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.

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

Insulin-like growth factor II (IGF-II) is a peptide growth factor that is homologous to both insulin-like growth factor I (IGF-I) and insulin and plays an important role in embryonic development and carcinogenesis. IGF-II is believed to mediate its cellular signaling via the transmembrane tyrosine kinase type 1 insulin-like growth factor receptor (IGF-I-R), which is also the receptor for IGF-I. Earlier studies with both cultured cells and transgenic mice, however, have suggested that in the embryo the insulin receptor (IR) may also be a receptor for IGF-II. In most cells and tissues, IR binds IGF-II with relatively low affinity. The IR is expressed in two isoforms (IR-A and IR-B) differing by 12 amino acids due to the alternative splicing of exon 11. In the present study we found that IR-A but not IR-B bound IGF-II with an affinity close to that of insulin. Moreover, IGF-II bound to IR-A with an affinity equal to that of IGF-II binding to the IGF-I-R. Activation of IR-A by insulin led primarily to metabolic effects, whereas activation of IR-A by IGF-II led primarily to mitogenic effects. These differences in the biological effects of IR-A when activated by either IGF-II or insulin were associated with differential recruitment and activation of intracellular substrates. IR-A was preferentially expressed in fetal cells such as fetal fibroblasts, muscle, liver and kidney and had a relatively increased proportion of isoform A. IR-A expression was also increased in several tumors including those of the breast and colon. These data indicate, therefore, that there are two receptors for IGF-II, both IGF-I-R and IR-A. Further, they suggest that interaction of IGF-II with IR-A may play a role both in fetal growth and cancer biology.

Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells.

Several decades of basic and clinical research have demonstrated that there is an association between the insulin-like growth factors (IGFs) and neoplasia. We begin with a brief discussion of the function and regulation of expression of the IGFs, their receptors and the IGF-binding proteins (IGFBPs). A number of investigational interventional strategies targeting the GH or IGFs are then reviewed. Finally, we have assembled the available scientific knowledge about this relationship for each of the major tumor types. The tumors have been grouped together by organ system and for each of the major tumors, various key elements of the relationship between IGFs and tumor growth are discussed. Specifically these include the presence or absence of autocrine IGF-I and IGF-II production; presence or absence of IGF-I and IGF-II receptor expression; the expression and functions of the IGFBPs; in vitro and in vivo experiments involving therapeutic interventions; and available results from clinical trials evaluating the effect of GH/IGF axis down-regulation in various malignancies.

The Effects of Insulin-Like Growth Factors on Tumorigenesis and Neoplastic Growth

Serum levels of insulin-like growth factor-I (IGF-I) increase with age and pubertal development. The large variation in circulating IGF-I levels in adolescence makes it difficult to use the IGF-I value of a single child in the assessment of his growth status. In addition, the interference of IGF-binding proteins in many IGF-I assays contributes to this problem. We measured IGF-I in acid-ethanol-extracted serum from 1030 healthy children, adolescents, and adults, employing a RIA that reduces interference of IGF-binding proteins by using monoiodinated Tyr31-[125I]des-(1-3)IGF-I as radioligand. Mean serum IGF-I concentrations increased slowly in prepubertal children from 80-200 micrograms/L with a further steep increase during puberty to approximately 500 micrograms/L. After puberty, a subsequent continuous fall in circulating IGF-I levels was apparent throughout adulthood to a mean of 100 micrograms/L at the age of 80 yr (P < 0.0001). Girls had maximal IGF-I levels at 14.5 yr of age, whereas boys had peak IGF-I levels 1 yr later. This is almost 2 yr later than average peak height velocity. The large variation in serum IGF-I levels during puberty was diminished when data were separated according to sex and Tanner stage of puberty. Interestingly, we found a significant variation with age within the Tanner stages; there was an increase in serum IGF-I concentrations with age in the early pubertal stages and a decrease in the late stages (P < 0.05). Serum IGF-I increased concomitantly with increasing testicular volume. Multiple regression analysis revealed that serum IGF-I levels predicted height velocity in the following year (r = 0.33; P < 0.0001). Body mass index did not correlate significantly with serum IGF-I in prepubertal children in a multiple regression analysis. In conclusion, there was a significant variation in serum IGF-I levels with age within a given Tanner stage of puberty in addition to the well known increase with increasing age or pubertal stage. Accordingly, the effects of sex, age, and puberty on serum IGF-I cannot be separated into simple additive components when studying 1030 children in a cross-sectional design. Thus, the age-, sex-, and puberty-corrected IGF-I values may, in fact, improve the use of serum IGF-I as a diagnostic tool to distinguish between a child with retarded puberty and a GH-deficient individual.

Serum insulin-like growth factor I in 1030 healthy children, adolescents and adults ; relation to age, sex, stage of puberty, testicular size and body mass index

A radioimmunoassay has been developed for IGF-II, using Sepharose-coupled antibodies. Porcine insulin, human insulin and human proinsulin showed no cross-reaction, whereas the cross-reaction for IGF-I was 10%. To minimize the influence of the binding protein(s), all serum samples were extracted with acid ethanol before assay. The mean serum level of immunoreactive IGF-II and 95% confidence limit in 46 healthy adults were 587 ng/ml and 354-974 ng/ml, respectively. In contrast to the declining levels of IGF-I with increasing age, no such age-dependent decrease was found for IGF-II levels between 20 to 70 years. No difference in IGF-II levels was found between patients with acromegaly and healthy adult controls. In cord serum and serum from adult patients with GH deficiency the levels were significantly lower (P less than 0.001) compared to controls. In diabetic patients with uraemia the mean level and 95% confidence limit were 1222 ng/ml and 532-2808 ng/ml, respectively. Thus, significantly increased serum levels of immunoreactive IGF-II have only been found in serum from patients with uraemia. Whether this is due to an increased production of IGF-II, or secondary to other factors such as the binding protein(s), will require further investigation.

Immunoreactive IGF-II in serum of healthy subjects and patients with growth hormone disturbances and uraemia.

Background
EHR systems are widely used in hospitals and primary care centres but it is usually difficult to share information and to collect patient data for clinical research. This is partly due to the different proprietary information models and inconsistent data quality. Our objective was to provide a more flexible solution enabling the clinicians to define which data to be recorded and shared for both routine documentation and clinical studies. The data should be possible to reuse through a common set of variable definitions providing a consistent nomenclature and validation of data. Another objective was that the templates used for the data entry and presentation should be possible to use in combination with the existing EHR systems.

/pdf/julius-a-template-based-supplementary-electronic-health-17el98r2jf.pdf

Julius – a template based supplementary electronic health record system

The two main forms of somatomedins, termed insulin-like growth factor I and II (IGF-I and IGF-II), have been isolated from human plasma. Pure IGF-I or IGF-II was incubated with foetal rat brain cells and found to be equipotent in stimulating the [3H]thymidine incorporation into DNA, despite the fact that IGF-I not is present during foetal life.

The influence of purified somatomedins and insulin on foetal rat brain DNA synthesis in vitro.

Enhancement of insulin-like growth factor 2 receptors in glioblastoma.

Two major somatomedin peptides have been isolated from human plasma, somatomedin-C⁄insulin-like growth factor I (SMC⁄IGF-I) and insulin-like growth factor II (IGF-II) Also, two types of SM⁄IGF receptors have been defined Type I receptors have a higher affinity for SMC⁄IGF-I than IGF-II, and insulin binds to this receptor at high concentrations Type II receptors have a higher affinity for IGF-II than SMC⁄IGF-I, and insulin does not bind to this receptor site In this study, we characterized the binding of IGF-II to human monolayer fibroblast cultures, and the affinity and specificity of this binding We also compared the binding of IGF-II to the binding of insulin and SMC⁄IGF-I to these cells The receptors for IGF-II on normal human fibroblast monolayers fit the criteria for type II SM⁄IGF receptors, and there were more type II receptors on these cells than either insulin receptors or type I SM⁄IGF receptors The type II receptors on human fibroblasts did not demonstrate autoregulation by homologous ho

Characterization of Insulin-Like Growth Factor II Binding to Human Fibroblast Monolayer Cultures*

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