It is now clear that PCOS is often associated with profound insulin resistance as well as with defects in insulin secretion. These abnormalities, together with obesity, explain the substantially increased prevalence of glucose intolerance in PCOS. Moreover, since PCOS is an extremely common disorder, PCOS-related insulin resistance is an important cause of NIDDM in women (Table 3). The insulin resistance in at least 50% of PCOS women appears to be related to excessive serine phosphorylation of the insulin receptor. A factor extrinsic to the insulin receptor, presumably a serine/threonine kinase, causes this abnormality and is an example of an important new mechanism for human insulin resistance related to factors controlling insulin receptor signaling. Serine phosphorylation appears to modulate the activity of the key regulatory enzyme of androgen biosynthesis, P450c17. It is thus possible that a single defect produces both the insulin resistance and the hyperandrogenism in some PCOS women (Fig. 19). Recent studies strongly suggest that insulin is acting through its own receptor (rather than the IGF-I receptor) in PCOS to augment not only ovarian and adrenal steroidogenesis but also pituitary LH release. Indeed, the defect in insulin action appears to be selective, affecting glucose metabolism but not cell growth. Since PCOS usually has a menarchal age of onset, this makes it a particularly appropriate disorder in which to examine the ontogeny of defects in carbohydrate metabolism and for ascertaining large three-generation kindreds for positional cloning studies to identify NIDDM genes. Although the presence of lipid abnormalities, dysfibrinolysis, and insulin resistance would be predicted to place PCOS women at high risk for cardiovascular disease, appropriate prospective studies are necessary to directly assess this.

Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis.

The Brush Foundation studies on human growth and development, begun in 1931 and terminated in 1942, have been intensively reviewed and studied by Dr Greulich and Miss Pyle in the formulation of this Radiographic Atlas of Skeletal Development of the Hand and Wrist Serial radiographs of from 2 to 20 hand-films made at successive examinations of each of 1000 boys and girls made up the radiographic material Standards were selected that were judged to be the most representative of the central tendency or anatomic mode of each chronologic age group from birth through 18 years

Radiographic Atlas of Skeletal Development of the Hand and Wrist

There is currently widespread interest in the IGFs (IGF-I and IGF-II) and their roles in the regulation of growth and differentiation of an ever increasing number of tissues are being reported. This selective review focused on the current state of our knowledge about the structure of mammalian IGFs and the multiple forms of mRNAs which arise from alternative splicing and promoter sites which arise from gene transcription. Current progress in the immunological measurement of the IGF is reviewed including different strategies for avoiding binding protein interference. The results of measurements of serum IGF-I and IGF-II in fetus and mother and at various stages of postnatal life are described. Existing knowledge of the concentration of these peptides in body fluids and tissues are considered. Last, an attempt is made to indicate circumstances in which the IGFs are exerting their actions in an autocrine/paracrine mode and when endocrine actions predominate. In the latter context it was concluded that an important role for GH action on skeletal tissues via hepatic production of IGF-I and endocrine action of IGF-I on growth cartilage is likely.

Insulin-Like Growth Factors I and II. Peptide, Messenger Ribonucleic Acid and Gene Structures, Serum, and Tissue Concentrations

argument is often, if not acrimonious, at least heated. It gives an impression of the fluidity of opinion on many fundamental ideas under discussion and of the urgency with which cardiac cyanosis in the newborn is regarded. When Dr. William Muscott says that the earliest he has operated for pulmonary stenosis is on an infant 3 days old, and Sir Russell Brock agrees that the earlier in the first month that operation is undertaken the better, and when Dr. Varco asks Dr. Senning 'so far as I know they have never yet catheterized any child intrauterine in Sweden, but they have done it through the delivery canal sometimes-would you tell us the indications of the Scandinavian group for catheterization in the immediate newborn period?', one is indeed being kept up with the times. But that was two years ago and already some of the questions then debated have since been answered. This beautifully printed and well-illustrated stiff paperbacked volume is, and will for a few years yet remain, an invaluable companion to a full-scale textbook on congenital heart disease.

Growth at Adolescence.

The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin.

Brain growth appears to be regulated by a growth hormone dependent growth factor called BGA (brain growth-promoting activity). A family of growth hormone dependent growth-promoting polypeptides has recently been isolated from serum. These hormones, the somatomedins, are believed to develop from a common embryonic form to the slightly different polypeptides found in the adult circulation. BGA appears to be the embryonic somatomedin and, until its isolation is complete, one of the adult forms, somatomedin A (SMA), has been used. SMA has a direct growth-promoting action on cultured fetal brain cells. Specific SMA binding sites are found in both human and rat brain. In the human fetus, there is an increase in specific SMA binding to brain plasma membranes during the rapid growth phase. In the rat, the concentration of SMA binding sites is increased in the growing fetal brain. Animal studies reveal a significant relationship between circulating levels of BGA and brain growth in vivo. The presence of specific SMA binding sites on mature brain tissue indicates a role in adult brain function. Significant amounts of BGA are found in cerebrospinal fluid. Administration of SMA to hypophysectomized rats stimulates labelled amino acid uptake into brain protein. Such findings led to the proposal that BGA is the growth and maintenance hormone for the brain.

Growth hormone dependent polypeptides and the brain

Objective GH replacement to growth hormone deficient (GHD) adults improves body composition. In a subset however, lean body mass (LBM) fails to increase despite normalization of IGF-I and amino acid availability could be of importance. We analyzed amino acid (AA) profiles in plasma and erythrocytes (RBC) and associations with LBM, serum IGF-I and IGFBP-1 before and during GH replacement. Design and methods Examinations were performed in 15 GHD patients (six women), aged 34–61 yrs before and after 12 months of GH therapy and in a control group of 20 healthy males aged 31–68 yrs. LBM was measured by dual energy X-ray absorptiometry (DXA), free AAs in plasma and RBC by high performance liquid chromatography and serum IGF-I and IGFBP-1 by in-house RIAs. Setting Tertiary care referral centre. Results At baseline, female GHD patients tended to have lower concentrations of the essential branched – chain AAs isoleucine and leucine, total essential AAs, and of the non-essential AA glutamine than the male patients. Male GHD patients tended to have higher plasma and RBC glutamate than controls. At 12 months, IGF-I had normalized in all but one patient and mean LBM gain was 1.9±0.4kg. AA levels were unchanged. The change in LBM at 12 months was positively correlated to the ratio between the sum of isoleucine, leucine and valine and baseline LBM kg/m 2 ( r =0.76, p =0.001, n =15). Conclusion Our results suggest that the essential branched-chain amino acids in plasma are important for the LBM response to GH substitution. Our finding has to be confirmed in larger groups of GHD adults before making a proper selection of AAs to be measured in plasma and added as dietary supplement during GH therapy. GH administration did not change AA levels and measurements are not useful for monitoring of GH therapy at the time being.

Amino acid profiles in adults with growth hormone (GH) deficiency before and during GH replacement therapy

Des-(1-3) insulin-like growth factor-I (IGF-I) is an IGF analogue lacking aminoacid 1 to 3 which displays reduced binding to insulin-like growth factor binding protein-1 (IGFBP-1). A greater inhibition of immunoreactive IGFBP-1 was obtained with des-(1-3) IGF-I (10 ng/ml) in Hep G2 medium when incubated in Eagle's Modified Essential Medium (EMEM) without phenolred compared to EMEM with phenolred; EMEM without phenolred was chosen for further experiments. Des-(1-3)IGF-I decreases dose dependently the concentration of IGFBP-1, with a maximal effect at 3-10 micrograms/l when incubated for 24 h; 10 micrograms/l of des-(1-3)IGF-I caused a small but significant inhibition of IGFBP-1 after 8 h incubation and this inhibition was 41% and 33% of controls after 14 and 19 h incubation. The relative potencies at 16 h of incubation of IGF-I and insulin in suppressing IGFBP-1 in comparison to des-(1-3)IGF-I were 0.41 (0.25-0.78) and 0.08 (0.01-0.26), respectively. A dose-dependent decrease of IGFBP-1 mRNA to 30% of control was observed after 4 h incubation with 0.1-10 micrograms/l des-(1-3)IGF-I. Changes of glucose concentration (0-20 mmol/l) in the medium did not affect the IGFBP-1 concentration in the medium. In summary: Des-(1-3)IGF-I was tenfold more potent than insulin, and threefold more potent than IGF-I in decreasing IGFBP-1 concentration in medium conditioned by Hep G2 cells.

Insulin-like growth factor binding protein-1 from Hep G2 cells is potently inhibited by the truncated IGF-I analogue des-(1-3) IGF-I.

The erythroleukemia cell line K562 was previously shown to have specific binding sites for insulin but not for insulin-like growth factor I (IGF-I). In this study the presence of specific receptors for insulin-like growth factor II (IGF-II) is established. Scatchard analysis of the competition curve for IGF-II disclosed a non-cooperative binding kinetic with a calculated affinity constant 2.4 X 10(8) M-1 and a receptor number of 4.8 X 10(4) sites/cell. IGF-I displayed 10% crossreactivity over the IGF-II receptor but insulin did not crossreact at all. Instead insulin, present in high concentrations, enhanced the binding of IGF-II. The presence of IGF II but not IGF-I receptors makes the K562 cell line suitable for studying properties of the type-2 receptor.

The binding of insulin-like growth factor II to the erythroleukemia cell line K562

Glucagon has previously been reported to increase serum levels of insulin-like growth factor binding protein-1 (IGFBP-1) in humans. The in vitro effect of glucagon and glucagon-like peptide-1 (7–36) amide (GLP-1) was investigated in Hep G2 human hepatoma cells. The expression of IGFBP-1 mRNA was determined by solution hybridization assay and IGFBP-1 secretion was measured by radioimmunoassay. In contrast to forskolin the peptides glucagon and GLP-1 had no effect on IGFBP-1 mRNA at 3, 6 and 24 h incubation or any detectable effect on the apparent half-life of IGFBP-1 mRNA. However, the exposure to glucagon (10 μg/mL, 2.87 μM) and GLP-1 (1 μM) caused a two-fold stimulation in protein levels of IGFBP-1 after 6 h incubation, declining to control levels after 24 h. This transient effect was dose dependent, remained when transcription was inhibited and required protein synthesis. The regulation of IGFBP-1 secretion by glucagon and GLP-1 appeared to be cAMP independent. In conclusion, glucagon and GPL-1 were shown to have a post-transcriptional stimulatory effect on IGFBP-1 release.

Glucagon and GLP-1 stimulate IGFBP-1 secretion in Hep G2 cells without effect on IGFBP-1 mRNA.

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