duodenum, jejunum, ileum, and colon. Histologic and biochemical analyses of the jejunum showed greater villus height and crypt depth and higher mucosal DNA and protein content in the IGF group. The arterial concentration of endotoxin was not significantly different between the two groups, whereas its level in portal blood was significantly lower in the IGF group (23.2 +/- 9.9 pg/mL) than in the control group (95.5 +/- 37.9 pg/mL), an indication that IGF-I treatment decreased the amount of endotoxin that traversed the gut barrier. These results indicate that IGF-I can improve gut metabolism and reduce mucosal atrophy and that it may play a role in maintaining the gut barrier function in sepsis.

Protein metabolism in lambs from lines divergently selected for weaning weight

SUMMARYThe physiological consequences of selection for weaning weight were investigated using 14-month-old castrated male Merino lambs from lines selected for (W +) and against (W – ) weight at weaning for over 10 generations. The selection experiment commenced in 1953 and was conducted at Trangie, NSW, Australia. Lambs from these lines now differ by 42% in weight at weaning and maturity, and have a proportionately similar composition of protein, fat and ash in their bodies at similar stages of maturity. In the whole body, there were no apparent between-strain differences in protein synthesis, but W + lambs had lower (P &lt; 0·05) rates of phenylalanine oxidation than W – lambs. In hind limb muscle, protein metabolism of W + lambs was more responsive to food intake than in W – lambs. In particular, the rate of change of protein degradation differed (P &lt; 0·05) between the lines in response to food intake per unit liveweight with protein degradation decreasing with increased feed intake in W + lambs. W + lambs had lower (P &lt; 0·05) rates of blood flow to, and used less (P &lt; 0·05) oxygen per kg hind limb muscle than W— lambs. Endocrine differences between the lines included increased (P &lt; 0·05) plasma insulin-like growth factor-I (IGF-1) concentration in W + compared to W— lambs and, from regression analysis, an indication that there was a higher (P &lt; 0·01) response in hind limb protein gain to insulin in the W + lambs.These results suggest that selection for weaning weight has altered the dynamics of protein metabolism in lambs, principally through alterations in protein breakdown in muscle. Moreover, they suggest that there are associated genetic differences in endocrine control of protein metabolism which involve insulin and possibly IGF-I.

Effect of alpha 2-adrenergic agonist clonidine on plasma growth hormone and insulin-like growth factor-I concentrations in barrows.

The effects of infusion of clonidine, an alpha2-adrenergic agonist, on plasma insulin-like growth factor-I (IGF-I) concentrations were investigated with a single growth hormone (GH) injection in pigs. Four barrows were subjected to four treatments: saline infusion with a vehicle injection, clonidine infusion (0.5 nmol/kg/min for 8 h) with a vehicle injection, saline infusion with a bovine GH (bGH: 100 micrograms/kg) injection, and clonidine infusion with a bGH injection. Infusion was started 1 h before the injection. Plasma IGF-I, bGH, porcine GH (pGH), insulin, glucose, non-esterified fatty acid (NEFA), and blood urea nitrogen (BUN) concentrations were measured. Plasma IGF-I concentrations during saline infusion increased after a bGH injection (P < 0.05). However, the IGF-I concentrations during clonidine infusion did not increase after the bGH injection. Plasma endogenous GH (pGH) was not increased during clonidine infusion. The plasma glucose concentration was noticeably increased during clonidine infusion and moderately increased after the GH injection. Despite the extreme increase in plasma glucose during clonidine infusion, plasma insulin did not change. Neither plasma NEFA nor BUN was changed by these treatments. These results demonstrate that the alpha 2-adrenergic agonist clonidine altered the action of GH to increase the plasma IGF-I concentrations.

Fetal plasma insulin-like growth factor-binding protein-3 concentrations are elevated following bilateral nephrectomy in fetal sheep.

Insulin-like growth factors mediate many of the effects of growth hormone and are important in the regulation of growth, especially in the fetus where growth is less dependent on circulating growth hormone. In the ovine fetus, insulin-like growth factor-I (IGF-I) is bound mainly to the low molecular weight insulin-like growth factor-binding proteins (IGFBP), IGFBP-1 and IGFBP-2, with little binding to IGFBP-3 until near term at 147 days gestation. To determine if there was any difference in plasma IGF-I and IGFBP-3 concentrations in growth-retarded fetal sheep with altered renal status, concentrations were measured by specific radioimmunoassay from bilaterally nephrectomized fetal sheep between Days 113 and 135 gestation. Plasma IGFBP-3 concentrations were significantly (P < 0.001) increased in bilaterally nephrectomized fetuses (4.19 +/- 0.19 micrograms mL-1, n = 7) compared with control fetuses (2.33 +/- 0.10 micrograms mL-1, n = 7). There was no change in plasma IGFBP-3 concentration with gestational age in either experimental group. Maternal plasma IGFBP-3 concentrations did not differ between the bilateral nephrectomy group (3.11 +/- 0.09 micrograms mL-1, n = 7) and the control group (3.25 +/- 0.11 micrograms mL-1, n = 7) and showed no change within groups over the experimental period. Total plasma IGF-I concentrations in bilaterally nephrectomized fetuses and ewes were similar to those in control fetuses and ewes. The results indicate that the profile of IGF binding in fetal plasma is altered in the anephric fetal sheep. In nephrectomized fetal sheep, increased IGFBP-3 concentrations, and therefore increased IGF-binding capacity in fetal plasma, may have contributed to a decrease in free IGF in plasma and decreased IGF-I bioactivity. This would provide a possible mechanism for the growth retardation reported in bilaterally nephrectomized fetal sheep.

Acute effect of human recombinant insulin-like growth factor I on renal function in humans.

We examined the acute effects of insulin-like growth factor I (IGF-I) on renal function in 8 normal subjects who received a 3-hour intravenous infusion of IGF-I at a rate of 0.4 micrograms/kg.min. After starting the IGF-I infusion, the plasma IGF-I concentration rose quickly and achieved a plateau after 90 min that was threefold above the basal value. During IGF-I infusion, progressive rises in glomerular filtration rate (from 93 +/- 4 to 121 +/- 6 ml/173 m2.min; p < 0.01) and renal plasma flow (from 529 +/- 31 to 703 +/- 55 ml/1.73 m2.min; p < 0.01) were observed, with no change in filtration fraction. The plasma levels of potassium and phosphate decreased significantly during the last 90 min of the study, while the plasma sodium concentration remained unchanged. A significant decrease in the fractional excretion of sodium, potassium, and phosphate was observed during the last 90 min of the IGF-I infusion period. The heart rate rose modestly with no change in mean arterial pressure. These findings show that, when administered acutely, IGF-I is a potent renal vasodilator, but is antinatriuretic. IGF-I also enhances potassium and phosphate uptake by extrarenal tissues and reduces renal potassium and phosphate excretion.

Effect of exogenous insulin on plasma and follicular insulin-like growth factor I, insulin-like growth factor binding protein activity, follicular oestradiol and progesterone, and follicular growth in superovulated Angus and Brahman cows

Angus (n = 14) and Brahman (n = 14) cows were used to evaluate the effects of insulin administered concomitantly with FSH in a superovulation regimen. Cows were allotted to four pen replicates by treatment and breed, and received FSH (i.m.) twice a day for 5 consecutive days (first day of injections = day 0 of study) plus concomitant administration of either saline (control) or long-acting bovine insulin (0.25 iu kg-1 body mass; s.c.). Blood samples were collected at intervals of 6 h during the injection period and analysed for plasma insulin, glucose, insulin-like growth factor I (IGF-I) and IGF-I binding protein (IGFBP) activity. Cows were ovariectomized on day 5. The number and diameter of follicles were recorded. Follicular fluid was aspirated for determination of IGF-I, IGFBP activity, oestradiol and progesterone. Mean plasma concentration of glucose was lower in insulin-treated than in control cows averaged over days 1-5 (56 +/- 3 versus 82 +/- 3 mg dl-1; P < 0.01). Plasma concentration of IGF-I and IGFBP activity were not affected (P > 0.10) by treatment, but were higher in Brahman than in Angus cows (IGF-I: 41 +/- 6 versus 19 +/- 6 ng ml-1, P < 0.05; IGFBP activity: 17.5 +/- 0.4 versus 15.8 +/- 0.04% (10 microliters)-1; P < 0.03). Insulin treatment did not affect the number of small (1.0-3.9 mm), medium (4.0-7.9 mm) or large (> or = 8.0 mm) follicles. Brahman cows had a greater (P < 0.01) number of medium and total follicles (19.4 +/- 2.5 and 60.5 +/- 5.5, respectively) than did Angus cows (7.5 +/- 2.6 and 30.5 +/- 5.6, respectively). Diameter of large follicles was greater in insulin-treated than in control cows (11.4 +/- 0.2 versus 10.6 +/- 0.1 mm; P < 0.05). Follicular fluid IGF-I concentration in large follicles was higher in insulin-treated Brahman cows (60 +/- 2 ng ml-1) than in control Brahman cows (37 +/- 2 ng ml-1), but was lower in insulin-treated Angus cows (31 +/- 3 ng ml-1) than in control Angus cows (38 +/- 2 ng ml-1; treatment x breed interaction, P < 0.01). IGFBP activity in fluid from large follicles was not affected by insulin treatment in Brahman cows but was reduced (P < 0.05) by insulin treatment in Angus cows.(ABSTRACT TRUNCATED AT 400 WORDS)

Pituitary size assessed with magnetic resonance imaging as a measure of growth hormone secretion in long term survivors of childhood cancer.

We investigated 37 long term survivors of childhood cancer to study the relationship among growth, GH secretion, and pituitary size. The median follow-up time after diagnosis was 13.2 yr. The pituitary gland was visualized with magnetic resonance imaging. Radiated patients (n = 25) had a reduced relative height and showed a greater reduction in relative height after diagnosis than nonradiated patients (n = 12). The patients had lower spontaneous nocturnal GH secretion than controls due to a reduced peak amplitude. Spontaneous GH secretion was lower in radiated patients than in nonradiated subjects. The patients had lower plasma insulin-like growth factor-I (IGF-I) and serum IGF-binding protein-3 (IGFBP-3) concentrations than the controls. Radiated subjects had decreased IGF-I and IGFBP-3 concentrations compared to nonradiated subjects. Half of the patients (20 of 37) evaluated with magnetic resonance imaging had a reduced pituitary size (pituitary height, < -2 SD score). Radiated subjects had smaller pituitary glands than nonradiated ones. Seventeen of 20 patients (85%) with reduced pituitary size had decreased nocturnal GH release. There was a positive correlation between nocturnal GH secretion, plasma IGF-I, and serum IGFBP-3 levels, on the one hand, and pituitary height, on the other. These results indicate that cranial radiation may result in tissue damage, leading to decreased pituitary size, reduced spontaneous GH secretion, and impaired linear growth. The finding of reduced IGF-I levels in both radiated and nonradiated patients combined with decreased IGFBP-3 concentrations in radiated patients, indicates that cytotoxic chemotherapy may induce hepatic damage resulting in decreased IGF-I synthesis.

Blood levels of insulin-like growth factors I and II in neonates of non-insulin-dependent diabetic rats

Circulating levels of insulin like growth factor I (IGF-I) and insulin like growth factor II (IGF-II) were evaluated in plasma samples during the first 72 h of life in neonates of diabetic and control mother rats. Diabetes had been induced in the diabetic dams by streptozotocin at 2 days of age. The rats developed non-insulin dependent diabetes (at 6 weeks of age) and became pregnant at 11 weeks of age. Maternal blood glucose levels were higher in the diabetic mothers (P < 0.05) during the last two-thirds of gestation. Complications occurred at the end of 7.1% of the diabetic pregnancies but none of the controls. Analysis of neonates plasma glucose, IGF-I, and IGF-II concentrations in the first 12, 24, 48, and 72 h after birth revealed higher glucose levels in neonates of diabetic mothers at 72 h compared with controls (118 +/- 7 vs 85 +/- 5 mg/dl, P < 0.05) but there was no difference in IGF-I or IGF-II levels between the groups at any time point. Thus, acquired impaired glucose homeostasis may be seen in neonates of mildly diabetic mothers at early stages of their life but their circulating insulin-like growth factors levels are normal. These data do not support the proposition that fetal IGF-I and -II affect the outcome of pregnancies complicated by mild diabetes in the rodent.

Estrogen receptor blockade with tamoxifen diminishes growth hormone secretion in boys: evidence for a stimulatory role of endogenous estrogens during male adolescence.

The increase in GH production during the male adolescent growth spurt has been attributed to both androgen and estrogen receptor-mediated processes. To evaluate the role of endogenous estrogens in the control of GH secretion, we administered the estrogen receptor antagonist tamoxifen to 10 late pubertal males. Blood samples were obtained for GH determination at 10-min intervals on 2 occasions during the last 24 h of a 4-day course of either tamoxifen or placebo. Waveform-specific, multiple parameter deconvolution analysis was employed to assess GH secretory and elimination dynamics. Estrogen receptor blockade resulted in a significant (P < 0.05) diminution in mean 24-h serum GH concentrations, from 3.9 +/- 1.0 (placebo; mean +/- SEM) to 2.7 +/- 0.6 micrograms/L (tamoxifen). This was associated with a significant (P < 0.01) decline in the GH production rate [237 +/- 55 vs. 155 +/- 33 micrograms/L GH distribution volume (Lv).24 h]. Furthermore, this reduction in GH secretion was the result of significant decreases in both the maximal GH secretory rate (0.46 +/- 0.08 vs. 0.34 +/- 0.06 microgram/Lv.min; P < 0.01) and, to a smaller degree, GH secretory burst number (16 +/- 1 vs. 14 +/- 1/24 h; P < 0.05). There was also a trend toward reduced mass of GH secreted per burst (13.3 +/- 2.5 vs. 10.3 +/- 2.0 micrograms/Lv; P = 0.06). No significant alterations in either GH elimination t1/2 or GH secretory burst half-duration were observed during estrogen receptor antagonism. Tamoxifen treatment was associated with a significant (P < 0.05) decrease in plasma insulin-like growth factor-I concentrations. However, total and free testosterone, 17 beta-estradiol, insulin-like growth factor-binding protein-3, and pooled 24-h LH concentrations were not significantly changed by short term blockade of estrogen action. We postulate that endogenous estrogens play a facilitatory role in neuroendocrine control of the somatotropic axis during puberty in boys. Tamoxifen blocks this estrogen-dependent stimulation of GH secretion without altering the hormone elimination t1/2. Furthermore, we speculate that any stimulatory role of androgens on GH secretion is exerted primarily through the estrogen receptor after aromatization.