ABSTRACT
The growth hormone (GH)-insulin-like growth factor (IGF) cascade is central to the regulation of growth and metabolism. This article focuses on the history of the components of the IGF system, with an emphasis on the peptide hormones, IGF-I and -II, their cell surface receptors, and the IGF binding proteins (IGFBPs) and IGFBP proteases that regulate the availability of the peptide hormones for interaction with their receptors in relevant target tissues. We describe landmark events in the evolution of the somatomedin hypothesis, including evidence that has become available from experiments at the molecular and cellular levels, whole animal and tissue-specific gene knockouts, studies of cancer epidemiology, identification of prismatic human cases, and short- and long-term clinical trials of IGF-I therapy in humans. In addition, this new evidence has expanded our clinical definition of GH insensitivity (GHI) beyond growth hormone receptor mutations (classic Laron syndrome) to include conditions that cause primary IGF deficiency by impacting post-receptor signal transduction, IGF production, IGF availability to interact with the IGF-I receptor (IGF-1R), and defects in the IGF-1R, itself. We also discuss the clinical aspects of IGFs, from their description as insulin-like activity, to the use of IGF-I in the diagnosis and treatment of GH deficiency, and to the use of recombinant human IGF-I for therapy of children with GHI.
Subject(s)
Insulin-Like Growth Factor II , Insulin-Like Growth Factor I , Laron Syndrome , Animals , Humans , Insulin-Like Growth Factor I/deficiency , Insulin-Like Growth Factor I/history , Insulin-Like Growth Factor I/physiology , Insulin-Like Growth Factor I/therapeutic use , Laron Syndrome/drug therapy , Laron Syndrome/genetics , Laron Syndrome/history , Laron Syndrome/physiopathology , Peptide Hormones , Protein Processing, Post-Translational , Signal Transduction , Somatomedins/deficiency , Somatomedins/history , Somatomedins/physiology , Insulin-Like Growth Factor II/deficiency , Insulin-Like Growth Factor II/history , Insulin-Like Growth Factor II/physiology , Insulin-Like Growth Factor II/therapeutic useABSTRACT
Exercise training improves muscle fitness in many aspects, including induction of mitochondrial biogenesis and maintenance of mitochondrial dynamics. The insulin-like growth factors were recently proposed as key regulators of myogenic factors to regulate muscle development. The present study aimed to investigate the physical exercise impact on insulin-like growth factor 2 (IGF2) and analyzed its functions on skeletal muscle cells in vitro. Using online databases, we stated that IGF2 was relatively highly expressed in skeletal muscle cells and increased after exercise training. Then, IGF2 deficiency in myotubes from C2C12 and primary skeletal muscle cells (PMSCs) led to impaired mitochondrial function, reduced mitochondria-related protein content, and decreased mitochondrial biogenesis. Furthermore, we explored the possible regulatory pathway and found that mitochondrial regulation in skeletal muscle cells might occur through IGF2-Sirtuin 1 (SIRT1)-peroxisome proliferator-activated receptor-γ co-activator-1α (PGC1α) signaling pathway. Therefore, the present study first demonstrated the relationship between IGF2 and mitochondria in skeletal muscle.
Subject(s)
Mitochondria, Muscle/metabolism , Muscle, Skeletal/metabolism , Somatomedins/deficiency , Animals , Animals, Newborn , Cell Line , Cells, Cultured , Mice , Mice, Inbred C57BL , Muscle Fibers, Skeletal , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Signal Transduction , Sirtuin 1/metabolismABSTRACT
Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) represents a profound change in cell fate. Here, we show that combining ascorbic acid (AA) and 2i (MAP kinase and GSK inhibitors) increases the efficiency of reprogramming from fibroblasts and synergistically enhances conversion of partially reprogrammed intermediates to the iPSC state. AA and 2i induce differential transcriptional responses, each leading to the activation of specific pluripotency loci. A unique cohort of pluripotency genes including Esrrb require both stimuli for activation. Temporally, AA-dependent histone demethylase effects are important early, whereas Tet enzyme effects are required throughout the conversion. 2i function could partially be replaced by depletion of components of the epidermal growth factor (EGF) and insulin growth factor pathways, indicating that they act as barriers to reprogramming. Accordingly, reduction in the levels of the EGF receptor gene contributes to the activation of Esrrb. These results provide insight into the rewiring of the pluripotency network at the late stage of reprogramming.
Subject(s)
Ascorbic Acid/pharmacology , Chromatin/drug effects , Epigenesis, Genetic , Induced Pluripotent Stem Cells/drug effects , Protein Kinase Inhibitors/pharmacology , Signal Transduction , Animals , Astrocytes/cytology , Astrocytes/drug effects , Astrocytes/metabolism , Cell Differentiation , Cellular Reprogramming/drug effects , Chromatin/chemistry , Chromatin/metabolism , Embryo, Mammalian , Epidermal Growth Factor/deficiency , Epidermal Growth Factor/genetics , ErbB Receptors/genetics , ErbB Receptors/metabolism , Fibroblasts/cytology , Fibroblasts/drug effects , Fibroblasts/metabolism , Gene Regulatory Networks/drug effects , Genes, Reporter , Green Fluorescent Proteins , Induced Pluripotent Stem Cells/cytology , Induced Pluripotent Stem Cells/metabolism , Mice , Primary Cell Culture , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Receptors, Estrogen/antagonists & inhibitors , Receptors, Estrogen/genetics , Receptors, Estrogen/metabolism , Somatomedins/deficiency , Somatomedins/geneticsABSTRACT
The emergence of autism in young children appears to result from dysmyelination of brain neurons, related to inadequate supply of insulin-like growth factor (IGF) in the newborn. This report is intended to bring together relevant observations from prior research to develop a new, innovative hypothesis to elucidate the mechanism underlying autism development. The deficiency of IGF in affected infants may be due to a combination of genetic and environmental factors yet to be determined. If this hypothesis is correct, breastfeeding in particular could increase IGF levels, thereby compensating for an inborn deficiency of the growth factor.
Subject(s)
Autistic Disorder/prevention & control , Breast Feeding/methods , Models, Biological , Somatomedins/deficiency , Autistic Disorder/etiology , Enzyme-Linked Immunosorbent Assay/methods , Female , Humans , Somatomedins/metabolismABSTRACT
There are eight known genetic causes of short stature characterized by low serum IGF-1 (IGF-1 deficiency, IGFD) and normal GH secretion. One of these (GHSR defect) is a form of secondary IGFD, although the GH peak in provocation tests can be normal. Bioinactive GH (GH1 mutations) can disturb GH secretion, but also GH binding and signaling. The remaining conditions are classified as primary IGFD (GH insensitivity). The clinical phenotype of GH receptor (GHR) defects is variable. Of the three GH signal transduction defects, a STAT5B defect is well established, but abnormalities in the MAPK pathway (such as PTPN11 mutations in Noonan syndrome) and NF-ĸB pathway (IĸBα mutation) may also cause IGFD. Homozygous IGFALS defects are relatively common, and lead to moderate growth failure, very low serum IGF-1 and even lower IGFBP-3, while a heterozygous IGFALS mutation decreases height by 1 SD. Most cases with a homozygous IGF1 defect are very short, microcephalic, and deaf, but heterozygous mutations may also lead to short stature. IGFD can also have a digenic or oligogenic origin. The diagnostic yield of genetic testing in children with a height <-2.5 SDS and a serum IGF-1 <-2 appears sufficient to perform genetic tests for known candidate genes.
Subject(s)
Growth Disorders/classification , Somatomedins/deficiency , Animals , Carrier Proteins/genetics , Dwarfism, Pituitary/diagnosis , Dwarfism, Pituitary/genetics , Dwarfism, Pituitary/therapy , Glycoproteins/deficiency , Glycoproteins/genetics , Growth Disorders/diagnosis , Growth Disorders/genetics , Growth Disorders/therapy , Hormone Replacement Therapy , Human Growth Hormone/deficiency , Human Growth Hormone/genetics , Human Growth Hormone/therapeutic use , Humans , Laron Syndrome/diagnosis , Laron Syndrome/genetics , Laron Syndrome/therapy , Receptors, Ghrelin/deficiency , Receptors, Ghrelin/genetics , STAT5 Transcription Factor/genetics , Somatomedins/geneticsABSTRACT
Specific lesions of the growth hormone (GH)/insulin-like growth factor (IGF) axis have been identified in humans, each of which has distinctive auxologic and biochemical features. Measures of circulating IGF-I are useful in diagnosing growth disorders in childhood and in evaluating response to GH therapy. Recombinant human IGF-I is an effective treatment of severe primary IGF deficiency, which is typical of patients with GH receptor defects (Laron syndrome). Such treatment has been limited to a few severely affected patients. Future studies will provide new insight into IGF-I as treatment and into the nature of growth disorders that involve the IGF axis.
Subject(s)
Growth Disorders , Somatomedins , Child , Female , Growth Disorders/diagnosis , Growth Disorders/drug therapy , Growth Disorders/metabolism , Humans , Insulin-Like Growth Factor Binding Proteins/blood , Insulin-Like Growth Factor Binding Proteins/physiology , Intercellular Signaling Peptides and Proteins/therapeutic use , Laron Syndrome/drug therapy , Laron Syndrome/metabolism , Male , Recombinant Proteins/therapeutic use , Somatomedins/deficiency , Somatomedins/genetics , Somatomedins/therapeutic use , Treatment OutcomeABSTRACT
The post-transplant bone disease of the peripheral skeleton in pediatric renal transplant recipients is characterized by an inadequately thin bone cortex in relation to muscular force. A major hormonal modulator of periosteal growth is the insulin-like growth factor (IGF)/IGF binding protein (IGFBP) system. We therefore hypothesized that the reduced cortical thickness in these patients may be due to functional IGF deficiency. To test this hypothesis, we investigated 55 patients (mean estimated glomerular filtration rate 86.3 +/- 30.0 ml/min/1.73 m(2)) in a cross-sectional study. Parameters of macroscopic bone architecture and forearm muscle size were analyzed by peripheral quantitative computed tomography (pQCT), and serum IGF/IGFBP system components were measured by specific radioimmunoassays. The mean (+/- standard deviation) standardized serum IGF-I (0.20 +/- 1.16 score) level was normal, while the mean IGF-II (1.16 +/- 0.11 score) level was significantly elevated. Serum IGFBP-1 and IGFBP-2 levels were not altered, whereas the IGFBP-3 (1.34 +/- 0.15 score) level was significantly increased. The serum IGFBP-4 level was slightly elevated (by 11%), the IGFBP-6 level was markedly (2.3-fold) elevated, while the IGFBP-5 level was comparable to that of the control. The respective age-adjusted cortical thickness at both the proximal (r = 0.407, P < 0.005) and distal (r = 0.383, P < 0.01) forearm was positively correlated with the standardized serum IGF-I level. In conclusion, the serum IGF/IGFBP system in pediatric renal transplant recipients is characterized by an increase in the levels of the inhibitory IGFBPs, IGFBP-3, -4 and -6, resulting in a functional IGF deficiency. The positive correlation of IGF-I with cortical thickness underlines the importance of this hormonal system in the modeling of bone, particularly periosteal growth.
Subject(s)
Bone and Bones/diagnostic imaging , Chronic Kidney Disease-Mineral and Bone Disorder/metabolism , Insulin-Like Growth Factor Binding Proteins/blood , Kidney Transplantation , Somatomedins/analysis , Somatomedins/deficiency , Adolescent , Child , Chronic Kidney Disease-Mineral and Bone Disorder/etiology , Chronic Kidney Disease-Mineral and Bone Disorder/pathology , Cross-Sectional Studies , Female , Glomerular Filtration Rate , Humans , Kidney Failure, Chronic/surgery , Male , Muscle, Skeletal/diagnostic imaging , Muscle, Skeletal/pathology , Prospective Studies , Radioimmunoassay , Tomography, X-Ray Computed , Young AdultABSTRACT
El factor de crecimiento semejante a la insulina tipo I (IGF-I) es una hormona polipeptídica segregada en múltiples tejidos por efecto de la hormona de crecimiento (GH). Es responsable de parte de las acciones de la GH y además tiene efecto hipoglucemiante y anabolizante. El 90% del IGF-I circulante es de origen hepático y ejerce efectos autocrinos, paracrinos y endocrinos, estos últimos en múltiples tejidos. En la cirrosis hepática se produce una disminución progresiva de la producción hepática de IGF-I que llega a ser indetectable en la enfermedad avanzada. Algunas de las complicaciones de la cirrosis, fundamentalmente nutricionales y metabólicas (resistencia a insulina, desnutrición, osteopenia, hipogonadismo, alteraciones intestinales) podrían estar, al menos en parte, relacionadas con esta carencia de IGF-I dado que algunas acciones de IGF-I representan la imagen inversa de las complicaciones de la cirrosis. A pesar de ello, nunca se había propuesto tratamiento sustitutivo con IGF-I en la cirrosis. En una serie de estudios experimentales realizados en ratas cirróticas se demostró que el tratamiento con dosis bajas de IGF-I recombinante produce dos tipos de efectos en la cirrosis experimental: a) mejoría del hígado, dado que mejora la función hepatocelular, la hipertensión portal y la fibrosis hepática; y b) mejoría de las alteraciones extrahepáticas de la cirrosis dado que mejora la eficiencia del alimento ingerido, la masa muscular, la masa ósea, la función y estructura gonadales y la función y estructura intestinales con normalización de la malabsorción de azúcares y aminoácidos y la mejoría de la función intestinal de barrera manifestada por disminución de la endotoxemia y la translocación bacteriana. Posteriormente el primer ensayo clínico piloto, aleatorizado, doble ciego y controlado con placebo llevado a cabo en un número reducido de pacientes cirróticos demostró aumento de la albúmina sérica y mejoría del metabolismo energético por efecto del IGF-I. Se precisan ensayos clínicos adicionales para identificar la dosis adecuada de IGF-I, el tiempo y ritmo de administración y el subgrupo de pacientes cirróticos que obtendrán mayor beneficio de este tratamiento sustitutivo
Insulin-like growth factor I (IGF-I) is a polypeptide hormone secreted by multiple tissues in response to growth hormone (GH). It is partly responsible for GH activity, and also has glucose-lowering and anabolizing effects. Ninety percent of circulating IGF-I originates in the liver and has autocrine, paracrine, and endocrine effects, the latter on multiple tissues. Liver cirrhosis results in a progressive decline of hepatic IGF-I output, and this factor may become undetectable in advanced disease. Some cirrhosis complications, mainly those nutritional and metabolic in nature (insuline resistance, malnutrition, osteopenia, hypogonadism, intestinal disorders), may be at least partly related to this IGF-I deficiency, since some IGF-I effects represent a reverse image of cirrhosis complications. Despite this, IGF-I replacement therapy has been never suggested for cirrhosis. A number of experimental studies in cirrhotic rats showed that therapy using low-dose recombinant IGF-I exerts two types of effect on experimental cirrhosis: a) liver improvement driven by improved hepatocellular function, portal hypertension, and liver fibrosis; and b) cirrhosis-related extrahepatic disorder improvement driven by improved food efficiency, muscle mass, bone mass, gonadal function and structure, and intestinal function and structure, with a normalization of sugar and amino acid malabsorption, and improved intstinal barrier function, manifested by reduced endotoxemia and bacterial translocation. Subsequently, the first randomized, double-blind, placebo-controlled, pilot clinical trial in a small number of cirrhotic patients showed increased serum albumin and improved energy metabolism as a result of IGF-I use. Further clinical trials are needed to identify adequate IGF-I doses, administration duration and frequency, and the subgroup of cirrhotic patients who will benefit most from this replacement therapy
Subject(s)
Humans , Liver Cirrhosis/physiopathology , Insulin-Like Growth Factor Binding Protein 1/deficiency , Somatomedins/deficiency , Hepatocytes/physiology , Liver Transplantation , Insulin-Like Growth Factor Binding Protein 1/therapeutic useABSTRACT
OBJECTIVE: Previous evidence indicated that, in adults with organic hypopituitarism, GH deficiency (GHD) may mask the presence of other pituitary deficits, in particular central hypothyroidism and hypoadrenalism. Little and conflicting information is available about the relationship between GHD, rhGH therapy and gonadal function in males. The aim of the present study was to investigate the hypothalamic-pituitary-gonadal axis (HPG) in male adults with organic GHD and normal HPG axis. PATIENTS: Twelve male adults (mean age 48 +/- 7 years) with organic GHD and normal HPG axis. MEASUREMENTS: Serum levels of testosterone, LH and FSH (basal and after GnRH stimulation test), SHBG and IGF-I and percentage body fat (BF%) were evaluated before and during rhGH (mean dose 0.24 +/- 0.02 mg/day for 13 +/- 1 months) treatment. RESULTS: Serum IGF-I levels normalized during rhGH treatment and BF% significantly decreased. Serum testosterone levels significantly decreased (from 18.1 +/- 1.7 to 14.2 +/- 1.6 nmol/l, P = 0.01), with a parallel and significant decrease of serum SHBG (from 31.1 +/- 3.6 to 24.3 +/- 2.3 nmol/l, P < 0.05). Thus, calculated free testosterone (cFT) did not change (from 0.39 +/- 0.17 to 0.33 +/- 0.14 nmol/l, P = ns). Finally, no difference was found in basal and GnRH stimulated gonadotrophins levels. CONCLUSIONS: In conclusion, the condition of GHD does not seem to mask central hypogonadism, in contrast to what is observed for central hypothyroidism and hypoadrenalism. However, the significant decrease in serum testosterone levels, strictly related to SHBG decrease, suggests that evaluation of the HPG axis during rhGH treatment cannot be based on the measurement of total testosterone levels, but should mainly rely on calculation of cFT and a careful clinical evaluation, in order to avoid unnecessary replacement therapy.
Subject(s)
Human Growth Hormone/therapeutic use , Hypopituitarism/drug therapy , Somatomedins/deficiency , Testis/metabolism , Adult , Area Under Curve , Body Composition , Follicle Stimulating Hormone/blood , Gonadotropin-Releasing Hormone , Humans , Hypopituitarism/metabolism , Insulin-Like Growth Factor I/analysis , Luteinizing Hormone/blood , Male , Middle Aged , Prospective Studies , Sex Hormone-Binding Globulin/analysis , Testosterone/bloodABSTRACT
CONTEXT: Primary IGF deficiency (IGFD) describes the condition in which serum concentrations of IGF-I are low in the face of normal to elevated GH production. Because IGF-I, which circulates as part of a ternary complex with IGF binding protein (IGFBP)-3 and acid-labile subunit (ALS), mediates the growth-promoting effects of GH, IGFD is associated with severe growth failure in humans. OBJECTIVE: We investigated a case of IGFD in which serum IGF-I and IGFBP-3 were abnormally low, yet growth failure was modest (-2.1 sd score at 15.5 yr of age). RESULTS: The young male subject, from a consanguineous pedigree, had a postnatal growth profile consistently below the third percentile. The subject had a normal fasting GH level of 3.7 muU/ml and normal serum GH binding protein level (1258 pmol/liter; normal range 431-1892 pmol/liter), but serum IGF-I and IGFBP-3 were profoundly reduced (-5.8 and -7.2 sd score, respectively, at age 12.3 yr), even through puberty. A novel homozygous missense mutation was subsequently identified in the ALS gene, which resulted in severe deficiency of serum ALS (undetectable). CONCLUSIONS: ALS is critical for maintaining normal serum concentrations of IGF-I and IGFBP-3, most likely by prolonging the half-lives of both proteins. ALS deficiency can be associated with moderate growth failure, but in this patient, the onset and progression of puberty appear to be normal. Altogether the results support a modest role for the ternary complex in the regulation of stature.
Subject(s)
Carrier Proteins/genetics , Glycoproteins/genetics , Growth Disorders/genetics , Mutation, Missense/genetics , Mutation, Missense/physiology , Somatomedins/deficiency , Blotting, Western , Cells, Cultured , Child , DNA, Complementary/genetics , Fibroblasts/metabolism , Glycoproteins/deficiency , Human Growth Hormone/blood , Humans , Insulin-Like Growth Factor Binding Protein 3/deficiency , Insulin-Like Growth Factor I/deficiency , Ligands , Male , Puberty/physiology , Skin/cytologyABSTRACT
The potential therapeutic applications of the insulin-like growth factors (IGFs) are broad. This review focuses on treatment of humans with recombinant human IGF-I (rhIGF-I), and with a rhIGF-I/IGF binding protein-3 (IGFBP-3) complex. Several groups of patients have been treated effectively, including individuals with growth hormone insensitivity syndrome (GHIS) secondary to GH receptor deficiency, to IGF-I gene deletion, or to defects in GH signal transduction pathways, patients with type 1 and type 2 diabetes mellitus, or individuals with severe insulin resistance syndromes. In each of these conditions rhIGF-I therapy has been demonstrated to be of clear clinical benefit. Other conditions, which may potential targets for therapy with rhIGF-I or rhIGF-I/IGFBP-3, include chronic inflammatory or nutritional disorders such as Crohn's disease, juvenile chronic arthritis, or cystic fibrosis. Therapy with IGFs has not been attempted in these disorders yet, in part because of lack of adequate supplies. Recently, the newly developed rhIGF-I/IGFBP-3 complex has been used in early clinical studies. Pharmacokinetic analyses in patients with diabetes mellitus and GHIS have suggested that a more physiological profile of serum IGF-I results. Improved glycaemic control has been reported in type 1 and type 2 diabetes in adults. A therapeutic trial in naïve children with GHIS is currently under way.
Subject(s)
Diabetes Mellitus/drug therapy , Growth Disorders/drug therapy , Laron Syndrome/drug therapy , Somatomedins/therapeutic use , Adolescent , Adult , Genetic Diseases, Inborn/drug therapy , Humans , Insulin Resistance , Insulin-Like Growth Factor Binding Protein 3/therapeutic use , Male , Recombinant Proteins , Somatomedins/deficiency , Somatomedins/geneticsABSTRACT
The concept of growth hormone (GH) insensitivity has evolved since the condition was originally identified in 1966, and we now know that the primary defect involved is in the GH receptor. Cloning of the receptor molecule has led to great progress in our understanding of GH insensitivity (GHI) and its therapy, including the roles of GH and insulin-like growth factor I (IGF-I) in growth and development, and the relationships between height and serum levels of GH, IGF-I and their binding proteins. Despite the success of work on GHI and IGF-I, a number of opportunities have been missed in the past. The differences between the metabolic effects of GH and IGF-I are not fully understood, while measurements of IGF-I and IGF-binding protein 3 are perhaps not the ideal means of diagnosing GHI. Finally, the use of IGF-I to treat GHI has a number of limitations, and work is underway to develop alternative therapies.
Subject(s)
Human Growth Hormone/physiology , Drug Resistance , Humans , Mutation/physiology , Phenotype , Receptors, Somatotropin/genetics , Somatomedins/deficiency , SyndromeABSTRACT
BACKGROUND/AIMS: Almost all circulating insulin-like growth factor-1 (IGF-1) is produced and secreted from the liver. However, the possible role of IGF-1 in local regulation of liver functions including liver growth is unclear. In the present study, we investigated the role of IGF-1 on liver growth in vivo and in hepatic stellate cell function in vitro. RESULTS: Liver-specific knock-out of the IGF-1 gene by use of the cre-loxP system caused enhanced liver growth, possibly reflecting increased growth hormone (GH) secretion due to decreased negative feedback by IGF-1. Studies on cultured rat hepatic stellate cells (HSC) showed that IGF-1 and hepatocyte-conditioned medium (PCcM) time- and dose-dependently increased hepatocyte growth factor (HGF) mRNA and HGF immunoreactivity. IGF-1 and PCcM also enhanced DNA synthesis in the HSC cultures. The PCcM did not contain bioactive IGF-1 and was also able to stimulate proliferation when prepared under serum- and hormone-free conditions. CONCLUSION: In vivo results show that IGF-1 is not essential for normal growth of the intact liver. The in vitro results indicate that both IGF-1 and IGF- 1-independent factor(s) from hepatocytes can stimulate HGF production by HSC. It remains to be investigated whether these effects are of importance for liver regeneration or pathological conditions.
Subject(s)
Liver Diseases/physiopathology , Liver/growth & development , Somatomedins/physiology , Animals , Cell Division/physiology , Culture Media, Conditioned/pharmacology , DNA/biosynthesis , Hepatocyte Growth Factor/biosynthesis , Hepatocyte Growth Factor/genetics , Hepatocytes/cytology , Hepatocytes/pathology , Liver/cytology , Liver/metabolism , Liver/pathology , Mice , Mice, Knockout/genetics , Mitogens/pharmacology , Somatomedins/deficiencyABSTRACT
The insulin-like growth factor (IGF) system composed of two ligands, their receptors and regulatory proteins (acid-labile subunit and IGF-binding proteins) plays a central role in the regulation of growth and development in mammals. In addition to its key role in the stimulation of cellular proliferation and growth, IGF-I has important effects on carbohydrate, protein and bone metabolism. The molecular biology and physiology of the IGF system are complex, resulting in many potential mechanisms of IGF deficiency. Briefly, IGF-I deficiency may result from a primary defect in the IGF-I gene, its promoters, or may be secondary to a defect outside the gene itself. It may also result as a consequence of growth hormone (GH) deficiency, GH receptor/post-receptor abnormalities or abnormalities of the IGF-I receptor. The purpose of this presentation is to review the different types of IGF-I deficiency using the well-characterized clinical conditions with its associated biochemical and molecular defects. The clinical consequences in terms of phenotype-genotype, linear growth and body composition in patients with primary and secondary IGF deficiency will be presented, together with results from recombinant human (rh)IGF-I replacement therapy. Finally, as primary IGF-I deficiency is associated with insulin resistance, some of the metabolic actions of IGF-I will be briefly discussed.
Subject(s)
Somatomedins/deficiency , Humans , Insulin-Like Growth Factor I/therapeutic use , Mutation/physiology , Receptors, Somatomedin/genetics , Recombinant Proteins/therapeutic useABSTRACT
Our understanding of the physiology of the growth hormone-insulin-like growth factor (GH-IGF) axis has been characterized by remarkable advances in the past decade, with clarification of genetic defects in the development of somatotropes, GH secretion and action, and IGF synthesis and action. Combined efforts of research in this area and the development of animal models of growth retardation have also indicated new genetic abnormalities that might prove to cause short stature in humans. Genetic defects, both established and hypothetical, are reviewed, and a pragmatic clinical approach to the genetic investigation of short-statured patients is presented.
Subject(s)
Growth Hormone/physiology , Hypothalamic Diseases/genetics , Pituitary Diseases/genetics , Somatomedins/physiology , Animals , Humans , Somatomedins/deficiencySubject(s)
Fetal Growth Retardation/classification , Fetal Growth Retardation/etiology , Growth Disorders/congenital , Growth Disorders/diagnosis , Growth Disorders/genetics , Growth Hormone , Human Growth Hormone/deficiency , Human Growth Hormone/pharmacology , Insulin-Like Growth Factor Binding Protein 1/pharmacology , /pharmacology , Receptors, Somatotropin , Hypothalamo-Hypophyseal System/growth & development , Somatomedins/deficiency , Gonadal Steroid Hormones , Thyroid Hormones , Molecular BiologyABSTRACT
Gene knockout studies in mice, and a recent case report, have demonstrated that insulin-like growth factors (IGFs) are major mediators of pre- and postnatal growth, whereas the growth-promoting role of growth hormone (GH) appears to be confined largely to the postnatal period. The IGF axis is now known to consist of the growth factors themselves and at least seven, and probably ten, IGF-binding proteins. These act either by regulating the availability of IGFs to their receptors, or directly on their target cells. Because of the difficulties associated with GH provocative testing, the central role of IGFs in pre- and postnatal growth, and the ease of assaying the various components of the IGF axis, it is suggested that the differential diagnosis of short stature should be based on the concept of IGF deficiency rather than on GH secretory status.
