Somatomedin Research Articles

Gestasyonel diyabetik anne bebeklerinde kalp fonksiyonlarının ekokardiyografik bulguları ve somatomedin c ile ilişkisi

Gestasyonel diyabetik anne bebeklerinde kalp fonksiyonlarının ekokardiyografik bulguları ve somatomedin c ile ilişkisi

The application of insulin-like growth factors system in the diagnosis and treatment of tumor

Malignancies threaten human health seriously. Recently studies show that intercellular signal transduction influences the biological characteristics of tumor cells. It has closely relationship with tumor growth and metastasis. Insulin-like growth factor (IGFs) signal transduction system is a potential mitogen that distributed in the body's tissues, organs and blood. Researches show that the abnormal expression of IGFs exists in many tissues, such as breast cancer, colorectal cancer, gastric carcinoma, lung carcinoma, pancreatic cancer and so on, which may play an important role in occurrence and metastasis as a novel tumor marker.(Chin J Lab Med, 2016, 39: 575-577) Key words: Neoplasms; Somatomedins; Signal transduction; Tumor markers, biological

Structural and biochemical evidence for disulfide bond heterogeneity in active forms of the somatomedin B domain of human vitronectin

Structural and biochemical evidence for disulfide bond heterogeneity in active forms of the somatomedin B domain of human vitronectin

Free fatty acid responses to growth hormone (GH)-releasing factor and the GH-GH receptor axis

The functional assessment of GH receptor has been previously performed by GH-induced somatomedin (SM) generation test. There is a specific GH receptor on adipocytes, and GH induces lipolysis with an increment of plasma free fatty acid (FFA). In this report, we examined GH and FFA responses to GRF loading tests and GH-binding protein, which reflects the tissue GH-receptor concentration, in 30 short children, and we evaluated the lipolysis mediated by GH and GH-receptor axis. Following GRF administration, there was a definite increase in plasma FFA levels, which mainly consisted of palmitic acid and oleic acid on HPLC analysis. In the group of GH high responders, peak GH levels more than 30 ng/ml, the increments of FFA were apparently more than those in the GH low responders, peak GH levels less than 30 ng/ml. There was a significant correlation between the integrated GH secretion and the integrated FFA net-increments. In the GH low responders, the integrated FFA net-increments significantly correlated with their serum GH-binding protein activities. The net increments of FFA were also correlated with basal SM-C levels. In a case of GH-resistant dwarfism, in which GH-binding protein activity was markedly reduced, the patient's GH secretion to GRF as high as 51 ng/ml did not induce any increment of FFA levels. These results suggest that FFA responses to GRF loading depend on the integrated GH secretion and tissue GH-receptor content. FFA measurements in GRF test samples may be a simple and useful method for the functional assessment of GH and GH-receptor axis.

Somatomedin C (IGF I) plasma levels after orthotopic liver transplantation (OLT) in end-stage cirrhotic patients.

Insulin-like growth factors [IGF I and II or somatomedins (SMS)] are polypeptides chemically and biologically correlated with insulin. The main source of synthetic activity and secretion is the liver, although many other tissues have been demonstrated to synthesize SMS. In the circulation, they are not present in a free form, but are mostly bound to a specific carrier protein independently synthesized in the liver. Hepatic or extrahepatic storage organs have not been demonstrated; the half life of the SMS-binding protein complex is between 3 and 4. Synthesis of SMS is regulated by GH, insulin, thyroxine and nutrition (caloric and protein intake, and nitrogen balance). The role of corticosteroids is still a matter of debate: in patients treated with steroids SMS blood levels have been shown to be within normal limits, while biological activity has been demonstrated to be significantly reduced by SMS inhibitors, probably induced by corticosteroid therapy. The biological properties of SMS are related to their structural homology with insulin, and can be summarized as follows: A. Insulin-like activity (glucose oxidation, lipogenesis, glycogen synthesis, inhibition of lipolysis and glycogenolysis); B. Sulphation activity (incorporation of sulphate and leucine into glycosaminglycans of the cartilage); C. Stimulation of fibroblast multiplication; D. Amplification of other hormone activities (GH); E. Complementary anabolic activity with insulin. Low levels of SMS have been demonstrated in hypopituitarism (secondary) or in other diseases independent of GH reduced secretion (primary) such as malnutrition, malabsorption, acute or chronic liver failure and uraemia. Negative nitrogen balance, hypocaloric and/or low protein diets are usually correlated with low levels of SMS. Recently, Schalch et al. reported on the role of orthotopic liver transplantation (OLT) in normalizing SMS blood levels in a group of end-stage liver diseased patients. This preliminary paper deals with changes in IGF-I plasma levels (somatomedin C) in a group of patients affected by end-stage liver cirrhosis before and after OLT.

Somatomedin C (IGF I) plasma levels after orthotopic liver transplantation (OLT) in end-stage cirrhotic patients

Insulin-like growth factors [IGF I and II or somatomedins (SMS)] are polypeptides chemically and biologically correlated with insulin. The main source of synthetic activity and secretion is the liver, although many other tissues have been demonstrated to synthesize SMS [5]. In the circulation, they are not present in a free form, but are mostly bound to a specific carrier protein independently synthesized in the liver. Hepatic or extrahepatic storage organs have not been demonstrated; the half life of the SMS-binding protein complex is between 3 and 4 [1]. Synthesis of SMS is regulated by GH, insulin, thyroxine and nutrition (caloric and protein intake, and nitrogen balance). The role of corticosteroids is still a matter of debate: in patients treated with steroids SMS blood levels have been shown to be within normal limits, while biological activity has been demonstrated to be significantly reduced by SMS inhibitors, probably induced by corticosteroid therapy [2]. The biological properties of SMS are related to their structural homology with insulin, and can be summarized as follows [5]: Insulin-like activity (glucose oxidation, lipogenesis, glycogen synthesis, inhibition of lipolysis and glycogenolysis) Sulphation activity (incorporation of sulphate and leucine into glycosaminglycans of the cartilage) Stimulation of fibroblast multiplication Amplification of other hormone activities (GH) Complementary anabolic activity with insulin. Low levels of SMS have been demonstrated in hypopituitarism (secondary) or in other diseases independent of GH reduced secretion (primary) such as malnutrition, malabsorption, acute or chronic liver failure and uraemia [2]. Negative nitrogen balance, hypocaloric and/or low protein diets are usually correlated with low levels of SMS. Recently, Schalch et al. reported on the role of orthotopic liver transplantation (OLT) in normalizing SMS blood levels in a group of end-stage liver diseased patients [3]. This preliminary paper deals with changes in IGF-I plasma levels (somatomedin C) in a group of patients affected by end-stage liver cirrhosis before and after OLT.

Serum somatomedin binding proteins: physiologic significance and interference in radioligand assay.

Mammalian sera contain binding proteins that specifically complex with somatomedins (insulin-like growth factor I and II) so that there are no detectable free somatomedins. There is immunologic evidence of two distinct types of serum binding proteins. The major binding protein complex (150,000 Mr) is growth hormone dependent. Binding proteins protect somatomedins from proteolytic degradation, retard plasma clearance, and decrease the availability to tissue receptors. The presence of serum binding proteins interferes with radioimmunoassays and radioreceptor assays for somatomedins. Proposed strategies to neutralize the interference from binding proteins without their elimination do not achieve this goal. Extraction of somatomedins by acid ethanol, hydrophobic absorption on C18 silicates (SepPak), and acid gel filtration are effective with human serum, but only acid gel filtration is satisfactory with rat serum. Failure to eliminate binding proteins from assays can lead to serious artifacts in conditions where abnormalities of binding proteins exist.

Receptors for insulin-like growth factors I and II in developing embryonic mouse limb bud

Insulin-like growth factors (IGF) or somatomedins (SM) have been classically defined as promoting the actions of growth hormone in skeletal growth. IGF is divided into two groups, IGF-I and II, and are presumed to act via IGF type I (higher affinity for IGF-I and II and very low affinity for insulin) and II (higher affinity for IGF-II than I and no affinity for insulin) receptors, respectively. Recently, a switchover role of IGF-II to I during fetal to adult growth has been suggested. We have investigated the possible transitional role of IGF-II to I in a developing mouse embryonic limb bud organ culture model. In this in vitro system, limb bud develops from the blastoma stage to a well-differentiated cartilage tissue. Both IGF type I and II receptors were found to be present in limb buds at all stages of differentiation. Type I receptor decreased with differentiation while Type II receptor increased. The effect of IGF-I on [ 3H]thymidine and [ 35S]sulfate uptake by the tissue increased with differentiation while the effect of IGF-II on [ 3H]thymidine uptake of the undifferentiated tissue was abolished with differentiation of the tissue. The increase of the IGF-I response with decreased type I receptor may reflect an altered receptor sensitivity (occupancy) during differentiation. The decrease of the IGF-II response with increased type II receptor with differentiation may on the other hand suggest that IGF-II in differentiated tissue no longer acts as a classical growth factor. These results tend to support the hypothesis of the switchover role of IGF-I and II during fetal and adult growth, however, confirmation of the precise role of IGF-I and II in biological growth may have to wait until further studies clarifying the significance of the increased IGF type II receptor in differentiated tissue are made.

Low circulating somatomedin-C/insulin-like growth factor I in insulin-dependent diabetes and malnutrition: growth hormone receptor and post-receptor defects.

Although growth hormone (GH) is the principal stimulus for somatomedin (SM) production (Van Wyk, 1984), serum SM concentrations are reduced markedly despite normal or elevated GH in children with poorly controlled insulin-dependent diabetes or protein-calorie malnutrition (Winter et al., 1980; Grant et al., 1973). Furthermore, rats that are diabetic or chronically protein-deficient have low serum SM concentrations that do not increase after injection of GH (Phillips and Young, 1976; Shapiro and Pimstone, 1978). The in vitro production of SM by the livers of such diabetic or protein-deprived animals is reduced, and cannot be restored to normal by GH added in vitro (Miller et al., 1981; Shapiro et al., 1978). These observations suggest that the liver in insulin-dependent diabetes and in malnutrition is resistant to GH action. This paper reviews studies directed at determining the mechanisms responsible for this hepatic GH resistance. Specifically, we have sought to determine whether the GH resistance present in diabetes and malnutrition is due to alterations of GH receptors or to post-receptor defects.

Profile of serum immunoreactive insulin-like growth factor I during gestation in Wistar rats

It has been reported that there is a striking homology between the basic insulin-like growth factors (IGF)-somatomedins (SM) found in humans and rats. The radioimmunoassay (RIA) developed for the human hormone IGF-I (basic somatomedin, B-SM) can measure immunoreactive IGF-I in rat serum (IrIGF-I). Using this RIA, the profile of serum IrIGF-I was measured at each day of gestation in groups of inbred and Charles River Wistar rats. In each case IrIGF-I showed a gradual increase in early and mid gestation followed by a sharp decrease that occurred late in gestation to values 20-40% of control. The profile obtained from Charles River Wistars was shifted in time compared with the inbred group. Neither ovariectomy nor progesterone administration to ovariectomized nonpregnant animals altered serum IrIGF-I levels. Thus, although rat IGF-I and human IGF-I can be measured using the same assay, the changes that occur in gestation are in opposite directions.

Molecular aspects of the human somatomedins.

The primary structure of the somatomedins (SM) IGF-I and IGF-II has been known for some years. Both from isolation of the SMs from plasma and from the study of cDNAs it has become evident that there are more SMs, needing further study. In plasma the SMs are present in larger molecules of two size-classes: 150 kD and 40 kD, behaving as specific SM-binding proteins. The possibility that such protein classes are heterogeneous and also contain precursor molecules undergoing proteolytic processing is considered. The somatomedin genes are discontinuous and span large regions of the human genome.

Somatomedin synthesis by a subclone of Buffalo rat liver cells. Influence of divalent cations on rIGF-II release.

Previous studies have provided evidence that biosynthesis and secretion of somatomedin (SM) is not only hormone dependent, but also modulated by nutritional factors. Little is known, however, about the role of divalent cations in these processes. A subclone of Buffalo rat liver (BRL) cells, known to secrete rat insulin-like growth factor-II (rIGF-II) into serum-free medium, was used to define the influence of Ca2+, Mg2+ and Zn2+ on this function. The secretion of rIGF-II by subclone BRL-3SC appears to be quite stable in minimal essential medium (MEM) over a wide range in Ca2+ concentrations (0.18-3.0 mM) but is reduced to only 8% of controls in the absence of Ca2+ (P less than 0.01). Reducing, and even eliminating, the extracellular concentration of Mg2+ alone caused no change in basal rIGF-II release, while simultaneously decreasing Mg2+ and Ca2+ results in a marked drop in the secretion of this SM, reaching a nadir of 38% of controls in the absence of Mg2+ (P less than 0.001). A Mg2+ concentration of 10 mM, or 25 times 'normal', did not alter the basal secretion of rIGF-II. Eliminating the trace amount (0.8 nM) of Zn2+ in MEM by chelation with EDTA decreased rIGF-II secretion to 62% of control levels (P less than 0.01), while increasing the concentration of this cation to 3 mM did not alter the basal release of this SM. Decreased rIGF-II release in the presence of EGTA and EDTA is not due to irreversible cell damage since the secretion of this SM was restored to normal during subsequent reincubation in MEM alone.(ABSTRACT TRUNCATED AT 250 WORDS)

94 HUMAN PLACENTAL LACTOGEN PROMOTES CELL PRCLTFERATION, DNA SYNTHESIS, AND SOMATOMEDIN RELEASE BY ISOLATED HUMAN FETAL CONNECTIVE TISSUES

Since placental lactogens have been implicated in the control of fetal metabolism, and in the release of somatomedins (SM) by fetal tissues, we examined the actions of human placental lactogen (HPL) on the growth of isolated human fetal myoblasts, fibroblasts and cartilage explants, and on their release of immunoassayable SM-C. Myoblasts were derived from skeletal muscle and fibroblasts from the skin of abortuses delivered between 12 to 17 weeks after prostaglandin induction. Costal cartilage explants were obtained from one hemithorax. After myoblasts and fibroblasts were plated at low density (0.3 × 105 cells per well) HPL (50-1000 ng ml−1) caused a dose-dependent increase in cell number over a 7 day incubation, becoming statistically significant between 50 and 250 ng/ml with individual experiments. After sub-confluent mycblasts and fibroblasts were growth-restricted by exposure to medium containing 1% fetal calf serum, HPL caused a significant increase in [3H] thymidine uptake during a subsequent exposure at similar concentrations. Human growth hormone (HGH) failed to increase thymidine incorporation by myoblasts or fibroblasts, while neither HPL or HGH affected isotope uptake by cartilage explants. Culture medium conditioned for 44 h by exposure to myoblasts or fibroblasts was assayed for SM-C by RIA after extraction with acid-ethanol. The SM-C present in conditioned medium was significantly elevated after exposure of cells to HPL (250 ng ml−1) but not HGH. The results show that HPL is mitogenic for cultured human fetal myoblasts and fibroblasts and that this may be due partly to an increase in SM-C release by the cells.

Plasma hormone levels in growth-retarded rats with dorsomedial hypothalamic lesions

Rats with lesions in the dorsomedial hypothalamic nuclei (DMNL rats) are hypophagic and growth-retarded. Since previous work had shown normal plasma growth hormone and insulin levels in DMNL rats we investigated the diurnal patterns of these and other hormones involved in growth. Trial 1: Rats received electrolytic DMNL or sham operations (SCON). The DMNL rats exhibited no differences from SCON rats in plasma triiodothyronine (T3), growth hormone (GH), insulin and somatomedin (SM) concentrations, Trial 2: kainic acid, a neurotoxin, was used for lesion production. Again, DMNL rats showed no deficiencies in plasma levels of T3, GH or insulin. Trial 3: In this experiment, diurnal hormone profiles were assessed. The GH profile and mean 24-hour secretion of both DMNL and SCON groups did not differ significantly. Both groups exhibited a diurnal release of T3, with the DMNL rats showing slightly higher levels. Plasma insulin rose after dark, i.e., at the onset of feeding, in SCON but not in DMNL rats; the later have a previously reported disrupted feeding rhythm. Glucose patterns were in keeping with insulin profiles. Controls showed a normal plasma corticosterone rhythm whereas DMNL rats had an altered pattern. The data suggest that deficiencies in the principal anabolic and growth-promoting hormones cannot be responsible for the retarded growth of DMNL rats.

279 SYNERGISTIC EFFECTS OF EPIDERMAL GROWTH FACTOR AND SOMATOMEDIN IN CHICK CHONDROCYTES

Multiple growth factors (GF) have been isolated, characterized and shown to stimulate growth in at least one tissue. Some have been termed competence factors, while others are termed progression factors dependent upon their site of action in the cell cycle of 3T3 cells. Somatomedin (SM) is the major regulator of cartilage growth and glycosaminoglycan (GAGS) biosynthesis. Epidermal, fibroblast, platelet derived growth factors, and multiple stimulating activity (EGF, FGF, PDGF, and MSA) are known to be important for growth of other tissues. The combined effects of these GF factors with SM in cartilage cells have not been defined. We have studied the interaction of these GF with SM-C in embryonic chick cartilage cells using radioactive precursors. The cells are grown in Ham's F-12 nutrient mixture with 6% serum for 4-6 days following which the media is removed and replaced with media containing 0.5% albumin and the factor or factors to be studied. Radioactive precursors were added after one hour and incubation continued for 2-3 hours. In 2-12 hour incubations SM-C is stimulatory for 3 5SO4 uptake, [3H]-thymidine into DNA, [3H]-uridine into RNA, and [1 4CJ-serine into protein with no potentiation by EGF, FGF, PDGF, or MSA. However, when the incubations are extended 24-30 hours, there is a synergistic effect of EGF and FGF on DNA, RNA, and protein synthesis with less potentiation of the SM effect on GAGS biosynthesis. The data suggests a synergistic interaction between SM and other GF for optimal cartilage growth.

Impaired somatomedin generation test in children with insulin-dependent diabetes mellitus.

Recent studies have suggested a partial block in somatomedin (SM) production or growth hormone (GH) action in IDDM. Twelve well-nourished diabetic children (9 males and 3 females with a mean age of 11.2 +/- 3.3 yr), six with an HbA1c of 7.9-11.2% (group A) and six with an HbA1c of 12.5-15.6% (group B), were studied as follows: the GH response after 100 micrograms of oral clonidine and the SM generation capacity after i.m. administration of 0.2 U/kg/dose of human growth hormone (hGH) for 4 days. Group B diabetic subjects had a significantly higher mean +/- SD GH increase after clonidine than did group A patients (delta of 17.4 +/- 4.9 versus 5.7 +/- 6.0 ng/ml, P less than 0.01); the basal GH of both groups were similar (1.6 +/- 0.7 versus 2.3 +/- 1.4 ng/ml). In contrast, the SM response to hGH was significantly decreased in group B children as compared with those in group A (delta of 0.3 +/- 0.3 versus 1.2 +/- 0.4 U/ml, P less than 0.01). The basal SM levels of both groups were normal for age. GH and SM correlated with HbA1c levels (r = +0.80, P less than 0.01; r = -0.79, P less than 0.01, respectively); there was no correlation with plasma and urine glucose or serum cholesterol, cortisol, and transferrin. Our data indicate a blunted SM response to hGH in group B diabetic subjects; this defect in SM generation is apparently not present in group A subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma Somatomedin in Children with Perthes’ Disease

Plasma Somatomedin in Children with Perthes’ Disease

Changes in somatomedin activity in anorexia nervosa.

Somatomedin (SM) activity, GH, T3 and T4 were investigated in 6 girls with anorexia nervosa during hospitalization and at outpatient clinic. On admission, serum T3 (27-62 ng/dl) and SM activity (0.24-0.55 U/ml) were low in all cases, while basal GH was extremely high in 2 cases. A significant negative correlation was found between SM activity and basal GH during the course of treatment (r = -0.61, p less than 0.02). The change in SM activity was related to that of the serum T3 level and a significant positive correlation was found between SM activity and serum T3 (r = 0.80, p less than 0.001). These data suggest that decreased SM activity may suppress the inhibitory effect of SM on GH release and may raise the basal GH level. SM activity is one of the indicators of the nutritional condition in anorexia nervosa as well as the serum T3 concentration.

Enhanced hGH pituitary secretion rate associated with somatomedin deficiency as manifested in Laron type dwarfism (LTD)

In 3 patients with LTD and 8 normal subjects the following parameters were determined: Integrated 24h hGH concentration (IC-hGH) was elevated in the 2 teenager LTD females and at the upper limit of normal in the young LTD male. The metabolic clearance rate (MCR) was lower in the 2 LTD patients studied than in normal subjects, as in patients with hGH deficiency. The production rate (PR) was elevated in the girl (within the range of acromegaly) whereas in the young man it was only slightly elevated. All 3 LTD patients showed secretory 24h patterns having more frequent and greater fluctuations than in normals. In view of recent findings that the primary defect in LTD is an inability of liver receptors to bind hGH, causing a lack of somatomedin (SM), it is suggested that the enhancement and irregularity of hGH secretion in LTD is due to a dual mechanism, both pathways being related to SM deficiency: 1) lack of negative feedback on pituitary hGH and possibly on GH-RH; 2) lack of stimulating effect on somatostatin secretion.

Serum somatomedin C concentrations following pneumonectomy.

Because a somatomedinlike substance appears in rabbit serum 9 days after pneumonectomy, which has the capacity to make cultured type II cells incorporate 3H thymidine into DNA, we measured serum immunoreactive somatomedin C concentrations following pneumonectomy, nephrectomy, and sham operation (thoracotomy). We found no striking differences in somatomedin C levels between the 3 groups at 5, 9, 13, 17, and 21 days postsurgery, indicating that somatomedin-C and the serum postpneumonectomy factor are unlikely to be the same. Serum somatomedin-C concentrations, however, rose following surgery in all groups, suggesting that serum somatomedin-C responds to surgical wounding. We speculate that the increase in serum somatomedin-C reflects production of somatomedin-C by the healing tissue.