Use Of Insulin-like Growth Factor Research Articles

Diagnostic Usefulness of Insulin-Like Growth Factor 1 and Insulin-Like Growth Factor Binding Protein 3 in Children with Suspected Pituitary Dwarfism

Pituitary dwarfism (also known as short stature) is a medical condition in which the pituitary gland does not produce enough growth hormone (GH). To confirm the diagnosis of growth hormone deficiency the overnight profile of GH secretion and GH provocative tests are usually performed; however, due to wide GH fluctuations throughout the day and night and the invasiveness of stimulation tests, their clinical utility is limited. Therefore, screening for IGF-1 (insulin-like growth factor 1) and IGFBP-3 (insulin-like growth factor binding protein type 3) is proposed, suggesting that these tests provide a more accurate reflection of the mean plasma GH level, although the results of these tests are still problematic. In this context, the aim of this study was to assess the diagnostic usefulness of IGF-1 and IGFBP-3 in children with suspected pituitary dwarfism. Studies were carried out in 127 children with abnormal growth and low spontaneous 24-hour plasma GH profiles and abnormal results of GH stimulation tests. Fasting serum IGF-1 and IGFBP-3 were determined by chemiluminescent quantitative measurement using the IMMULITE 1000 IGF-1 and IGFBP-3 kits (Siemens Healthcare Diagnostics, United Kingdom) on the IMMULITE 1000 analyzer (Siemens Healthcare Diagnostics, USA). Results were compared to the normal range by children's age. Mean serum IGF-1 concentrations were within the lower normal range (41.7% cases), and 58.3% results were below the normal reference range in the study group. The average serum IGFBP-3 levels were within the lower normal range. We conclude that IGF-1 test can be a useful tool in the diagnosis of pituitary dwarfism in children suspected of this condition, but due to relatively poor sensitivity the testing cannot be performed alone, but in combination with other tests. The IGFBP-3 test is not useful for the diagnosis of this disease.

Usefulness of Insulinlike Growth Factor 1 as a Marker of Heart Failure in Children and Young Adults After the Fontan Palliation Procedure

Growth hormone and its mediator, insulinlike growth factor 1 (IGF-1), are key determinants of growth in children and young adults. As patients with Fontan physiology often experience diminished longitudinal growth, we sought to describe IGF-1 levels in this population and to identify factors associated with IGF-1 deficiency. Forty-one Fontan subjects ≥5 years were evaluated in this cross-sectional study. Age- and gender-specific height Z scores were generated using national data. Laboratory testing included IGF-1 and brain natriuretic peptide (BNP) levels. IGF-1 levels were converted to age-, gender-, and Tanner stage-specific Z scores. BNP levels were log transformed to achieve a normal distribution (log-BNP). Medical records were reviewed for pertinent clinical variables. Predictors of IGF-1 Z score were assessed through the Student t test and Pearson's correlation. Median age was 11.1 years (range 5.1 to 33.5 years), and time from Fontan was 8.2 years (1.1 to 26.7). Mean height Z score was -0.2 ± 0.9 with a mean IGF-1 Z score of -0.1 ± 1.3. There was no association between IGF-1 Z score and height Z score. Longer interval since Fontan (R = -0.32, p = 0.04), higher log-BNP (R = -0.40; p = 0.01), and lower indexed systemic flow on cardiac magnetic resonance (R = 0.55, p = 0.02) were associated with lower IGF-1 Z scores. In conclusion, in this cohort with Fontan physiology, higher BNP and lower systemic flow were associated with lower IGF-1 Z score. Longitudinal studies are needed to determine if these relations represent a mechanistic explanation for diminished growth in children with this physiology and with other forms of congenital heart disease.

Use of insulin-like growth factor in the healing of open wounds in diabetic and non-diabetic rats

To analyze the effects of application of 1% and 3% insulin-like growth factor I (IGF-1) cream on the process of wound healing in induced skin lesions in diabetic and non-diabetic rats and evaluate its effect on expression of myofibroblasts. Ninety-six Wistar adult male rats were divided into six groups, with 16 rats in each group, as follows: group 1: non-diabetic, untreated; group 2: non-diabetic, treated with 1% IGF-1 cream; group 3: non-diabetic, treated with 3% IGF-1 cream; group 4: diabetic, untreated; group 5: diabetic, treated with 1% IGF-1 cream; and group 6: diabetic, treated with 3% IGF-1 cream. In groups 4, 5, and 6, diabetes was induced by intravenous injection of alloxan. After diabetes had been induced, animals were mantained for 3 months. The experimental procedure consisted of the creation of a circular incision of 0.9 mm in diameter using a metal punch. Following this, wounds were treated daily according to the assigned treatment regimen. Groups 2 and 5 were treated with 1% IGF-1 cream, groups 3 and 6 with 3% IGF-1 cream, and groups 1 and 4 and the untreated groups with 0.9% saline solution. From each group, samples from 4 rats were taken at three, seven, 14, and 21 days after the injury. Samples were fixed in 10% formalin to prepare slides for histological analysis. Slides stained with hematoxylin-eosin (H&E) and Masson were observed vascular proliferation, mononuclear cells, polymorphonuclear cells, fibroblast proliferation, re-epithelialization, and collagen fibers. This study analyzed the expression of α-smooth muscle actin using specific antibodies to correlate the temporal expression of α-smooth muscle-specific actin (α-SM actin), a molecular marker for myofibroblast transformation. Macroscopic observation of wounds showed a more rapid re-epithelialization of wounds treated with IGF. Regarding acute inflammatory reactions, the results of the analysis of vascular proliferation and polymorphonuclear and mononuclear cells showed no statistically significant differences in any of the periods studied (according to the results of a Mann-Whitney test). The initial immunohistochemical analysis of tissue samples conducted to compare the expression of α-smooth muscle actin between groups showed a relevant response in the expression of myofibroblasts. Data were analyzed using ANOVA and were found to be statistically significant. The topical application of 1% and 3% IGF-1 creams increases the expression of myofibroblasts in the process of wound healing in rats.

Abstract 3845: Developing a novel 3D model to study colon cancer cell invasion.

Abstract Introduction: Colon cancer is the fifth most diagnosed in the UK, with nearly 22,000 cases diagnosed in 20101 with a five-year survival rate of 54.75%2. The formation of distant metastases also influences patient survival, causing a decline from 93% for the earliest stage tumours down to below 7% for tumours with distant metastases3. Previous literature has highlighted the limitations of two-dimensional (2D) cancer cell migration assays4. These include alterations in gene expression of cells and the provision of a migration substrate that does not closely reflect that of the in vivo environment. This project aims to mimic the in vivo situation to investigate factors that affect cancer cell invasion; including the expression of EMT markers and signalling by developing a three-dimensional (3D) model of colon cancer. Methods: This project utilises commercial scaffold known as Alvetex®5 and two colon cancer cell lines (SW480 and SW620) were used to look at the differences between pre- and post-metastatic colon cancer respectively. Both cell lines were cultured prior to analysis using various biochemical assays and histological processing. Results: Our data show a difference in cell penetration between the two cell lines. The later stage SW620 cells, which have a more motile phenotype in 2D, migrate and penetrate the scaffold to a greater extent than the earlier stage, less invasive, SW480 cells. This reflects a known difference in the level of EMT markers between the two cell lines, a result of the Wnt signalling pathway. This model also allows for the use of the known chemoattractant Insulin-like Growth Factor (IGF) to encourage cell penetration. IGF has been shown to play an important role in cancer cell migration. The use of IGF results in a 54% increase in cell penetration by the SW480 cell line, but not the SW620 cell line. Discussion: Our data shows great potential for further development of a 3D cancer invasion model using these scaffolds. This model provides a more realistic 3D environment and will be a tool for chemoattractant and co-culture studies to determine the mechanism of invasion utilised by these cells and to develop this model further to obtain an assay which is closer to the in vivo situation. Acknowledgements: This work was carried out with funding from the Grevillea Trust, Reinnervate Limited and BBSRC. Citation Format: Rosie Adams. Developing a novel 3D model to study colon cancer cell invasion. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3845. doi:10.1158/1538-7445.AM2013-3845

The insulin and insulin-like growth factor receptor family in neoplasia: an update

Although several early phase clinical trials raised enthusiasm for the use of insulin-like growth factor I receptor (IGF1R)-specific antibodies for cancer treatment, initial Phase III results in unselected patients have been disappointing. Further clinical studies may benefit from the use of predictive biomarkers to identify probable responders, the use of rational combination therapies and the consideration of alternative targeting strategies, such as ligand-specific antibodies and receptor-specific tyrosine kinase inhibitors. Targeting insulin and IGF signalling also needs to be considered in the broader context of the pathophysiology that relates obesity and diabetes to neoplasia, and the effects of anti-diabetic drugs, including metformin, on cancer risk and prognosis. The insulin and IGFI receptor family is also relevant to the development of PI3K-AKT pathway inhibitors.

Use of insulin-like growth factor (IGF) pathway polymorphism IGF1R_rs2016347 to predict tumor recurrence in estrogen receptor–positive breast cancer patients.

538 Background: Accumulating evidence suggests that insulin-like growth factor (IGF) signaling is an important pathway for breast cancer pathogenesis which regulates both cellular proliferation and apoptosis. Recently, IGF1 receptor (IGF1R) expression has been correlated and functionally linked with estrogen receptor (ER) signaling in breast cancer. We tested whether functional germline variations in the IGF-pathway are associated with clinical outcome in ER positive primary invasive breast cancer patients, who were treated with surgery and adjuvant hormone treatment. Methods: Tissue samples of 222 patients with ER positive primary invasive breast cancer, who had undergone surgery at Charing Cross Hospital, London, UK between 1981 and 2003, were analyzed. gDNA was extracted from formalin fixed paraffin embedded (FFPE) tissue samples and six (IGF1_rs6214, IGF1_rs2946834, IGF1_rs7136446, IGF1R_rs2016347, IGFBP3_rs2854744, IRS1_rs1801123) functional IGF1-pathway polymorphisms were analyzed using direct DNA-sequencing and PCR-RFLP. Results: In univariate analysis patients with primary invasive breast cancer carrying at least one T allele (GT or TT) of IGF1R_rs2016347 polymorphism had a significant better disease free survival (DFS) than patients with GG genotype (DFS 5.3 years versus 7.6 years; p=0.02). This association remained significant in multivariate analysis adjusting for tumor size, lymph node involvement, and c-erbB2 status [HR=0.57 (CI 95%; 0.36-0.9); adjusted p=0.01). The other tested IGF-pathway polymorphisms did not show significant associations for DFS. Conclusions: These results indicate functional IGF1R_rs2016347 polymorphism as independent prognostic marker for tumor recurrence suggesting that co-targeting both ER and IGF1R holds promise for the treatment of patients with ER positive breast cancer.

The use of insulin like-growth factor II messenger RNA binding protein–3 in diagnostic pathology

The histologic distinction between reactive processes and malignant neoplasms and between low-grade and high-grade tumors is not always straightforward and is sometimes extremely challenging. This is especially the case when the diagnostic material is a small biopsy specimen or a cytology specimen with scant cellularity. In addition, suboptimal processing and crush artifact may limit accurate diagnosis. A reliable diagnostic biomarker that preferentially highlights malignant processes and high-grade tumors would be very valuable in segregating these entities from reactive processes and low-grade lesions. Recent extensive studies have shown that an oncoprotein, insulin like-growth factor II messenger RNA binding protein-3, is not only a prognostic biomarker but also a diagnostic molecule. This review focuses on discussing the value of insulin like-growth factor II messenger RNA binding protein-3 in diagnostic pathology, with a focus on utilization of insulin like-growth factor II messenger RNA binding protein-3 in the discrimination of benign effusions from malignant effusions, malignant mesothelioma from mesothelial hyperplasia, carcinoids from high-grade neuroendocrine carcinomas, low-grade dysplasia from high-grade dysplasia, hepatocellular carcinoma from hepatic adenoma, cholangiocarcinoma and metastatic pancreatic ductal carcinoma from benign bile duct lesions, melanoma from nevi, and follicular thyroid carcinoma from follicular adenoma of the thyroid, as well as examining insulin like-growth factor II messenger RNA binding protein-3 expression in lymphomas of germinal center origin.

Diagnostic Utility of IMP3 Expression in Thyroid Neoplasms

The capability of molecular markers to differentiate between benign and malignant well-differentiated thyroid tumors remains unclear. The aim of this study was to evaluate the use of insulin-like growth factor II mRNA binding protein-3 (IMP3) mRNA expression to distinguish benign from malignant thyroid tumors. RNA samples from 80 formalin-fixed, paraffin-embedded thyroid tissues, including 22 usual papillary thyroid carcinomas (PTCs), 18 follicular variants of PTC, 5 follicular thyroid carcinomas, 33 follicular adenomas, and 2 hyperplastic nodules, were used for quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. IMP3 mRNA expression levels in thyroid tumors were expressed as relative fold change (fold) after normalization with normal thyroid RNA. The results showed that thyroid carcinomas including PTC, follicular variants of PTC, and follicular thyroid carcinomas have significantly higher IMP3 expression levels with 48.3, 35.3, and 43.8 fold, respectively, compared with benign thyroid lesions (2.8 fold). Using the IMP3 expression value of 5 fold as a cutoff point to separate benign and malignant thyroid tumors, IMP3 qRT-PCR analysis had a 91.4% clinical specificity and 86.7% clinical sensitivity for the diagnosis of well-differentiated thyroid carcinomas. Conventional RT-PCR and immunohistochemical analysis for IMP3 in a subset of cases supported the qRT-PCR results. These results indicate that detection of IMP3 mRNA expression levels by qRT-PCR may be a useful molecular marker to assist in the diagnosis of well-differentiated thyroid carcinomas.

Resolution of diabetes mellitus but not acromegaly in a cat with a pituitary macroadenoma treated with hypofractionated radiation

The use of insulin-like growth factor 1 assays in the diagnosis and subsequent monitoring after radiotherapy of an acromegalic cat with a secretory pituitary adenoma and secondary insulin-resistant diabetes mellitus is described. Diabetes resolved, and exogenous insulin was no longer required for the maintenance of normoglycaemia 10 months after completion of a course of hypofractionated radiotherapy. However, insulin-like growth factor 1 remained elevated, and the cat's size and appetite continued to increase. It is suggested that radiotherapy may decrease growth hormone concentration to a level such that diabetogenic effects are no longer evident but not to a level required to decrease insulin-like growth factor 1 secretion.

An Insulin‐like Growth Factor 2‐Derived Self‐Antigen Inducing a Regulatory Cytokine Profile after Presentation to Peripheral Blood Mononuclear Cells from DQ8+ Type 1 Diabetic Adolescents: Preliminary Design of a Thymus‐Based Tolerogenic Self‐Vaccination

This work aims to evaluate the potential use of insulin-like growth factor 2 (IGF-2) as the dominant thymic self-antigen precursor of the insulin family in designing a tolerogenic approach to type 1 diabetes (T1D) prevention. This evaluation was primarily based on cytokine profile driven by MHC presentation of insulin and IGF-2-derived antigens to PBMC cultures derived from 16 T1D DQ8(+) adolescents. Insulin B9-23, one dominant beta-cell autoantigen, and the homologous sequence B11-25 of IGF-2 display the same affinity and fully compete for binding to DQ8, a MHC-II allele conferring major genetic susceptibility to type 1 diabetes (T1D). However, compared to insulin B9-23, presentation of IGF-2 B11-25 elicits a suppressive/regulatory cytokine profile with a higher number of IL-10-secreting cells (P < 0.05), a much higher ratio of IL-10/IFN-gamma (P < 0.01), as well as a lower number of IL-4-secreting cells (P < 0.05). Thus, with regard to T1D prevention, administration of IGF-2-derived self-antigen(s) seems to be an efficient approach that combines both antagonism for binding to a major susceptibility MHC-II allele, as well as downstream promotion of an antigen-driven tolerogenic response.

Reconstruction of erectile reflex circuit by autologous vein graft combined with use of insulin-like growth factor

To explore the feasibility of erectile reflex circuit reconstruction by autologous vein graft combined with the use of insulin-like growth factor-I (IGF-I). 48 male adult Sprague-Dawley rats were randomized into 4 groups of 12 rats: group I (sham-operation group), undergoing operation to identify the bilateral cavernous nerves (CNs) only; group II (bilateral CN ablation group) in which the bilateral CNs of the length of at least 5 mm were ablated; group III (vein graft plus IGF-I group) in which the ablated CNs were repaired by autologous vein graft and IGF-I was injected into the venous cavity; and group IV (vein graft plus normal saline group), in which the ablated CNs were repaired and normal saline was injected instead. Four months later, apomorphine test was performed on each rat, and the erection times during the following half hour were recorded. After that, 4% fluoro-gold was injected into the bilateral corpus cavernosum of penis for each rat after anesthesia. Five days later, the rats were sacrificed and their bilateral major pelvic ganglia were obtained for detection of fluoro-gold by fluorescent microscopy. Apomorphine test showed an erection rate of 92% in group III, significantly higher than those of the group II (0%) and group IV (50%, both P < 0.01), and close to that of the sham-operation group (100%, P > 0.05). The average erection times of the group III was (1.5 +/- 0.8) times, significantly more than those of the group II and group IV [(0.0 +/- 0.0) times and (0.6 +/- 0.7) times respectively, both P < 0.05], but significantly less than that of the sham-operation group [(2.7 +/- 0.9) times, P < 0.05]. Five days after injection of fluoro-gold solution, the number of fluoro-god positively stained neural cells of the group III was 86 +/- 14, significantly more than those of the group II (14 +/- 6) and group IV (46 +/- 14, both P < 0.05), but significantly less than that of the sham-operation group (152 +/- 36, P < 0.05). And the fluoro-gold stained neural cells of the group III was brighter than those of the group II and group IV, but not so bright as those of the sham operation group. Reparation of ablated CNs by autologous vein graft combined with local injection of IGF-I is a new effective method to treat ED following CN injury.

Progestins abrogate estrogen-induced changes in the insulin-like growth factor axis

Objective: We sought to investigate the effect of oral progestins on estrogen-mediated changes in the insulin-like growth factor axis in the peripheral circulation. Study Design: Oral conjugated equine estrogen alone or in combination with medroxyprogesterone acetate, desogestrel, or norethindrone was given in a randomized triple-crossover fashion to 10 healthy postmenopausal women, and the effects on the insulin-like growth factor axis were determined. Results: Baseline circulating insulin-like growth factor I levels were significantly reduced by conjugated equine estrogen (359 ± 54 vs 225 ± 44 ng/mL; P =.0001). This effect was reversed by progestins (medroxyprogesterone acetate, 254 ± 44 ng/mL; desogestrel, 266 ± 50 ng/mL; norethindrone, 286 ± 48 ng/mL; F = 12.2; P =.0015). Free insulin-like growth factor I was reduced by conjugated equine estrogen (1.00 ± 0.15 ng/mL vs 2.10 ± 0.39 ng/mL; P =.004), but addition of progestogens had no further effect. Insulin-like growth factor II and insulin levels were unaffected by conjugated equine estrogen or progestins. Plasma insulin-like growth factor binding protein 1 concentration increased significantly from baseline with conjugated equine estrogen alone (44.1 ± 6.0 vs 154 ± 30 μg/L; P =.003). This rise was opposed by progestins of increasing androgenicity (medroxyprogesterone acetate, 130 ± 26 μg/L; desogestrel, 100 ± 16 μg/L; norethindrone, 78.0 ± 12 μg/L; F = 12.5; P =.0015). Insulin-like growth factor binding protein 3 levels fell with conjugated equine estrogen, and this was reversed by progestins (conjugated equine estrogen, 2.17 ± 0.13 mg/L; vs norethindrone and conjugated equine estrogen, 2.41 ± 0.12 mg/L; F = 7.6; P =.01). Insulin-like growth factor binding protein 4 levels increased with conjugated equine estrogen with or without progestins, whereas insulin-like growth factor binding protein 2 levels were unchanged. Conclusions: Coadministration of androgenic progestins abrogates estrogen-related changes in circulating insulin-like growth factor I, insulin-like growth factor binding protein 1, and insulin-like growth factor binding protein 3. Such hormone replacement therapy–induced changes may have significant consequences for the development of cardiovascular disease and osteoporosis and implications for the use of insulin-like growth factor I in monitoring growth hormone replacement. (Am J Obstet Gynecol 2000;183:593-600.)

Insulin-like growth factors in obstetrics.

Data from a number of studies reported during the past two decades indicate that the insulin-like growth factor (IGF) system, including IGF-I and IGF-II, their receptors and six high-affinity binding proteins, is involved in the control of foetal and placental growth and development. Recent studies that addressed the role of the IGF system in pregnancy and the clinical usefulness of IGF and IGF-binding protein measurements in obstetrics are reviewed and discussed.

Usefulness of insulin-like growth factor I levels in the diagnosis of growth hormone deficiency in adults

Usefulness of insulin-like growth factor I levels in the diagnosis of growth hormone deficiency in adults

Physiology and potential use of insulin-like growth factor 1 in acute and chronic renal failure

Physiology and potential use of insulin-like growth factor 1 in acute and chronic renal failure

Use of insulin-like growth factor I (IGF-I) and IGF-binding protein measurements to monitor feeding of premature infants.

To determine whether peptides of the insulin-like growth factor (IGF) system might be useful indicators of nutritional adequacy in premature infants, we studied 50 premature (25-34 weeks gestation) infants prospectively to define the relationship between nutrient intake and serum concentrations of IGF-I, IGF-binding protein-2 (IGFBP-2), and IGFBP-3. Each infant was monitored for at least 2 weeks. Nutrient intake was quantified from daily logs; weight was determined daily, and measurements of IGF-I, IGFBP-2, and IGFBP-3 in serum were made twice weekly. Serum IGF-I correlated strongly with length of gestation, increasing 4.03 +/- 0.95 ng/mL for each additional week of gestation (P < 0.0001) and 0.36 +/- 0.07 ng/mL day each day since birth (P < 0.0001). A higher intake of calories increased IGF-I by 0.07 +/- 0.01 ng/mL for each calorie per kg ingested over the previous 3 days (P < 0.0001). IGF-I increased quadratically as protein intake increased. For each change of 1% in calories as protein squared, IGF-I increased 0.36 +/- 0.11 ng/mL (P < 0.0001). Serum IGFBP-3 concentrations also correlated with length of gestation, increasing 25.06 +/- 11.83 micrograms/L.wk (P = 0.035) and 4.14 +/- 1.33 micrograms/.day since birth (P = 0.003). Unlike IGF-I, variation in the amount of protein supplied did not change IGFBP-3. As calorie intake increased, IGFBP-3 increased by 0.54 +/- 0.17 microgram/L for each calorie per kg consumed over the previous 3 days (P = 0.0015). In contrast to IGF-I and IGFBP-3, IGFBP-2 declined as the length of gestation increased (56.12 +/- 16.92 ng/mL.week; P = 0.001) and with each additional day of life (7.57 +/- 2.44 ng/mL.day; P = 0.003). Dietary protein, the predominant regulator of IGFBP-2, caused a decrease of 33.22 +/- 9.00 ng/mL with each percent increase in dietary calories as protein (P < 0.0003). Calorie intake had less effect on IGFBP-2 than protein intake. These results indicate that each of the three peptides studied is regulated in premature infants by nutritional intake, and that their regulatory patterns are qualitatively similar to those observed in older individuals. Measurements of these peptides in premature infants may be useful indicators of nutritional status and adequacy of nutrient intake.

Use of Insulin-Like Growth Factor I (IGF-I) and IGF-Binding Protein Measurements to Monitor Feeding of Premature Infants

Use of Insulin-Like Growth Factor I (IGF-I) and IGF-Binding Protein Measurements to Monitor Feeding of Premature Infants

Insulin-like growth factor I (IGF-I) and IGF-binding protein-3 concentrations compared to stimulated and night growth hormone in the evaluation of short children--a clinical research center study.

To evaluate the relative usefulness of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) in screening for GH status, GH stimulation (arginine-insulin/L-DOPA) tests and overnight GH studies (every 20 min sampling) were performed in 104 healthy short children (32 girls), aged 3-16 yr (height, -1.8 or more SD). IGFBP-3 had no advantage over IGF-I in screening sensitivity or specificity. IGF-I correlated with mean nighttime GH. Both IGF-I and IGFBP-3 correlated with peak stimulated GH. To identify more than 90% of children with GH deficiency (GHD) and borderline GHD, the mean values for age for IGF-I and IGFBP-3 were required as the cut-off criterion. However, at this criterion, 70% or more of idiopathic short stature (ISS) children would have to undergo testing to identify 90% of GHD or borderline GHD. More stringent criteria (-1.0, -1.64, and -2.0 SD) were more specific, but lost sensitivity. A practical application is suggested. Screening use of IGF-I with criterion of -1.0 SD would identify a subgroup that includes 88% of GHD, 71% of borderline GHD, and 46% of ISS. Both IGF-I and IGF-BP-3 higher than -1.0 SD would accurately identify 68% of ISS as not needing GH testing. Evaluation of growth velocity would identify the remaining children requiring definitive testing. Thus, combined screening for GHD using both IGF-I and IGFBP-3 has no better sensitivity than either test alone. However, such combined screening will improve the specificity and thus decrease the number of normal but short children who might otherwise undergo unnecessary testing.

Cellular and clinical perspectives on skeletal insulin‐like growth factor I

Insulin-like growth factor (IGF) I, a polypeptide synthesized by skeletal cells, is presumed to act as an autocrine regulator of bone formation. IGF I stimulates bone replication of preosteoblastic cells and enhances the differentiated function of the osteoblast. The synthesis of skeletal IGF I is regulated by systemic hormones, most notably parathyroid hormone and glucocorticoids, as well as by locally produced factors, such as prostaglandins and other skeletal growth factors. Whereas hormones and growth factors regulate IGF I synthesis, the exact level of regulation has not been established and may involve both transcriptional and posttranscriptional mechanisms. The IGF I gene contains six exons, and both exon 1 and 2 contain transcription initiation sites. Extrahepatic tissues, including bone, express exon 1 transcripts, and regulation of the exon 1 promoter activity in osteoblasts is currently under study. It is apparent that the regulation of IGF I gene transcription as well as the regulation of mRNA stability is complex and tissue specific. It is possible that abnormalities in skeletal IGF I synthesis or activity play a role in the pathogenesis of bone disorders. In view of its important anabolic actions in bone, it is tempting to postulate the use of IGF I for the treatment of disorders characterized by decreased bone mass. An alternative could be the stimulation of the local production of IGF I in bone.

Rat models for clinical use of insulin-like growth factor I in acute renal failure

Insulin-like growth factor I (IGF-I) improves kidney function and histopathology, when given within a short time (0.5 or 5 h) after an ischemic renal insult in rats. To examine the effects of IGF-I at times that would be more applicable if it were to be used as a therapeutic agent for acute renal failure in humans, we administered IGF-I to rats 24 h after ischemic injury or prior to the induction of injury (pretreatment). In rats that received IGF-I 24 h postischemia, serum creatinine and blood urea nitrogen (BUN) values were significantly lower during the subsequent 6 days than in vehicle-treated rats, and incorporation of 5-bromo-2'-deoxyuridine into tubular cells of the regenerating cortex, measured 48 h postischemia, was enhanced. When examined 7 days postinjury, kidneys from rats that received IGF-I 24 h postischemia were improved in histopathological appearance compared with kidneys from vehicle-treated animals. Whereas creatinine and BUN values were elevated above baseline in both vehicle and IGF-I-pretreated groups, recovery of normal renal function was accelerated by pretreatment with IGF-I. In addition, although we could detect no differences in histopathology at 24 h postinjury, IGF-I pretreatment resulted in more normal renal histology at 7 days postischemic injury and reduced weight loss after injury. Our data show that IGF-I hastens recovery and accelerates regeneration or repair of damaged epithelia following acute renal failure in rats when administered either 24 h postinjury or prior to induction of acute renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)