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Frontiers in Endocrinology 2023Linear growth during childhood is the result of the synergic contribution of different factors. The best growth determinant system during each period of life is... (Review)
Review
Linear growth during childhood is the result of the synergic contribution of different factors. The best growth determinant system during each period of life is represented by the growth hormone-insulin-like growth factor axis (GH-IGF), even if several other factors are involved in normal growth. Within the broad spectrum of growth disorders, an increased importance has been placed on growth hormone insensitivity (GHI). GHI was reported for the first time by Laron as a syndrome characterized by short stature due to GH receptor (GHR) mutation. To date, it is recognized that GHI represents a wide diagnostic category, including a broad spectrum of defects. The peculiar characteristic of GHI is the low IGF-1 levels associated with normal or elevated GH levels and the lack of IGF-1 response after GH administration. Recombinant IGF-1 preparations may be used in the treatment of these patients.
Topics: Dwarfism; Human Growth Hormone; Insulin-Like Growth Factor I; Humans; Growth Disorders
PubMed: 37008935
DOI: 10.3389/fendo.2023.1141039 -
Cellular and Molecular Life Sciences :... Mar 2023Signal transducer and activator of transcription (STAT) proteins act downstream of cytokine receptors to facilitate changes in gene expression that impact a range of...
Signal transducer and activator of transcription (STAT) proteins act downstream of cytokine receptors to facilitate changes in gene expression that impact a range of developmental and homeostatic processes. Patients harbouring loss-of-function (LOF) STAT5B mutations exhibit postnatal growth failure due to lack of responsiveness to growth hormone as well as immune perturbation, a disorder called growth hormone insensitivity syndrome with immune dysregulation 1 (GHISID1). This study aimed to generate a zebrafish model of this disease by targeting the stat5.1 gene using CRISPR/Cas9 and characterising the effects on growth and immunity. The zebrafish Stat5.1 mutants were smaller, but exhibited increased adiposity, with concomitant dysregulation of growth and lipid metabolism genes. The mutants also displayed impaired lymphopoiesis with reduced T cells throughout the lifespan, along with broader disruption of the lymphoid compartment in adulthood, including evidence of T cell activation. Collectively, these findings confirm that zebrafish Stat5.1 mutants mimic the clinical impacts of human STAT5B LOF mutations, establishing them as a model of GHISID1.
Topics: Animals; Humans; Zebrafish; STAT5 Transcription Factor; Laron Syndrome; Mutation; Growth Hormone
PubMed: 36995466
DOI: 10.1007/s00018-023-04759-y -
Endocrine-related Cancer May 2023Interest in investigating the role of the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis in the initiation and progression of experimentally induced... (Review)
Review
Interest in investigating the role of the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis in the initiation and progression of experimentally induced carcinomas has arisen due to several observations in the human population. First, subjects with Laron syndrome who lack GH signaling have significantly lower rates of cancer than people who have normal GH signaling. Second, epidemiologic studies have found strong associations between elevated circulating IGF-1 and the incidence of several common cancers. Third, women who bear children early in life have a dramatically reduced risk of developing breast cancer, which may be due to differences in hormone levels including GH. These observations have motivated multiple studies that have experimentally altered activity of the GH/IGF-1 axis in the context of experimental carcinoma models in mice and rats. Most of these studies have utilized carcinoma models for four organ systems that are also frequent sites of carcinomas in humans: the mammary gland, prostate gland, liver, and colon. This review focuses on these studies and describes some of the most common genetic models used to alter the activity of the GH/IGF-1 axis in experimentally induced carcinomas. A recurring theme that emerges from these studies is that manipulations that reduce the activity of GH or mediators of GH action also inhibit carcinogenesis in multiple model systems.
Topics: Male; Female; Rats; Mice; Humans; Animals; Growth Hormone; Insulin-Like Growth Factor I; Neoplasm Recurrence, Local; Human Growth Hormone; Carcinoma
PubMed: 36826838
DOI: 10.1530/ERC-22-0403 -
Cureus Dec 2022Laron syndrome is a rare, genetic, growth hormone insensitivity disorder caused by mutations in the growth hormone receptor gene. Affected patients have severe postnatal...
Laron syndrome is a rare, genetic, growth hormone insensitivity disorder caused by mutations in the growth hormone receptor gene. Affected patients have severe postnatal growth failure, characteristic facial features, and metabolic abnormalities, including severe obesity and metabolic syndrome. Women with Laron syndrome are usually subfertile, mainly due to obesity and metabolic dysregulation, and require treatment for their chronic reproductive dysfunction. To date, infertility in Laron syndrome patients is a rarely addressed problem and, as a result, adequate data regarding its treatment are lacking. Here we present, for the first time in the literature, a rare case of successful treatment of a young woman with Laron syndrome who suffered from infertility due to hyperprolactinemia.
PubMed: 36721555
DOI: 10.7759/cureus.33090 -
Diabetes Research and Clinical Practice Feb 2023We examined the effect of growth hormone (GH) counter-regulation on carbohydrate metabolism in individuals with life-long diminished insulin secretion (DIS).
AIMS
We examined the effect of growth hormone (GH) counter-regulation on carbohydrate metabolism in individuals with life-long diminished insulin secretion (DIS).
METHODS
Adults homozygous for the E180 splice site mutation of GHR [Laron syndrome (LS)], adults with a gain-of-function mutation in CDKN1c [Guevara-Rosenbloom syndrome (GRS)], and controls were evaluated for body composition, leptin, total and high molecular weight (HMW) adiponectin, insulin-like growth factor (IGF) axis molecules, and a 5-hour oral glucose tolerance test (OGTT), with measurements of glucose, insulin, glucagon, ghrelin, pancreatic polypeptide, gastric inhibitory peptide, glucagon-like peptide-1, peptide YY, and islet amyloid polypeptide (IAPP).
RESULTS
Both syndromic cohorts displayed DIS during OGTT. LS subjects had higher serum concentrations of total and HMW adiponectin, and lower levels of IGF-I, IGF-II, and IGF-Binding Protein-3 than individuals in other study groups. Furthermore, they displayed normal glycemic responses during OGTT with the lowest IAPP secretion. In contrast, individuals with GRS had higher levels of protein glycation, deficient glucose control during OGTT, and increased secretion of IAPP.
CONCLUSIONS
A distinct metabolic phenotype depending on GH counter-regulatory status, associates with diabetes development and excess glucose-induced IAPP secretion.
Topics: Humans; Insulin Secretion; Adiponectin; Syndrome; Insulin; Human Growth Hormone; Glucose; Islet Amyloid Polypeptide; Phenotype; Insulin-Like Growth Factor I
PubMed: 36549505
DOI: 10.1016/j.diabres.2022.110228 -
Hormone Research in Paediatrics 2022The 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... (Review)
Review
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.
Topics: Animals; Humans; Insulin-Like Growth Factor I; Laron Syndrome; Peptide Hormones; Protein Processing, Post-Translational; Signal Transduction; Somatomedins; Insulin-Like Growth Factor II
PubMed: 36446332
DOI: 10.1159/000527123 -
Cells Oct 2022The growth hormone (GH)-insulin-like growth factor-1 (IGF1) signaling pathway plays a major role in orchestrating cellular interactions, metabolism, growth and aging....
The growth hormone (GH)-insulin-like growth factor-1 (IGF1) signaling pathway plays a major role in orchestrating cellular interactions, metabolism, growth and aging. Studies from worms to mice showed that downregulated activity of the GH/IGF1 pathway could be beneficial for the extension of lifespan. Laron syndrome (LS) is an inherited autosomal recessive disorder caused by molecular defects of the GH receptor (GHR) gene, leading to congenital IGF1 deficiency. Life-long exposure to minute endogenous IGF1 levels in LS is associated with low stature as well as other endocrine and metabolic deficits. Epidemiological surveys reported that patients with LS have a reduced risk of developing cancer. Studies conducted on LS-derived lymphoblastoid cells led to the identification of a novel link between IGF1 and thioredoxin-interacting protein (TXNIP), a multifunctional mitochondrial protein. TXNIP is highly expressed in LS patients and plays a critical role in cellular redox regulation by thioredoxin. Given that IGF1 affects the levels of TXNIP under various stress conditions, including high glucose and oxidative stress, we hypothesized that the IGF1-TXNIP axis plays an essential role in helping maintain a physiological balance in cellular homeostasis. In this study, we show that TXNIP is vital for the cell fate choice when cells are challenged by various stress signals. Furthermore, prolonged IGF1 treatment leads to the establishment of a premature senescence phenotype characterized by a unique senescence network signature. Combined IGF1/TXNIP-induced premature senescence can be associated with a typical secretory inflammatory phenotype that is mediated by STAT3/IL-1A signaling. Finally, these mechanistic insights might help with the understanding of basic aspects of IGF1-related pathologies in the clinical setting.
Topics: Animals; Mice; Carrier Proteins; Cellular Senescence; Glucose; Growth Hormone; Insulin-Like Growth Factor I; Laron Syndrome; Mitochondrial Proteins; Thioredoxins; Humans; Fibroblasts; 3T3-L1 Cells
PubMed: 36291127
DOI: 10.3390/cells11203260 -
Stem Cell Reviews and Reports Feb 2023Pathway involving insulin-like growth factor 1 (IGF-1) plays significant role in growth and development. Crucial role of IGF-1 was discovered inter alia through studies...
Pathway involving insulin-like growth factor 1 (IGF-1) plays significant role in growth and development. Crucial role of IGF-1 was discovered inter alia through studies involving deficient patients with short stature, including Laron syndrome individuals. Noteworthy, despite disturbances in proper growth, elevated values for selected stem cell populations were found in IGF-1 deficient patients. Therefore, here we focused on investigating role of these cells-very small embryonic-like (VSEL) and hematopoietic stem cells (HSC), in the pathology. For the first time we performed long-term observation of these populations in response to rhIGF-1 (mecasermin) therapy. Enrolled pediatric subjects with IGF-1 deficiency syndrome were monitored for 4-5 years of rhIGF-1 treatment. Selected stem cells were analyzed in peripheral blood flow cytometrically, together with chemoattractant SDF-1 using immunoenzymatic method. Patients' data were collected for correlation of experimental results with clinical outcome. IGF-1 deficient patients were found to demonstrate initially higher levels of VSEL and HSC compared to healthy controls, with their gradual decrease in response to therapy. These changes were significantly associated with SDF-1 plasma levels. Correlations of VSEL and HSC were also reported in reference to growth-related parameters, and IGF-1 and IGFBP3 values. Noteworthy, rhIGF-1 was shown to efficiently induce development of Laron patients achieving at least proper rate of growth (compared to healthy group) in 80% of subjects. In conclusion, here we provided novel insight into stem cells participation in IGF-1 deficiency in patients. Thus, we demonstrated basis for future studies in context of stem cells and IGF-1 role in growth disturbances.
Topics: Humans; Child; Insulin-Like Growth Factor I; Laron Syndrome; Stem Cells
PubMed: 36269524
DOI: 10.1007/s12015-022-10457-2 -
Frontiers in Physiology 2022Growth hormone (GH) is a peptide hormone that can signal directly through its receptor or indirectly through insulin-like growth factor 1 (IGF-1) stimulation. GH draws... (Review)
Review
Growth hormone (GH) is a peptide hormone that can signal directly through its receptor or indirectly through insulin-like growth factor 1 (IGF-1) stimulation. GH draws its name from its anabolic effects on muscle and bone but also has distinct metabolic effects in multiple tissues. In addition to its metabolic and musculoskeletal effects, GH is closely associated with aging, with levels declining as individuals age but GH action negatively correlating with lifespan. GH's effects have been studied in human conditions of GH alteration, such as acromegaly and Laron syndrome, and GH therapies have been suggested to combat aging-related musculoskeletal diseases, in part, because of the decline in GH levels with advanced age. While clinical data are inconclusive, animal models have been indispensable in understanding the underlying molecular mechanisms of GH action. This review will provide a brief overview of the musculoskeletal effects of GH, focusing on clinical and animal models.
PubMed: 35665221
DOI: 10.3389/fphys.2022.867921 -
Cells May 2022Normal growth and development in mammals are tightly controlled by numerous genetic factors and metabolic conditions. The growth hormone (GH)-insulin-like growth...
Normal growth and development in mammals are tightly controlled by numerous genetic factors and metabolic conditions. The growth hormone (GH)-insulin-like growth factor-1 (IGF1) hormonal axis is a key player in the regulation of these processes. Dysregulation of the GH-IGF1 endocrine system is linked to a number of pathologies, ranging from growth deficits to cancer. Laron syndrome (LS) is a type of dwarfism that results from mutation of the GH receptor () gene, leading to GH resistance and short stature as well as a number of metabolic abnormalities. Of major clinical relevance, epidemiological studies have shown that LS patients do not develop cancer. While the mechanisms associated with cancer protection in LS have not yet been elucidated, genomic analyses have identified a series of metabolic genes that are over-represented in LS patients. We hypothesized that these genes might constitute novel targets for IGF1 action. With a fold-change of 11.09, UDP-glucuronosyltransferase 2B15 () was the top up-regulated gene in LS. The gene codes for an enzyme that converts xenobiotic substances into lipophilic compounds and thereby facilitates their clearance from the body. We investigated the regulation of gene expression by IGF1 and insulin. Both hormones inhibited UGT2B15 mRNA levels in endometrial and breast cancer cell lines. Regulation of UGT2B15 protein levels by IGF1/insulin, however, was more complex and not always correlated with mRNA levels. Furthermore, expression was dependent on p53 status. Thus, UGT2B15 mRNA levels were higher in cell lines expressing a wild-type p53 compared to cells containing a mutated p53. Animal studies confirmed an inverse correlation between UGT2B15 and p53 levels. In summary, increased UGT2B15 levels in LS might confer upon patient's protection from genotoxic damage.
Topics: Animals; Glucuronosyltransferase; Glycosyltransferases; Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Laron Syndrome; Mammals; Neoplasms; RNA, Messenger; Tumor Suppressor Protein p53; Uridine Diphosphate
PubMed: 35626664
DOI: 10.3390/cells11101627