Nonsuppressible Insulin-like Activity Research Articles

From Insulin and Insulin-Like Activity to the Insulin Superfamily of Growth-Promoting Peptides: A 20th-Century Odyssey

In 1941, Gellhorn reported that administration of human blood to hypophysectomized/adrenodemedullated rats caused a fall in blood sugar. This was among the early demonstrations that human blood possesses glucose-lowering or insulin-like activity (ILA). Gellhorn assumed he had detected only insulin. During the 1960s, however, it became evident that plasma ILA contained at least two components: one, suppressible ILA (SILA), was inactivated by anti-insulin antibody and was therefore considered to be indistinguishable from pancreatic insulin; the other, nonsuppressible ILA (NSILA), was unaffected by anti-insulin antibody. Subsequent work resolved NSILA into insulin-like growth factors I and II (IGF-I and IGF-II), two 7.5 kilodalton peptides with potent mitogenic properties; established their identity with the somatomedins; and investigated both their therapeutic potential and role in the pathogenesis of neoplastic and other human diseases. Insulin and the IGFs exhibit striking homologies in amino acid composition and some degree of overlap in their signaling pathways and actions. Moreover, insulin-like proteins have been identified not only in all vertebrate classes but also in molluscs, insects, and worms. These observations are the basis for the hypothesis that the genes encoding vertebrate insulins and IGFs and invertebrate insulin-like molecules evolved from a common ancestral gene, and for the concept of an insulin superfamily of growth-promoting peptides.

Insulin-Like Growth Factors and Their Binding Proteins: Biological Actions*

THE insulin-like growth factors were discovered on the basis of their ability to stimulate cartilage sulfation and to replace the “sulfation factor activity” of GH, as determined using an in vivo assay, in an in vitro test system (1). The biological significance of this finding was quickly expanded beyond the study of cartilage sulfation to include stimulation of DNA synthesis (2), proteoglycan synthesis (3), glycosaminoglycan synthesis (4), and protein synthesis (5). Most of these studies used tissue preparations such as isolated diaphragm, cartilage, or epididymal fat pads to study biologicalactivity. In recognition of its generalized pleiotypic actions, in the early 1970's sulfation factor was renamed somatomedin (mediator of the effects of somatotropin) and was included in the emerging classification of broad spectrum growth factors along with platelet derived growth factor, fibroblast growth factor, and epidermal growth factor (6). During the period in which the biological actions of sulfation factor were being characterized, parallel studies were initiated that attempted to define factors in serum that could stimulate insulin-like effects. Because these factors were known to be distinct from immunoreactive insulin, their bioassay was based on insulin-like actions that could not be abolished by the simultaneous addition of anti-insulin antibody, and the factors were termed nonsuppressible insulin-like activity (NSILA) (7). Initial biological studies of both NSILA and somatomedin were based on the use of crude serum extracts. Early attempts to extract these factors from tissues were generally not successful, and by 1970 it had been concluded that no concentrated organ source for them existed (8). However, highly purified preparations of both factors were prepared from serum extracts.

Insulin-like growth factor II and nonsuppressible insulin-like activity levels in newborns

We measured insulin-like growth factor II and nonsuppressible insulin-like activity levels in the sera of newborn infants with different birth weights and gestational ages to determine the significance of these peptides in fetal growth. Our results obtained by use of one-way analysis of variance showed that the insulin-like growth factor II and nonsuppressible insulin-like activity levels in premature, average-weight-for-gestational-age, large-for-gestational-age, and small-for-gestational-age newborns were significantly different (p<0.01). Although levels in the premature neonates were less than the other three groups and large-for-gestational-age neonates had a higher insulin-like growth factor II level than the other three groups, maternal insulin-like growth factor II levels in all groups were similar. These results suggest that insulin-like growth factor II may play a major role in fetal growth.

Abnormal growth hormone dynamics in chronic liver disease do not depend on severe parenchymal disease

Abnormal basal serum levels of growth hormone (GH) and abnormal GH dynamics have been observed in patients with alcoholic cirrhosis (AC). To further characterize these abnormalities, patients with AC or schistosomal hepatic fibrosis (SHF) were evaluated. The former patients have parenchymal liver disease, portal hypertension, and portosystemic shunting. SHF, in contrast, is characterized by periportal fibrosis with minimal or no parenchymal cell disease, portal hypertension, and portosystemic shunting. We studied 20 patients with SHF and normal stature and 15 patients with AC. In these two groups of patients, basal serum GH was higher than normal ( P < .01). A paradoxical increase in GH was observed during the oral glucose tolerance test (OGTT) in 55% of SHF and in 40% of AC patients. Significant GH elevation followed thyrotropin-releasing hormone (TRH) administration in 80% of SHF and 66% of AC patients, but not in normals. Serum nonsuppressible insulin-like activity (NSILA) and serum somatomedin C (Sm-C) levels were reduced significantly in both groups. In SHF patients, the paradoxical increase in GH during OGTT correlated inversely with Sm-C ( r = −.6, P < .05). We conclude that (1) abnormal GH secretion occurs in both SHF and AC, (2) serum Sm-C and NSILA are diminished in both forms of liver disease, and (3) portosystemic shunting of blood appears to be the important pathology shared by both forms of liver disease.

Growth hormone, somatomedin C, and nonsuppressible insulin-like activity levels compared in premature, small average birth weight, and large infants

We have investigated the relationship between growth hormone, somatomedin C, nonsuppressible insulin-like activity, weight, gestational age, and 1-minute Apgar score in newborn infants. The 153 infants were categorized as small for gestational age (n = 19), average for gestational age (n = 59), large for gestational age (n = 60), and premature (gestational age at birth, 36 weeks or less (n = 15). Our study showed that (1) growth hormone levels were elevated in premature infants and correlated with Apgar scores and birth weights; (2) somatomedin C and nonsuppressible insulin-like activity levels were significantly lower in premature than in term infants; and (3) the birth weight of all infants studied had a significant overall effect on both somatomedin C and nonsuppressible insulin-like activity levels, suggesting that these factors may be involved in fetal growth. However, because in small for gestational age infants somatomedin C and nonsuppressible insulin-like activity were similar to levels in average for gestational age infants, it is suggested that other factors may inhibit fetal growth.

Carbohydrate metabolism in intact golden hamsters infected with plerocercoids of Spirometra erinacei (Cestoda: Diphyllobothriidae).

This study was performed to investigate the mechanism involved in a decrease in the serum glucose of golden hamsters infected with plerocercoids of Spirometra erinacei. The concentration of glucagon, the activity of glucose-6-phosphatase in the liver, and the in vivo incorporation of 2-deoxy-D-[1,2-3H]glucose into various organs increased in plerocercoid-infected hamsters compared with controls. Furthermore, the serum from the plerocercoid-infected hamsters enhanced the in vitro incorporation of [U-14C]glucose into adipose tissues, compared with control serum. The serum levels of immunoreactive insulin and somatomedin associated with nonsuppressible insulin-like activity in experimental animals, however, were not significantly different from those in controls. Therefore, we conclude that the decrease in serum glucose associated with plerocercoid infection is not the result of a decrease in gluconeogenesis, but the result of an increased utilization of glucose in the peripheral tissues.

Nonsuppressible insulin-like activity and somatomedin C levels in normal pregnant women, in pregnant women with gestational diabetes, and in umbilical cord blood of mature and premature infants

This study was undertaken to determine the significance of the changes in nonsuppressible insulin-like activity as measured by the fat pad assay and by the levels of immunoreactive somatomedin C, growth hormone, and human placental lactogen in sera of term normal pregnant women, mothers who delivered prematurely, and women with gestational diabetes at term as compared to normal nonpregnant subjects. These hormones were also measured in the umbilical cord blood of these patients at the time of delivery to determine the possible mechanisms of the fetal growth in utero. Our investigations showed that (1) nonsuppressible insulin-like activity is elevated during pregnancy, but its level was lower in mothers with gestational diabetes in spite of significantly higher serum human placental lactogen compared with normal pregnant mothers; (2) nonsuppressible insulin-like activity is significantly lower in premature infants than in term infants; (3) somatomedin C levels were significantly elevated in pregnant mothers in spite of suppression of growth hormone; (4) nonsuppressible insulin-like activity and somatomedin C levels in infants of mothers with gestational diabetes were not significantly elevated in spite of higher birth weight, indicating that nonsuppressible insulin-like activity and somatomedins are not the only factors responsible for the increase of birth weight of children of diabetic mothers; (5) there was marked discordance between the growth hormone level in the neonates and somatomedin C levels

BINDING SITES IN FETAL AND GROWTH PLATE CARTILAGE

In addition to genetic and nutritional factors, linear growth during the prenatal and postnatal periods is controlled by peptide, steroid, and thyroid hormones interacting with the receptors present on the membrane or in the cytosol and nuclei of growth plate cartilage. Using standard procedures, insulin and nonsuppressible insulin-like activity (a somatomedin) showed significant binding in 600, 15,000, and 105,000 g membrane fractions of epiphyseal cartilage of immature animals. The binding of growth hormone and prolactin was small and probably not significant. Specific uptake of glucocorticoid was demonstrated in viable canine chondrocytes, but not of androgen, estrogen, or vitamin D3 metabolite. A triiodothyronine receptor was present in nuclei from dog epiphyseal cartilage. Hormones that lack binding may affect cartilage only indirectly. Hormone receptors were studied in those portions of fetal growth cartilage that will later evolve into an ossification center, articular cartilage, and epiphyseal cartilage. Cytosol fractions contained a receptor for glucocorticoid but not for androgen or estrogen. Zonal analysis showed a higher level in the peripheral and central sections than in the palisade section. Triiodothyronine binding was also detected in nuclei prepared from whole fetal cartilage. Heterogeneity of cell function was obvious in fetal cartilage. Cell division was high in the central and peripheral zones as well as the upper half of the palisade zone, but low in the lower palisade section. Proline and sulfate incorporation predominated in the palisade section compared with the central and peripheral sections. Disease states with changes of metabolic activities in the cartilage may perhaps be better understood with a clearer knowledge of receptor levels and interactions.

Partial purification and characterization of somatomedin from sheep serum.

A rapid, high yield preparative technique for the isolation of sheep somatomedin is reported. Purification of biologically active somatomedin from the 60% ammonium sulfate precipitate of sheep serum was accomplished using three gentle fractionation steps. Biological activity during purification was monitored using the rat adipocyte nonsuppressible insulin-like activity (NSILA) assay. A stepwise pH elution (pH 2.85, 3.5, 4.5, and 6.0) from SP-Sephadex resulted in the elimination of more than 99% of the serum proteins and a 500-fold enhancement of biological activity. The active fraction eluted at pH 6.0 and was further fractionated on Sephadex G-50 (fine) chromatography at pH 2.85. This resulted in about a 10,000-fold enhancement of activity over serum activity. The most active fractions from Sephadex chromatography were further separated on reverse phase HPLC in 0.1% trifluoroacetic acid using a linear gradient of 24-60% acetonitrile. The biological activity of the final preparation was enhanced 61,000- to 182,000-fold over that of serum (mean, 93,000-fold) when assayed in the NSILA assay. Protein yield was estimated to be 467 micrograms/liter serum. In addition to the NSILA activity, the final preparation demonstrated dose-dependent sulfation factor activity in the embryonic chick pelvic leaflet bioassay. Sheep somatomedin was active at physiological levels in both bioassays. Analysis of the somatomedin preparation by sodium dodecyl sulfate-electrophoresis at pH 8.8 showed that it was homogeneous by this criterion. The activity eluted from Sephadex G-50 was estimated to have a molecular size of 6900. Two Coomassie blue-stained bands were present in the final sheep somatomedin preparation after polyacrylamide gel electrophoresis at pH 3.2. Our purification process is a rapid, high yield technique which yields a polypeptide fraction enriched in NSILA and somatomedin-like activity. The molecular size and biological activity in the NSILA and sulfation factor assays suggest that our sheep NSILA is analogous to somatomedins purified from other species of animals.

Characterization of insulin-degrading activity of intact and subcellular components of human fibroblasts.

We have studied insulin degrading activity (IDA) in cultured human fibroblasts and assessed the effect of various inhibitors of insulin processing on IDA. To evaluate the role of three enzymes of insulin degradation (neutral protease, microsomal glutathione insulin transhydrogenase, and lysosomal acid protease), we subfractionated homogenized fibroblasts into membrane (and nuclei) cytosol, mitochondria, microsomes, and lysosomes. Greater than 90% of IDA was found to be present in the cytosolar fraction containing neutral protease. IDA in intact fibroblasts was completely inhibited by 1 mM N-ethylmaleimide and partially by 0.5 mM dansylcadaverine (75%), 0.5 mM chloroquine (48%), 1 mg/ml bacitracin (32%) and Trasylol (30%). Lidocaine (5 mM) and glucagon (10(-6)M) exhibited about 15% inhibition with minimal inhibition (7%) by nonsuppressible insulin-like activity. Study of similar inhibitors on subfractionated components indicated inhibition of cytosolar enzyme by N-ethylmaleimide (100%), glucagon (30%), chloroquine (41%), nonsuppressible insulin-like activity (30%), Lidocaine (25%), dansylcadaverine (16%), and bacitracin (11%). Incubation of ammonium sulfate-fractionated cytosolar enzyme at 37 C with A14-125I-insulin resulted in generation of two intermediate peaks as early as 1 min. These peaks could be identified by HPLC but not by molecular sieve chromatography. These intermediates exhibited less immunoprecipitability with antiinsulin antibody and receptor binding with liver membrane preparations than intact insulin. Further incubation of A14-125I-insulin with the cytosolar enzyme(s) resulted in reduction of these peaks as well as insulin and formation of 125Iodotyrosine peak. We conclude that human fibroblast is capable of metabolizing cell-associated A14-125I-insulin in a time- and temperature-dependent manner. This process is inhibited by various inhibitors of insulin processing. The bulk of IDA consists of soluble neutral protease(s) with properties similar to other more purified neutral insulin protease preparations. This fraction, similar to the intact fibroblast degrades insulin to two intermediates with similar molecular weight to that of intact insulin but with more hydrophilicity and less binding affinity to antiinsulin antibody and liver membrane than intact insulin.

Differentiation between carrier-bound forms of non-suppressible insulin-like activity (NSILA) in serum

1. 1. Gel-permeation chromatography of serum on Sephacryl S-300 at pH 7.4 has shown that NSILA was detected over a range of MW 50,000–400,000 with a peak at about MW 200,000. 2. 2. When fractions from the above chromatography were rechromatographed on Sephadex G-75 at pH 2.4 major amounts of acid-stable NSILA were found in a fraction of MW 200,000–600,000 (77% of the fraction NSILA or 28% of total serum NSILA). 3. 3. Further evidence was obtained for the presence of an active acid-dissociable complex in serum. This was present in both the MW 100,000–200,000 and 35,000–100,000 fractions and corresponded to 37% of total serum NSILA. 4. 4. Con-A Sepharose affinity chromatography of the serum fractions from Sephacryl S-300 chromatography, followed by Sephadex G-75 chromatography under acid conditions, showed that the acid-stable complex was consistently found in weakly bound materials. The active acid-dissociable complex was found in the bound fractions, especially in the Sephacryl S-300 pool of MW 35,000–100,000. 5. 5. Low MW NSILA (<15,000) was also released on acid treatment from an otherwise inactive high MW complex(es) of MW 35,000–600,000. This complex was not bound by Con-A Sepharose.

Steindler lecture. Binding sites in fetal and growth plate cartilage.

In addition to genetic and nutritional factors, linear growth during the prenatal and postnatal periods is controlled by peptide, steroid, and thyroid hormones interacting with the receptors present on the membrane or in the cytosol and nuclei of growth plate cartilage. Using standard procedures, insulin and "nonsuppressible insulin-like activity" (a somatomedin) showed significant binding in 600, 15,000, and 105,000 g membrane fractions of epiphyseal cartilage of immature animals. The binding of growth hormone and prolactin was small and probably not significant. Specific uptake of glucocorticoid was demonstrated in viable canine chondrocytes, but not of androgen, estrogen, or vitamin D3 metabolite. A triiodothyronine receptor was present in nuclei from dog epiphyseal cartilage. Hormones that lack binding may affect cartilage only indirectly. Hormone receptors were studied in those portions of fetal growth cartilage that will later evolve into an ossification center, articular cartilage, and epiphyseal cartilage. Cytosol fractions contained a receptor for glucocorticoid but not for androgen or estrogen. Zonal analysis showed a higher level in the peripheral and central sections than in the palisade section. Triiodothyronine binding was also detected in nuclei prepared from whole fetal cartilage. Heterogeneity of cell function was obvious in fetal cartilage. Cell division was high in the central and peripheral zones as well as the upper half of the palisade zone, but low in the lower palisade section. Proline and sulfate incorporation predominated in the palisade section compared with the central and peripheral sections. Disease states with changes of metabolic activities in the cartilage may perhaps be better understood with a clearer knowledge of receptor levels and interactions.

Insulin-like growth factor characteristics of an acidic non-suppressible insulin-like activity.

The biological activities of an acidic form of non-suppressible insulin-like activity (ILA pI 4.8) have been studied. ILA pI 4.8 was isolated from Cohn fraction IV-1 of human serum by pH 5.5 ion-exchange chromatography on SP-Sephadex. Carrier-bound ILA was eluted at pH 9.7 and then sequentially gel chromatographed in 1% formic acid on Sephadex G-75 and Bio-Gel P-30. The low-Mr (7000) active material was subjected to flat bed isoelectric focusing. Overall recovery was 87 munit of insulin equivalents/100 g of Cohn fraction IV-1, with a specific activity in the range 4-10 munit/mg of protein, representing a purity of 1-6%. This material has been tested in a variety of insulin-like growth factor (IGF)/somatomedin assay systems. It stimulated, in a dose-related manner, [14C]glucose conversion into lipid by isolated rat adipocytes, 35SO4(2-) incorporation into weanling rat costal cartilage and [3H]thymidine incorporation into DNA of cultured human fibroblasts. Like IGF-I and -II, ILA pI 4.8 was able to inhibit degradation of 125I-insulin by crude homogenates of rat liver. In addition, the biological activity of ILA pI 4.8 was completely suppressible by a recently described inhibitor of IGF-I and IGF-II. ILA pI 4.8 was able to compete, in a parallel manner, with 125I-IGF-I and 125I-IGF-II and, at higher doses, with 125I-insulin in a placental radioreceptor assay. No cross-reactivity was seen in a radioimmunoassay for IGF-I and -II C-peptides, but at higher concentrations parallel displacement was observed in a somatomedin C/IGF-I radioimmunoassay using two different antisera. These data indicate that ILA pI 4.8 does possess many of the biological activities previously reported for the IGFs. Since ILA pI 4.8 does occur naturally in serum, it would appear reasonable to tentatively include it as one of the IGF/somatomedin family.

Reticuloendothelial system function and glucose-insulin dyshomeostasis in sepsis

Circulating glucose levels, peripheral glucose utilization, and hepatic gluconeogenesis were compared in late endotoxicosis and severe septic shock in rats. Endotoxin was administered intravenously as 5 mg of Salmonella enteritidis lipopolysaccharide B. Sepsis was induced in the peritoneal cavity by use of the cecal ligation and puncture technique. Late endotoxicosis and severe sepsis were comparable in hypoglycemia, increased peripheral glucose use, and depression of gluconeogenesis. Immunoreactive insulin was lower in endotoxicosis than in sepsis; both models demonstrated elevations in serum nonsuppressible insulin-like activity. Endotoxic pancreata secreted excessive insulin, as did pancreata obtained after blockade of the reticulo-endothelial system (RES). Macrophage-conditioned media induced a hypersecretory state of the beta cells in donor pancreata. The RES serves as a source of secretory products, i.e., glucoregulatory monokines, which affects insulinization of tissues in sepsis and thus underwrites the hypoglycemia of late endotoxicosis and severe sepsis.

Evidence for a biologically active, carrier-bound form of non-suppressible insulin-like activity (nsila) in human serum

1. 1. Quantitative gel nitration of Cohn fraction IV-1 has shown that high MW NSILA recovered under “neutral” conditions (pH 5.5) was greater in magnitude (~ × 2) than acid-stable high MW NSILA obtained under acid conditions. 2. 2. Recombination, at neutral pH, of high and low MW NSILA, obtained by previous acid gel filtration, gave quantitative recovery of activity which was solely of high MW. 3. 3. These data indicate that a biologically active, and dissociable high MW form of NSILA exists in serum. 4. 4. Con A-Sepharose affinity chromatography gave one unbound NSILA fraction and two bound fractions, which both gave high and low MW activity after acid chromatography. 5. 5. This study provides the first evidence for a carrier-bound form of low MW NSILA which retains biological activity.

Is extrapancreatic tumor hypoglycemia associated with elevated levels of insulin-like growth factor II?

We have tried to answer the still controversial question of whether or not extrapancreatic tumor hypoglycemia is associated with elevated levels of insulin-like growth factor II (IGF II), keeping in mind that controversial results may be due to methodological differences. Serum levels of IGF II were determined by a rat liver membrane radioreceptor assay and by RIA. Serum samples were gel filtered at acidic pH, and some sera were also tested after acid-ethanol extraction as an alternative method for dissociating and separating IGF from the IGF carrier protein. Additionally, the radioreceptor assay was performed with a labeled partially purified IGF preparation [nonsuppressible insulin-like activity soluble in acid-ethanol (NSILA-s "70")] that was used by a group reporting elevated NSILA-s levels in about 40% of their patients with tumor hypoglycemia. Mean serum levels of receptor-reactive IGF II and immunoreactive IGF II (+/- SD) were 436 +/- 169 and 540 +/- 256 ng/ml in 22 patients with tumor hypoglycemia, as compared with 578 +/- 155 and 647 +/- 217 ng/ml in 28 normal adults. This pattern of slightly, but not significantly lower mean IGF II values in tumor hypoglycemia was unchanged when a less pure IGF preparation (NSILA-s 70) was used as a tracer or when the sera were extracted with acid-ethanol. Thus, hypoglycemia resulting from extrapancreatic tumors is not likely to be associated with increased receptorreactive or immunoreactive IGF II levels.

Regulation of the Cell Cycle by Somatomedins

Publisher Summary This chapter discusses the regulation of the cell cycle by somatomedins. The chapter analyzes a group of growth factors that resemble insulin—insulin-like growth factors (ILGFs). The group consists of somatomedins A, nonsuppressible insulinlike activity (that is made up of insulin growth factors one and two, IGF I, IGF II), and multiplication stimulating activity (MSA). The ILGFs may constitute one of the first groups of growth regulators. A range of different culture lines has been evaluated for responses to insulin-like growth factors. In some cases, the cells are stimulated to increase DNA synthesis by a single purified factor whereas, in others, varying combinations are required. The ones responsive to somatomedin C are chondrocytes, frog and rabbit lens epithelium, Sertoli and granulosa cells, fetal liver and limb bud, some blood cell lines, and pituitary tumor cells. In the lens, the migration of epithelial cells and the fashioning of fibers from these cells are stopped in the absence of somatomedin-like molecules.

Somatomedins as regulators of proteoglycan synthesis.

The pleiotypic effect of somatomedins on cells is well-known. This review deals with somatomedins (SMs) as regulators of proteoglycan (PG) synthesis. Once the mechanism of this role of SMs is understood, it can be used as a general macromolecular model for studying the effects of SMs on matrix components of connective tissues. The factors regulating PG production rate can be classified into two categories: 1. Intracellular factors which integrate the following: the genetic code, the synthetic enzymes and their organization, the availability of building block substances, various cell nutritional factors, and =-degrading enzymes. All these determine the basic rate of production. 2. Extracellular factors, including hormones secreted from glandular organs and tissuelocal agents with regulation ability. The hormonal factors may alter rates of PG production and generate differences in the product composition, reflecting changes in the individual’s developmental, physiological and/or pathological status. While hormones such as thyroxine which stimulates the rate and glucocorticosteroids which suppress the rate have been reported to regulate PG synthesis, the somatomedin (SM) family seems to play a key role in this regulation. The term somatomedin denotes the relation of a substance to somatotrophin (growth hormone (GH)), and its intermediary (mediator) role in transmitting the message of GH to the target or soma cells (e.g. fibroblasts, chondrocytes, osteocytes, etc.). At most, the SM family includes six members: SM-A, SM-B, SM-C, NSILA (non-suppressible insulinlike activity) I and 11, or in the new terminology IGF (insulin-like growth factor) I and 11, and MSA (multiplication stimulating activity). The SMs share certain common elements, and some of their characteristics are listed in Table I. In brief, the SMs are a group of low molecular weight polypeptides (ranging from 4000 to 8000 daltons) whose biological activity can be expressed as growth-promoting , insulin-like and mitogenic. The growth-promoting activity is assessed mainly by the effect of SM on the rate of matrix production: this is measured as the stimulation of sulfate incorporation into cartilage slices of various animals. The endocrine route of SMs begins with the hypothalamic secretions which cause the release of GH from the pituitary. This GH is believed to generate the synthesis of SMs, mainly in the liver and kidney, which then operate on their target cells via specific receptor sites on the cell membranes. PG synthesis (matrix production) has become over the years the indicator of the overall growth process of the bony framework and the level of SMs in blood has come to serve as the clinical anabolic index of serum content in growth factors.

Permeability of heated skin

This chapter discusses the regulation of the cell cycle by somatomedins. The chapter analyzes a group of growth factors that resemble insulin—insulin-like growth factors (ILGFs). The group consists of somatomedins A, nonsuppressible insulinlike activity (that is made up of insulin growth factors one and two, IGF I, IGF II), and multiplication stimulating activity (MSA). The ILGFs may constitute one of the first groups of growth regulators. A range of different culture lines has been evaluated for responses to insulin-like growth factors. In some cases, the cells are stimulated to increase DNA synthesis by a single purified factor whereas, in others, varying combinations are required. The ones responsive to somatomedin C are chondrocytes, frog and rabbit lens epithelium, Sertoli and granulosa cells, fetal liver and limb bud, some blood cell lines, and pituitary tumor cells. In the lens, the migration of epithelial cells and the fashioning of fibers from these cells are stopped in the absence of somatomedin-like molecules.

Insulin-like stimulatory effect of human immunoglobulin G on adipocyte lipogenesis.

An investigation into the possible effect of thyroid stimulating immunoglobulin G on lipogenesis by adipocytes led to the discovery that all human IgGs exerted an insulin-like stimulatory effect of lipogenesis by rat adipocytes in vitro. Highly purified polyclonal IgGs prepared from normal subjects had stimulatory potencies similar to those of monoclonal IgGs obtained from patients with IgG myeloma. However, whole sera from myeloma patients with elevated IgG concentrations had a significantly higher stimulatory effect on adipocyte lipogenesis than control sera. These observations provide the first evidence that human IgG has an insulin-like metabolic effect, and that this effect is probably exerted by a nonspecific nonvariable portion of the IgG molecule. IgG may thus contribute to the non-suppressible insulin-like activity in the serum.