Somatomedina, crescimento e estado nutricional / Somatomedin, growth and nutritional status

Somatomedinas no plasma, originalmente caracterizadas como dependentes do hormônio do crescimento, foram encontradas também ser dependentes dos níveis de insulina e do estado nutricional. Quatro propriedades caracterizam as açöes da somatomedina: sua concentraçäo no soro é dependente do hormônio do crescimento, possuem açöes similares a da insulina em tecidos extraesqueléticos, promovem a incorporaçäo de sulfato no proteoglicano da cartilagem e estimulam a síntese de DNA e multiplicaçäo celular em crianças com desnutriçäo protéico-calórica onde se observa também que as concentraçöes de hormônio de crescimento e cortisol estäo aumentados. Há evidências experimentais e clínicas que sugerem a capacidade da somatomedina C em estimular o crescimento da cartilagem. Esta açäo é regulada por inibidores da somatomedina em condiçöes de deficiência hormonal ou nutricional. A energia e proteína da dieta säo fatores importantes na síntese e na atividade da somatomedina C nas células da cartilagem. Os níveis de somatomedina C plasmáticas representam um parâmetro sensível na detecçäo da deficiência protéico-calórica e posterior recuperaçäo nutricional em humanos e animais de laboratório

Molecular forms of serum insulin-like growth factor (IGF)-binding proteins in man: relationships with growth hormone and IGFs and physiological significance.

Insulin-like growth factor-I (IGF-I) and IGF-II are associated in the blood with specific binding proteins (BPs), forming complexes that elute in gel filtration with estimated mol wt around 40 and 150 kD. The latter appears to be under GH control. Five molecular forms of BP (41.5, 38.5, 34, 30, and 24 kD) have been identified by Western blotting using 125I-labeled IGF. All five forms are present in the smaller complexes, but only the 41.5- and 38.5-kD forms are found in the larger complexes. In this study immunoblotting showed that the 41.5- and 38.5-kD forms were recognized by antibodies directed against the GH-dependent BP purified from human plasma, and the 30-kD form was recognized by antibodies directed against the BP purified from amniotic fluid. The 34- and 24-kD forms proved to be immunologically unrelated to the other three. In sera with large quantities of the 41.5- and 38.5-kD forms, an additional band was often observed immediately ahead of the migration front of the 30 kD band. This was recognized by the anti-GH-dependent BP antibody and probably corresponds to a degradation product of the 41.5- and 38.5-kD BPs. Serum 41.5- and 38.5-kD BPs have been found to be elevated in acromegaly, where GH hypersecretion causes increased IGF-I levels, and diminished in cases of genetic or idiopathic GH deficiency and defects of the GH receptor (Laron's syndrome), where both IGF-I and IGF-II are decreased, as well as in Pygmy adults and children who have isolated IGF-I deficiency. In all of these conditions, the proportions of the 34- and 30-kD forms were inversely related to those of the 41.5- and 38.5-forms. Under treatment, the BP profiles tended to return to normal. In cases of GH deficiency caused by a tumor, the BP profiles resembled those of hypopituitary or normal serum, depending on whether IGF levels were diminished or normal. It, therefore, seems that BP synthesis is coordinated with IGF-I synthesis and may not be directly GH dependent. The results of neutral pH gel filtration analysis of hypopituitary (idiopathic and tumoral) and normal sera point to a relationship between the levels of circulating IGFs and those of the 150-kD IGF-BP complex whose binding units are the 41.5- and 38.5-kD BPs. It, therefore, seems that the 150-kD complex controls the bioavailability of IGF-I and IGF-II.(ABSTRACT TRUNCATED AT 400 WORDS)

The role of insulin-like growth factor I in growth of diabetic rats.

Insulin-deficient, streptozotocin-diabetic rats show severe metabolic disturbances and stop growing. Besides insulin, these animals also lack growth hormone and insulin-like growth factor-I. We examined whether or not growth parameters correlate with IGF-I serum levels in young rats with streptozotocin-diabetes of different severity. In the diabetic rats, blood glucose varied between 18.4 and 38.6 mmol/l (healthy controls between 6.1 and 9.3), IGF-I serum levels between 2.6 and 15.6 nmol/l (controls between 19.6 and 26.5), and serum insulin levels between 0.05 and 0.14 nmol/l (controls between 0.36 and 0.55). We found a highly significant linear correlation between IGF-I serum levels and the two investigated growth parameters, tibial epiphyseal width and longitudinal tibial bone growth. The finding that these indices of growth are strongly correlated with IGF-I serum levels in young rats with diabetes of different severity, suggests that IGF-I is a major determinant of growth. This is in keeping with our earlier demonstration that exogenously infused IGF-I promotes growth in diabetic rats.

Dietary carbohydrate content determines responsiveness to growth hormone in energy-restricted humans.

To determine if diet composition influences responses to GH, we fed 11 obese women diets containing 12 Cal/kg ideal BW (IBW) for 2 5-week study intervals. Nonprotein calories were supplied to 6 subjects as 72% carbohydrate (high carbohydrate diet), and 5 subjects received 80% of their nonprotein calories as lipid (high lipid diet). Protein intake was constant (1.0 g/kg IBW) in both groups. During 1 study interval we gave injections of GH (0.1 mg/kg IBW) every other day for 3 weeks (weeks 2-4), and in the other interval injections of vehicle were given. Subjects ingesting the high carbohydrate diet excreted significantly less urinary nitrogen [660.2 +/- 124.1 mmol/day (mean +/- SD)] than those who received high lipid (794.2 +/- 198.5 mmol/day; P less than 0.001), and GH injections reduced nitrogen excretion in the high carbohydrate subjects (532.8 +/- 123.8 mmol/day), but not in the high lipid subjects (743.7 +/- 126.6 mmol/day). The subjects receiving the high carbohydrate diet had a significant increase in serum insulin-like growth factor-I (IGF-I; from 36.2 +/- 9.7 to 55.9 +/- 6.6 nmol/L) and urinary C-peptide excretion (from 43.9 +/- 25.6 to 60.8 +/- 29.4 nmol/day) in response to GH. The IGF-I response attenuated slowly over the 3-week treatment interval. On the other hand, the high lipid group had lesser increases in IGF-I (from 31.0 +/- 6.5 to 41.7 +/- 8.8 nmol/L) and C-peptide excretion (from 24.3 +/- 28.9 to 29.8 +/- 32.8 nmol/day), and IGF-I concentrations declined to control values after only 5 days of GH injection. We believe that this initial IGF-I response was due to an antecedent 35-Cal balanced diet. The mean increment in serum FFA 4 h after GH injection was significantly less in subjects fed the high lipid diet (0.53 +/- 0.40 meq/L) than in those fed the high carbohydrate diet (0.83 +/- 0.43 meq/L). GH injections produced more body fat loss than injections of vehicle whether expressed as percent body fat lost (GH, 3.7 +/- 1.0%; vehicle, 2.8 +/- 0.7%, P less than 0.05) or as the fraction of weight lost as fat (fat loss/weight loss; GH, 0.81 +/- 0.13; vehicle, 0.64 +/- 0.08; P less than 0.005). There was an inverse correlation between the percentage of body fat lost and mean urinary C-peptide excretion during GH injections (r = -0.70; P less than 0.05), suggesting that stimulation of insulin secretion by GH might antagonize the tendency of GH to promote fat loss.(ABSTRACT TRUNCATED AT 400 WORDS)

Structure, specificity, and regulation of the insulin-like growth factor-binding proteins in adult rat serum.

Insulin-like growth factor-I (IGF-I), the principal IGF in adult rat serum, occurs complexed to specific binding proteins. After fractionation of serum on Sephadex G-200 at neutral pH, 62% of the immunoreactive IGF-I is recovered in the 150K region, 38% in the 40K region, and none is present as free 7.5K IGF-I. Adult rat serum also contains unoccupied binding sites for IGFs that also are predominantly (77%) located in the 150K region and have preferential binding affinity for IGF-II. IGF-binding protein components in the 150K and 40K regions were evaluated by affinity cross-linking to 125I-labeled IGFs and by ligand blotting (i.e. incubation of nitrocellulose blots of sodium dodecyl sulfate (SDS)-gels with [125I]IGFs). Affinity cross-linking of the 150K region revealed a major 43K binding protein complex and several minor covalent complexes of 97-210K that are formed during the cross-linking reaction. The 40K region of the gel filtration column contains a predominant 32K complex and smaller amounts of the 43K complex. Ligand blotting of the 150K region identifies a predominant cluster of binding components of about 40K and a smaller 29K protein. The apparent molecular masses of the 40K and 29K proteins are decreased by incubation with N-glycanase, indicating that they contain N-linked oligosaccharides. These glycoprotein components, designated gp40 and gp29, presumably combine with an acid-labile nonbinding subunit of about 100K to generate the 150K complex. The gp40 cluster represents glycosylation variants of a 34K protein; gp29 has been shown to correspond to an amino-terminal fragment of gp40. Ligand blotting of the 40K region indicates that it contains smaller amounts of gp40 and gp29, possibly representing free subunits not combined with the nonbinding subunit, as well as two proteins of apparent molecular mass 24K and 30K (p24 and p30) that are not glycosylated. Although p30 is similar in size to the binding protein from BRL-3A cells (BP-3A) that is present in fetal rat serum, immunoprecipitation and immunoblotting of whole and fractionated adult serum with an antiserum to BP-3A indicate that p30 in adult rat serum is an antigenically distinct protein. Serum levels of gp40 and gp29 are decreased by hypophysectomy and are restored by GH treatment; p24 and p30 show similar but smaller changes.

Identification of a type 1 insulin-like growth factor binding protein (IGF BP) in serum from rats with diabetes mellitus.

Circulating insulin-like growth factor binding protein (IGF BP) activity is increased in animals with streptozotocin-induced diabetes. Separation of BPs by SDS/PAGE for ligand and immunoblot analysis revealed that a 32,000 molecular weight BP is present and increased in diabetic serum. This BP is immunologically distinct from the low molecular weight fetal rat BP (rBP2) and is related to the human amniotic fluid BP (hBP1) that is increased in patients with insulin dependent diabetes mellitus.

Low somatomedin C and high growth hormone levels in newborns damaged by maternal alcohol abuse.

To study the mechanism of alcohol-induced fetal damage, we determined the somatomedin C and growth hormone (GH) concentrations of umbilical cord blood samples in 56 infants of alcohol-abusing women and in 20 infants of alcohol-abstinent women. In addition, maternal serum somatomedin C concentrations were determined 1-7 days before delivery. Twenty-five infants born to alcohol-abusing mothers were growth-retarded and also had other signs of fetal alcohol effects, but the remaining 31 infants born to the drinkers and all infants of abstinent mothers were healthy. The somatomedin C levels of infants with fetal alcohol effects (mean +/- SD 4.6 +/- 1.5 nmol/L) were lower (P less than .005) than the levels of healthy infants of drinking (6.8 +/- 4.0 nmol/L) or abstinent (7.1 +/- 3.3 nmol/L) mothers, but the levels did not correlate with infant birth weight, placental weight, or fetal GH or maternal somatomedin C levels. Alcohol drinking was not associated with any changes in maternal somatomedin C levels. The GH levels of infants with fetal alcohol effects (25.4 +/- 22.6 ng/mL) were elevated (P less than .01) when compared with those of infants of abstinent mothers (13.1 +/- 5.3 ng/mL), but did not differ from those of healthy infants of drinking mothers (19.9 +/- 15.1 ng/mL). Low somatomedin C levels and high GH levels in infants born to the drinkers suggest a disharmony in the regulation of the synthesis and/or release of these growth factors, which may be of importance in alcohol-induced fetal damage.

Significance of abnormal serum binding of insulin-like growth factor II in the development of hypoglycemia in patients with non-islet-cell tumors.

We reported that serum and tumor from a hypoglycemic patient with a fibrosarcoma contained insulin-like growth factor II (IGF-II), mostly in a large molecular form designated "big IGF-II." We now describe two additional patients with non-islet-cell tumor with hypoglycemia (NICTH) whose sera contained big IGF-II. Removal of the tumor eliminated most of the big IGF-II from the sera of two patients. Because specific IGF-binding proteins modify the bioactivity of IGFs, the sizes of the endogenous IGF-binding protein complexes were determined after neutral gel filtration through Saphadex G-200. Normally about 75% of IGFs are carried as a ternary complex of 150 kDa consisting of IGF, a growth hormone (GH)-dependent IGF-binding protein, and an acid-labile complexing component. The three patients with NICTH completely lacked the 150-kDa complex. IGF-II was present as a 60-kDa complex with variable contributions of smaller complexes. In the immediate postoperative period, a 110-kDa complex appeared rather than the expected 150-kDa complex. Abnormal IGF-II binding may be important in NICTH because the 150-kDa complexes cross the capillary membrane poorly. The smaller complexes present in our patients' sera would be expected to enter interstitial fluid readily, and a 4- to 5-fold increase in the fraction of IGFs reaching the target cells would result.

Caloric restriction and 7,12-dimethylbenz(a)anthracene-induced mammary tumor growth in rats: alterations in circulating insulin, insulin-like growth factors I and II, and epidermal growth factor.

Caloric restriction (CR) inhibits many neoplastic diseases in rodents, yet the biochemical mechanism(s) for these effects are poorly understood. We have examined the effects of ad libitum (AL) feeding with 25 or 40% CR on the promotion of 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis in virgin female Sprague-Dawley rats. Further, we have also studied the influence of chronic CR on temporal alterations in circulating insulin, insulin-like growth factor I/somatomedin C, insulin-like growth factor II/multiplication-stimulating activity, and epidermal growth factor levels at 0, 1, 3, 5, 11, and 20 weeks in carcinogen- and vehicle-treated animals. Tumor incidence and multiplicity were markedly inhibited (P less than 0.05) with increasing CR. Fasting serum insulin-like growth factor I/somatomedin C levels exhibited a significant acute decline with CR at 1 and 3 weeks, but were comparable to AL-fed controls throughout the remainder of the 5-month study, despite continued differences in weight gain between AL and CR rats. Levels of insulin-like growth factor II/multiplication-stimulating activity exhibited no discernible pattern in relation to CR. Serum insulin levels showed age-dependent increases, but were affected by increasing CR at all time points. Insulin levels were significantly (P less than 0.05) reduced in 40% CR rats from 3 weeks onward compared to controls, while 25% CR resulted in nonsignificant (P less than 0.07) reductions throughout the study. No significant differences in growth factor levels were observed between 7,12-dimethylbenz(a)anthracene- and vehicle-treated rats. Circulating epidermal growth factor was not detectable in any treatment group regardless of the nature or duration of the dietary regimen, time of blood collection, or subsequent tumor-bearing status. These data suggest that decreased serum insulin-like growth factor I/somatomedin C and insulin levels with CR and their complex interactions in vivo may play a role in the inhibition of mammary tumor promotion by CR.

The effects of altered nutritional status upon insulin-like growth factors and their binding proteins in neonatal rats.

To investigate the role of nutrition in the regulation of IGFs during the perinatal period, 10-d-old rats were infused intravenously with various concentrations of nutrients for 24 h. Breast-fed litter mates served as controls. The effect of caloric intake on concentrations of IGF-I and IGF-II as well as IGF-binding proteins in serum, liver, and brain of neonatal rats was studied. A total of 45 rats from 10 litters was infused with solutions ranging from a caloric intake of 0 (saline) to 75% (glucose, amino acids, and lipids) of the estimated intake of control rats. In serum, both IGF-I and -II concentrations fell markedly in response to fasting. Serum IGF-II levels were linearly related to caloric intake in the pooled data from all groups. Concentrations of IGF-II, but not IGF-I, in liver and brain were depressed by caloric restriction. In contrast to the fall in IGF concentrations, activity of IGF-associated binding proteins rose in serum and in liver cytosol 2- to 4-fold in response to decreased nutrient intake. In serum, but not liver, the rise in binding protein activity was inversely related to to caloric intake. In liver, cytosol, but not serum, the rise in binding protein activity was inversely related to total serum amino acid concentration. Thus, IGF concentrations in preweanling rats change in response to alterations of nutrient intake. The fasting induced decrements in IGF levels, as well as the elevations in IGF-associated binding protein activity, may serve as a protective mechanism to depress growth in times of caloric restriction.

Nutrition and somatomedin: nutritionally regulated release of somatomedins and somatomedin inhibitors from perfused livers in rats.

Circulating somatomedin activity reflects the presence of both somatomedins and somatomedin inhibitors, factors which antagonize the growth-promoting actions of somatomedins. Although both are regulated by nutrition, somatomedin inhibitors respond more rapidly than somatomedins to refeeding in fasted animals. To explore the role of the liver in such responses, release of somatomedin activity and somatomedin inhibitor activity was assessed during perfusion of livers from normal, fasted, and fasted-refed rats. Size-exclusion high-performance liquid chromatography (HPLC) revealed that liver perfusates contain both somatomedin and somatomedin inhibitor activity of apparent molecular weight (mol wt) comparable to that found in the circulation (approximately 7,000 and approximately 30,000, respectively), as well as activity of apparently higher wt. In subsequent studies, responses to nutrition were evaluated as fluctuations in bioactivity only of mol wt comparable to that found in the circulation. Release of both somatomedin and somatomedin inhibitor activity was progressive over at least two hours of recirculating perfusion. Perfusates of livers from normal fed rats had somatomedin activity (stimulation of cartilage SO4 uptake) 94 +/- 19% above buffer (P less than .01), which fell to undetectable levels after three days of fasting. With refeeding, perfusate somatomedin activity rose within three hours to approximately 25% of levels in fed rats, but did not become significant until after 12 hours (29 +/- 7%, P less than .02). Perfusates of livers of fed rats also contained somatomedin inhibitor activity (42 +/- 10% inhibition of cartilage stimulation by normal serum), which rose after three days of fasting to 114 +/- 22% (P less than .02).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of glucocorticoids on the regulation of the hypothalamic-pituitary-somatotropic system in depression.

In order to evaluate the possible effect of glucocorticoids as neuromodulators of the hypothalamic-pituitary-somatotropic system in depression, cortisol, growth hormone (GH), and insulin-like growth factor I (IGF-I) concentrations were studied before and after oral administration of 1 mg dexamethasone at 11 p.m. in 16 patients during depression and after recovery and in 28 healthy controls. While there were no significant differences in GH and IGF-I levels between depressed, recovered and control subjects, GH and IGF-I concentrations of cortisol non-suppressors were significantly elevated compared to suppressors. Moreover, post-dexamethasone cortisol, GH, and IGF-I levels were positively correlated. Dexamethasone had a stimulating effect on GH and IGF-I values in patients during depression and in cortisol non-suppressors only; this effect was absent in recovered and in control subjects and in cortisol suppressors. Thus, hypercortisolemia may be of great importance for the dysregulation of the hypothalamic-pituitary-somatotropic system reported in depression.

Insulin-like growth factor-I in human malnutrition: relationship with some body composition and nutritional parameters.

The insulin-like growth factor-I (IGF-I) plasma concentration was evaluated as a nutritional parameter in 18 patients affected with chronic malnutrition secondary to biliopancreatic bypass and compared with albumin, transferrin, and with body composition parameters: total body water (TBW), total body sodium (TBNa), total body potassium (TBK). Subjects were studied in malnutritional conditions and after 20 to 30 days of parenteral and enteral refeeding treatment. Immunoreactive IGF-I concentration was 0.35 U/ml +/- 0.07 (mean +/- SEM), significantly lower (p less than 0.01) than in age-matched controls (1.14 +/- 0.07 U/ml, n = 29) and rose significantly (0.84 +/- 0.12 U/ml; p less than 0.01) in parallel with the improvement of nutritional status. The ratios TBNa/TBW, TBNa/TBK, and TBK/TBW were then considered as reference parameters for definition of malnutritional state, and compared with IGF-I as well as with the most commonly used parameters, albumin and transferrin. Before treatment, IGF-I evidenced higher specificity (true negative ratios 0.63, 0.43, and 0.40 with regard to TBNa/TBW, TBNa/TBK, and TBK/TBW, respectively) than albumin (0.13, 0.14, and 0.10) and transferrin (0 in all cases), and slightly less sensitivity (true positive ratios for IGF-I 0.80, 0.67, and 0.67; always one for albumin and transferrin). Moreover, IGF-I resulted definitely more sensitive in assessing the effectiveness of the refeeding treatment and, on the basis of the likelihood ratio, it appeared a good discriminator of the nutritional status. The data indicate that different nutritional factors regulate IGF-I, albumin, and transferrin, and suggest that IGF-I can be used as a reliable and specific nutritional parameter, complementary to the others currently used.

Insulin-like growth factor I binding proteins in dairy cows, calves and bulls.

Our objective was to measure relative amounts and distributions of serum IGF-I binding proteins and concentrations of hormones and metabolites in dairy cows during the dry period and during lactation, as well as in calves and in growing bulls. Concentrations of IGF-I were lower in cows during lactation than during the dry period. Concentrations of IGF-I, growth hormone, insulin, T3, T1 and glucose were higher in calves and bulls as compared with cows, whereas concentrations of non-esterified fatty acids, urea, protein and albumin were lower. Three different IGF-I binding protein fractions were found with apparent molecular weights of greater than 200, 140-160 and 45-65 kD. Relative amounts of IGF-I binding proteins were similar, although great differences in hormones and metabolites were found in cows, bulls and calves. accessible binding sites were higher in dairy cows than in calves and bulls, mainly owing to the fact that dairy cows had lower concentrations of IGF-I bound to these fractions. additionally, we found significant negative correlations between total accessible binding sites and total IGF-I concentrations. There were significant differences in the distribution of binding proteins. In particular, there was a shift of binding ability from the 140-160 to the 45-65 kD binding sites from the end of pregnancy to early lactation. Amounts of IGF-I bound to proteins increased from lactating to dry cows and calves and were highest in bulls. IGF-I levels in the greater than 200 kD fraction were lower in lactating than in dry cows, and lower in cows than in calves and bulls. IGF-I measured in the 140-160 kD fraction was lowest in lactating cows and comparable in dry cows, calves and bulls. Concentrations of IGF-I in the 45-65 kD fraction were lowest in cows and highest in bulls. In conclusion, there were marked differences in growing, pregnant and lactating cattle, particularly as concerns accessible protein binding and amounts of IGF-I bound to proteins.

Growth hormone deficiency impedes the rise in plasma insulin-like growth factor I levels associated with precocious puberty.

We tested the hypothesis that growth hormone (GH) mediates the rise in insulin-like growth factor I (IGF-I) concentrations in children with precocious puberty. We studied three groups of patients. Group 1 included six children with GH deficiency and precocious puberty (precocious GH-deficient); group 2 included 10 GH-sufficient patients with idiopathic true precocious puberty (precocious GH-sufficient); and group 3 included 9 prepubertal children with GH deficiency (prepubertal GH-deficient). Growth rates, pubertal status, and plasma IGF-I concentrations were determined at regular intervals. The precocious children with GH deficiency had a mean (+/- SD) growth rate of 7.2 +/- 2.1 significantly below that of the precocious GH-sufficient patients (10.5 +/- 2.5 cm/yr, p less than 0.05) but above that of the prepubertal GH-deficient children (3.9 +/- 1.4 cm/yr, p less than 0.05). The mean IGF-I concentration in the precocious GH-deficient children was 0.77 +/- 0.39 U/ml, significantly lower than the mean level of 2.2 +/- 0.67 U/ml in the precocious GH-sufficient patients (p less than 0.01). However, precocious GH-deficient patients had significantly higher IGF-I values than the prepubertal GH-deficient children (0.24 +/- 0.10 U/ml, p less than 0.05). IGF-I values did not rise with the onset of precocious puberty in four of the precocious GH-deficient children evaluated before and after the development of precocious puberty. However, three patients who began GH treatment did have a rise in plasma IGF-I concentrations to levels of 1.2, 3.4, and 3.7 U/ml, respectively. These findings are compatible with the concept that sex steroids increase IGF-I levels in precocious puberty primarily by increasing GH production. A small but direct effect of sex steroids on IGF-I production may also exist. The onset of precocious puberty in children with organic GH deficiency may mask the abnormal growth pattern of these children and delay diagnosis; determinations of plasma IGF-I concentrations may be helpful in assessing the GH status of these patients.

Insulinlike growth factors in patients with active nephrotic syndrome.

The serum concentrations of insulinlike growth factors 1 and 2 (IGF-1 and IGF-2) were measured by specific radioimmunoassays in 25 nephrotic patients. The serum concentration of IGF-1 in nephrotic patients (mean +/- SEM, 169 +/- 17 ng/mL) was significantly lower than that observed in 20 control subjects matched for sex and age (338 +/- 36 ng/mL). The IGF-2 serum concentration was significantly lower in nephrotic patients (343 +/- 22 ng/mL) than in control subjects (898 +/- 80 ng/mL). The IGF-1 and IGF-2 150-kd and 45-kd carrier protein complexes were found in the urine of nephrotic patients, whereas there was no binding of radiolabeled IGF-1 or IGF-2 to IGF carrier proteins in the urine of control subjects. The low serum IGF-1 and IGF-2 levels observed in nephrotic patients could be partially due to the increased urinary losses of the IGF carrier proteins.

Fetal hypophysectomy causes a decrease in preadipocyte growth and insulin like growth factor-1 in pigs.

Fetal pigs in one uterine horn of each of five gilts were hypophysectomized (HX) in utero by electrical cauterization at 72-74 days of gestation and sera collected at 110 days of gestation. Sera from HX fetuses had lower levels of insulin-like growth factor-1 compared to control littermates (P less than .05). Sera were tested for their effects on primary cultures of stromal-vascular cells from adipose tissue. The soluble protein concentration/dish was lower when pig cells were cultured in sera from HX fetuses compared to sera from control fetuses (P less than .01). Sera from HX fetuses inadequately supported growth of stromal-vascular cells so subsequent experiments utilized pooled sera from normal and HX adult pigs. Sera from HX and control fetuses were mixed with sera from the two adult pools and tested for incorporation of tritiated thymidine into rat preadipocytes and the appearance of adipocytes (determined histochemically) in pig stromal-vascular cultures. In cultures fed sera from HX fetuses there was a lower (P less than .05) number of pig fat cells/culture and a lower level (P less than .06) of preadipocyte proliferation in rat cell cultures when compared to control fetal sera. Fetal pig serum contains factors (adipogenic) which promote the proliferation and differentiation of adipocytes in culture. Serum from HX fetuses has a lower level of adipogenic factors.

Inhibition of neonatal rat growth and circulating concentrations of insulin-like growth factor-I using an antiserum to rat growth hormone.

Treatment of rats for 24 h on day 2, 10 or 20 of age with a specific antiserum to rGH (anti-(rGH], GH, bromocriptine (CB-154) or prolactin failed to influence body weight gain or serum concentrations of insulin-like growth factor-I (IGF-I). On day 28 of age, however, anti-(rGH) completely inhibited body weight gain and markedly reduced circulating IGF-I concentrations, effects which were completely prevented by exogenous ovine GH (oGH). When administered to control rats on day 28 oGH caused supranormal weight gain and serum IGF-I concentrations. These results suggested that GH does not play a significant role in growth or regulation of serum IGF-I until after day 20 of age. By contrast, when anti-(rGH) was given for 4 consecutive days beginning on day 2 of life, body weight gain was reduced within 48 h and remained so until at least 28 days of age. Tail length was also significantly reduced. The effect was due to inhibition of GH effects since serum GH concentrations were low and exogenous GH prevented the effect. Inhibition of growth during the first 14 days of life occurred in the absence of any effect on serum IGF-I although by 21 days of age serum IGF-I was considerably lower than in control rats. The prolonged reduction in growth after treatment has stopped appeared to be due to a cytotoxic effect on the pituitary gland since pituitary weight and GH but not prolactin content were significantly decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of breed and wintering diet on growth, puberty and plasma concentrations of growth hormone and insulin-like growth factor 1 in heifers.

Twenty-five Brangus (BR) and 15 Angus (AN) heifers were used to study the effects of breed and wintering diet on average daily gain (ADG), onset of puberty and plasma concentrations of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). Wintering diets (fed for 107 days beginning November 15) consisted of the following: 1) native grass hay (NGH), 2) ammoniated NGH, 3) NGH plus cottonseed meal, 4) Diet 3 plus corn and 5) Diet 4 plus monensin. After wintering, heifers were transferred to ryegrass pasture for 70 days. Mean ADG during the wintering phase were -.20, -.10, .17, .29 and .39 kg for heifers fed Diets 1 through 5, respectively (P less than .01). ADG was greater (P less than .05) for BR than for AN heifers. Plasma concentrations of GH were higher (P less than .05) in heifers fed Diets 1 and 2 than in heifers fed Diets 3, 4 or 5. Plasma concentrations of IGF-1 were lowest in heifers fed Diet 1 and highest in heifers fed Diets 4 and 5. During ryegrass grazing, GH concentrations were similar for all groups. However, concentrations of IGF-1 were higher (P less than .05) in heifers fed Diets 3, 4 and 5 than in heifers fed Diets 1 and 2. Age at puberty (onset of cyclic progesterone concentrations) was greatest in heifers fed Diet 1 and lowest in heifers fed Diet 5. Weight at puberty was not affected (P greater than .10) by wintering diet but was greater (P less than .01) in BR than in AN heifers. Therefore, negative ADG appears to be associated with elevated plasma GH concentrations in heifers, and plasma IGF-1 concentration appears to be a more accurate indication of nutritional status than plasma concentrations of GH.

Decreased 34K insulin-like growth factor binding protein in polycystic ovarian disease.

Insulin and insulin-like growth factor I (IGF-I) have been implicated in ovarian androgen production. Insulin is closely related to IGF-I and cross-reacts with its receptor. The 34K IGF-binding protein (34K IGF-BP) has been shown to inhibit the binding of IGF-I to its receptor. The authors evaluated the role of insulin in the regulation of serum levels of 34K IGF-BP in patients with polycystic ovarian disease (PCOD). 34K IGF-BP levels during an oral glucose tolerance test (OGTT) were measured in 15 PCOD (8 obese and 7 nonobese) patients and in 10 healthy control subjects. The fasting level of 34K IGF-BP was decreased in nonobese PCOD patients (2.4 +/- 0.3 micrograms/l) (mean +/- standard error) (P = 0.02) and obese PCOD patients (0.59 +/- 0.2 micrograms/l) (P less than 0.001) as compared with healthy controls (4.8 +/- 0.9 micrograms/l). Both nonobese PCOD patients and normal controls demonstrated a significant decrease in 34K IGF-BP following OGTT. An insulin-related decrease in 34K IGF-BP may allow an increased pool of IGF-I able to bind to its receptor. This would provide a mechanism for increased ovarian androgen production via IGF-I stimulation of its receptor.