The insulin-like growth factor (IGF)-I is implicated in the regulation of protein turnover and exerts potent mi-togenic and differentiating effects on most cell types. IGF-I biological actions are mediated by the IGF-I receptor, com-prised of two extra-cellular -subunits, containing hormone binding sites, and two membrane-spanning -subunits, encod-ing an intracellular tyrosine kinase. Hormone binding activates the receptor kinase, leading to receptor autophosphoryla-tion and tyrosine phosphorylation of multiple substrates, including the IRS and Shc proteins. Through these initial tyro-sine phosphorylation reactions, IGF-I signals are transduced to a complex network of intracellular lipid and ser-ine/threonine kinases that are ultimately responsible for cell proliferation, modulation of tissue differentiation, and protec-tion from apoptosis. This review will focus on the IGF-I receptor structure and function, its intracellular signaling path-ways, and some important implications of the activation of the IGF-I signal transduction system on specific tissues.
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... Beberapa IGF-1 autokrin/parakrin yang disekresikan masuk ke dalam sirkulasi sistemik. 16,17 IGF-1 memiliki keterlibatan dalam mengatur perkembangan saraf termasuk neurogenesis, mielinisasi , sinaptogenesis , dan percabangan dendritik serta perlindungan saraf setelah kerusakan saraf. IGF-1 memediasi banyak aksi GH, merangsang pertumbuhan tulang dan jaringan lain, dan meningkatkan produksi massa otot tanpa lemak. ...
Septi Wulandari Desi Oktariana
Latar Belakang: Platelet Rich Plasma (PRP) merupakan suatu bagian plasma dari darah yang diambil dari pasien itu sendiri (autologous) dengan kandungan konsentrasi platelet atau trombosit yang cukup tinggi yakni 3 sampai 5 kali lebih besar dari konsentrasi trombosit dalam darah. PRP memiliki kandungan Growth Factor (GF) yang melimpah, di antaranya Platelet Derived Growth Factor (PDGF), Transforming Growth Factor (TGF), Vascular Endothelial Growth Factor (VEGF), Epithelial Growth Factor (EGF) dan Insulin-Like Growth Factor (IGF) yang berfungsi mempercepat regenerasi endothelial, epitel, dan epidermal, merangsang angiogenesis, meningkatkan sintesis kolagen, penyembuhan jaringan, mengurangi jaringan parut pada kulit, dan meningkatkan respon hemostatik terhadap cedera. Berbagai studi baik in vitro maupun uji klinis menunjukkan bahwa pemberian PRP berpengaruh signifikan dalam penyembuhan cedera, perbaikan jaringan dan angiogenesis. Terapi PRP telah digunakan dalam dunia kesehatan sebagai pengobatan dalam berbagai penyakit yang berkaitan dengan pertumbuhan sel Kata kunci : Plasma kaya trombosit, faktor pertumbuhan, pengobatan regeneratif
... Non-essential TMs, including cadmium and lead, are non-nutritional metals, with no documented health benefit. Cadmium and lead exposure leads to bioaccumulation, leading to damage of target intra-or extra-cellular proteins or organelles [19]. Other potentially harmful metals, including aluminium, copper, iron (Fe), mercury, and nickel, are chemical properties are in common with essential ones and are considered by IARC and WHO as possibly causing adverse effects in humans [20]. ...
Ameera Jasim Al-Aaraji Ruwaida Wahab Salman AL-Jebory Ahmed Hasan R. Al.Zurfi Haider Mahmod Jasim
Heavy metals such as lead, mercury, arsenic, and cadmium are ubiquitous environmental contaminants that pose significant health hazards. These metals disrupt normal cellular processes by inducing oxidative stress, lipid peroxidation, and DNA damage. On the molecular level, they interfere with enzymatic functions, disrupt calcium homeostasis, and trigger apoptosis or necrosis. Chronic exposure is linked to carcinogenesis, neurotoxicity, nephrotoxicity, and endocrine dysfunctions. This review examines the cellular and molecular mechanisms underlying heavy metal toxicity, highlighting recent findings on oxidative stress pathways, mitochondrial dysfunction, and inflammatory responses. It also discusses current strategies for detoxification and the role of chelation therapy. Better understanding these mechanisms is vital for developing preventive measures and therapeutic interventions to mitigate toxic effects.
... The insulin-like growth factor (IGF) signaling pathway plays a central role in cell proliferation and insulin sensitivity. IGF-1 binds to its receptor (IGF-1R), a tetramer of two extracellular a-subunits and two transmembrane b-subunits with intrinsic tyrosine kinase activity (101) This interaction activates the PI3K/AKT pathway, increases AKT phosphorylation, and drives HemSCs to differentiate into adipocytes (102). Similarly, IGF-2 promotes HemSCs adipogenesis via the same mechanism. ...
Zongdong Zhu Xiaoya Jiang Fang Wang Qinggao Song
Infantile hemangioma (IH), the most prevalent benign vascular tumor in neonates, typically appears several weeks after birth, undergoes rapid proliferation, and subsequently enters a prolonged phase of spontaneous involution. Recent advancements in molecular and cellular biology have revealed increasing evidence that the etiology and progression of IH arise from complex, multi-level interactions involving various factors. In this review, we examine the categorization of IH cells, analyze the pivotal roles of key molecular signaling pathways (e.g., VEGF, HIF, Notch), and elucidate the contributions of immune cells, hypoxia, the extracellular matrix, and exosome-mediated signaling within the tumor microenvironment to the angiogenic processes and regression of IH. These insights will enhance our understanding of IH pathogenesis, thereby laying the groundwork for the development of targeted therapeutic strategies.
... Among these, miR-125b-5p, a commonly expressed miRNA, is pivotal in TB infection and osteoporosis-related bone metabolism regulation. Research indicates that miR-125b-5p is highly expressed in TB-infected macrophages, where it modulates macrophage polarization and function by targeting multiple genes, thus impacting bone cell metabolic activity [13,14]. Notably, miR-125b-5p suppresses osteoblast proliferation and differentiation by targeting the IGF2 gene, essential in bone formation; reduced IGF2 expression may impair osteoblast function, exacerbating osteoporosis [15,16]. ...
Chenhao Zhao Qiuwei Li Peilin Jin Cailiang Shen
Background Tuberculosis (TB) is a major infectious disease that can lead to systemic complications, including osteoporosis, particularly in immunocompromised individuals. Exosomal miRNAs derived from TB-infected macrophages have been implicated in various pathophysiological processes, including bone metabolism. This study investigates how exosomal miR-125b-5p from TB-infected macrophages contributes to osteoporosis by targeting insulin-like growth factor 2 (IGF2) and modulating the PI3K/AKT signaling pathway. Methods We analyzed NHANES data to compare bone mineral density in TB patients and healthy controls. In vitro experiments were conducted with Mycobacterium tuberculosis-infected peritoneal macrophages from C57BL/6 mice, isolating exosomes and using Western blot, flow cytometry, and bioinformatics tools to assess the role of miR-125b-5p in regulating osteogenic markers. In vivo studies in mouse models were performed to evaluate the impact of exosomal miR-125b-5p on bone density and structure. Results Exosomes from TB-infected macrophages were found to contain elevated levels of miR-125b-5p, which targeted IGF2 and inhibited the PI3K/AKT pathway, leading to impaired osteoblast function and reduced bone formation. Knockdown of miR-125b-5p partially restored osteogenic markers and bone density. Furthermore, IGF2 silencing exacerbated bone loss, confirming the critical role of IGF2 in TB-induced osteoporosis. Conclusion This study demonstrates that miR-125b-5p from TB-infected macrophages promotes osteoporosis by disrupting the IGF2/PI3K/AKT signaling axis. Targeting this pathway could provide a potential therapeutic strategy for managing TB-induced osteoporosis. Further clinical studies are necessary to validate these findings and explore additional therapeutic options. Graphical abstract
... The IGF1R plays a key role in mediating the growth-promoting effects of IGF-1 at the cellular level, particularly in postnatal chondrocyte proliferation and survival [52]. Variants in IGF1 and IGF1R can impair downstream signaling, leading to postnatal growth failure. ...
Roberto Paparella
Arianna Bei Irene Bernabei
Luigi Tarani
Idiopathic short stature (ISS) represents one of the most frequent yet enigmatic conditions in pediatric endocrinology. Traditionally defined by auxological parameters in the absence of identifiable causes, ISS has long served as a diagnosis of exclusion. However, with the advent of next-generation sequencing, our understanding of the etiological landscape has significantly evolved. Recent studies have revealed that many children previously labeled as idiopathic actually harbor monogenic variants in genes related to the growth hormone–insulin-like growth factor axis, extracellular matrix components, or growth plate signaling pathways. This review integrates auxological assessment with current knowledge on molecular diagnostics to propose a more accurate and individualized approach to short stature. We examine emerging genotype–phenotype correlations, criteria for selecting candidates for genetic testing, and implications for recombinant human growth hormone therapy. Additionally, we advocate for a shift in clinical mindset: from a descriptive to a biologically grounded framework. ISS should be regarded as a transitional label pending further endocrine and genetic clarification. Recognizing this paradigm shift will improve diagnostic accuracy, personalize treatment strategies, and ultimately enhance care for children with growth failure in the genomic era.
Kai Wang Aneela Perveen
Jiakun Shen
Chunmei Li
T‐2 mycotoxin is a highly toxic type A trichothecene mycotoxin that widely contaminates livestock feed, posing a serious threat to animal and human health. Long‐term exposure can lead to immunosuppression, growth retardation, and liver damage, causing significant economic losses to the livestock industry. Offspring are particularly susceptible to maternal dietary influences during pregnancy and lactation. This research aimed to evaluate the impact of T‐2 mycotoxin exposure on both dams and their pups. Thirty pregnant mice were randomly allocated into three groups ( n = 10). From gestational day 14 to lactational day 21, the dams received gavage doses of T‐2 mycotoxin at concentrations of 0, 0.005, and 0.05 mg/kg/day. Randomly selected one male pup and one female pup from each dam were sacrificed on LD 1, 7, and 21; dams were dosed until the day they were sacrificed. T‐2 mycotoxin decreased the relative body/organ weights of the dams and offspring ( p < 0.05). Moreover, T‐2 mycotoxin‐induced oxidative stress in dams and offspring increased the malondialdehyde content, which led to reduced activities of antioxidant enzymes, including catalase, superoxide dismutase, and glutathione peroxidase, and total antioxidant capacity in the serum and liver ( p < 0.05). T‐2 mycotoxin induced histomorphological changes in the liver and early involution of the mammary gland acini in dams. The concentrations of liver‐metabolizing enzymes such as glutamic oxaloacetic transaminase and glutamic pyruvic transaminase increased in offspring ( p < 0.05). The serum insulin‐like growth factor‐1 level in offspring was decreased, which may impair the development of vital organs such as the liver, kidneys, and spleen in offspring. Consequently, the body weight and length of the offspring of exposed dams decreased. This study revealed that T‐2 mycotoxin exposure during late gestation and entire lactation harms dams, damages mammary gland acini, alters liver biochemistry, induces oxidative stress, and delays offspring growth while also impairing maternal weight gain during lactation.
AL FRATTALI JE PESSIN
Insulin receptor beta subunit autophosphorylation occurs in an intramolecular trans-reaction in which one beta subunit phosphorylates the adjacent beta subunit within an alpha2beta2 holoreceptor complex (Frattali, A. L., Treadway, J. L., and Pessin, J. E. (1992) J. Biol. Chem. 267, 19521-19528). To determine the spatial relationship between alpha subunit occupancy and beta subunit autophosphorylation, the vaccinia virus/bacteriophage T7 transient expression system was used to generate insulin/insulin-like growth factor (IGF)-1 hybrid receptors. The extent of hybrid receptor formation was proportional to the molar ratio of the insulin and IGF-1 receptor expression plasmids used for transfection of cultured fibroblasts. Insulin/IGF-1 hybrid receptors displayed high affinity binding for insulin and IGF-1 similar to that observed for homotypic insulin and IGF-1 receptors, respectively. As expected, insulin poorly competed for I-125-IGF-1 binding to the insulin/IGF-1 hybrid receptors compared with IGF-1. IGF-1, however, competed more efficiently than insulin for I-125-insulin binding, indicating interactions between the a subunit binding sites. Furthermore, insulin or IGF-1 stimulated the autophosphorylation of both beta subunits within wild type insulin/IGF-1 hybrid receptors. Ligand-stimulated autophosphorylation of two different mutant/wild type insulin/IGF-1 hybrid receptors also resulted in the labeling of each beta subunit independent of which alpha subunit was occupied with ligand. These data demonstrate that insulin/IGF-1 hybrid receptors bind both ligands with high affinity and that occupancy of either alpha subunit results in a series of intramolecular trans-autophosphorylation reactions between beta subunits.
Rohit Kulkarni
Jonathon Winnay Molly Daniels
C. Ronald Kahn
Insulin receptor substrate-1 (IRS-1) is pivotal in mediating the actions of insulin and growth factors in most tissues of the body, but its role in insulin-producing beta islet cells is unclear. Freshly isolated islets from IRS-1 knockout mice and SV40-transformed IRS-1-deficient beta-cell lines exhibit marked insulin secretory defects in response to glucose and arginine. Furthermore, insulin expression is reduced by about 2-fold in the IRS-1-null islets and beta-cell lines, and this defect can be partially restored by transfecting the cells with IRS-1. These data provide evidence for an important role of IRS-1 in islet function and provide a novel functional link between the insulin signaling and insulin secretion pathways. This article may have been published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.
Enrica Migliaccio Simonetta Mele
Anna Elisabetta Salcini
Pier Giuseppe Pelicci
Shc proteins are targets of activated tyrosine kinases and are implicated in the transmission of activation signals to Ras. The p46shc and p52shc isoforms share a C-terminal SH2 domain, a proline- and glycine-rich region (collagen homologous region 1; CH1) and a N-terminal PTB domain. We have isolated cDNAs encoding for a third Shc isoform, p66shc. The predicted amino acid sequence of p66shc overlaps that of p52shc and contains a unique N-terminal region which is also rich in glycines and prolines (CH2). p52shc/p46shc is found in every cell type with invariant reciprocal relationship, whereas p66shc expression varies from cell type to cell type. p66shc differs from p52shc/p46shc in its inability to transform mouse fibroblasts in vitro. Like p52shc/p46shc, p66shc is tyrosine-phosphorylated upon epidermal growth factor (EGF) stimulation, binds to activated EGF receptors (EGFRs) and forms stable complexes with Grb2. However, unlike p52shc/p46shc it does not increase EGF activation of MAP kinases, but inhibits fos promoter activation. The isolated CH2 domain retains the inhibitory effect of p66shc on the fos promoter. p52shc/p46shc and p66shc, therefore, appear to exert different effects on the EGFR-MAP kinase and other signalling pathways that control fos promoter activity. Regulation of p66shc expression might, therefore, influence the cellular response to growth factors.
WM He David W. Rose Jerrold M. Olefsky
Thomas Gustafson
The Grb10 protein appears to be an adapter protein of unknown function that has been implicated in insulin receptor (IR) signaling. The interaction of this protein with the IR has been shown to be mediated in part by the Src homology 2 (SH2) domain of Grb10. Here we demonstrate the existence of a second novel domain within Grb10 that interacts with the IR and insulin-like growth factor receptor in a kinase-dependent manner. This domain was localized to a region of approximately 50 amino acids, and we term it the BPS domain to denote its location between the PH and SH2 domains. The BPS domain does not bear any obvious resemblance to other known protein interaction domains but is highly conserved among the Grb10-related proteins Grb7 and Grb14. We show that the BPS domain interaction is dependent upon receptor tyrosine kinase activity. Furthermore, interaction of the BPS domain requires the kinase domain of the IR, since mutation of the paired tyrosine residues (Y1150F/Y1151F) within the IR activation loop dramatically reduced the interaction. Last, our data suggest that the presence of two distinct protein interaction domains may help to determine the specificity by which Grb10 interacts with different receptors. Specifically, the IR, which appears to interact most strongly with Grb10, interacts well with both the SH2 and BPS domains. Conversely, the insulin-like growth factor receptor and EGFR, which interact less avidly with Grb10, interact well only with the BPS domain or the SH2 domain, respectively. In summary, our findings demonstrate the existence of a previously unidentified tyrosine kinase activity-dependent binding domain located between the Pleckstrin homology and SH2 domains of Grb10.
Jane J Kim Byung-Chul Park
Yoshiaki Kido Domenico Accili
We have previously shown that hepatocytes lacking insulin receptors (Ir−/−) fail to mediate metabolic responses, such as stimulation of glycogen synthesis, while retaining the ability to proliferate in response to IGFs. In this study we have asked whether overexpression of type I IGF receptors would rescue the metabolic response of Ir−/− hepatocytes. After IGF-I stimulation, insulin receptor substrate-1 and -2 phosphorylation and PI3K activity were restored to levels similar to or greater than those seen in wild-type cells. Rates of cell proliferation in response to IGF-I increased approximately 2-fold, whereas glycogen synthesis was restored to wild-type levels, but was comparatively smaller than that elicited by overexpression of insulin receptors. In summary, overexpression of IGF-I receptors in Ir−/− hepatocytes normalized insulin receptor substrate-2 phosphorylation and glycogen synthesis to wild-type levels, whereas it increased cell proliferation above wild-type levels. Moreover, stimulation of gly...
John Rouse
Philip Cohen Sylviane Trigon
Angel R Nebreda
MAPK-activated protein kinase-2 (MAPKAP kinase-2) is activated in vitro by the p42 and p44 isoforms of MAPK (p42/p44MAPK). In several cell lines, however, MAPKAP kinase-2 is activated by sodium arsenite, heat shock, or osmotic stress and not by agonists that activate p42/p44MAPK. We have identified a MAPK-like enzyme that acts as a MAPKAP kinase-2 reactivating kinase (RK). RK is recognized by an antiserum raised against a Xenopus MAPK (Mpk2), which is most similar to HOG1 from S. cerevisiae. We also identified a RK kinase (RKK) on the basis of its ability to activate either RK or a GST-Mpk2 fusion protein. The RKK, RK, and MAPKAP kinase-2 constitute a new stress-activated signal transduction pathway in vertebrates that is distinct from the classical MAPK cascade.
Jeh-Ping Liu
Jo Baker Archlbald S. Perkins
Argiris Efstratiadis
Newborn mice homozygous for a targeted disruption of insulin-like growth factor gene (Igf-1) exhibit a growth deficiency similar in severity to that previously observed in viable Igf-2 null mutants (60% of normal birthweight). Depending on genetic background, some of the Igf-1(-/-) dwarfs die shortly after birth, while others survive and reach adulthood. In contrast, null mutants for the Igf1r gene die invariably at birth of respiratory failure and exhibit a more severe growth deficiency (45% normal size). In addition to generalized organ hypoplasia in Igf1r(-/-) embryos, including the muscles, and developmental delays in ossification, deviations from normalcy were observed in the central nervous system and epidermis. Igf-1(-/-)/Igf1r(-/-) double mutants did not differ in phenotype from Igf1r(-/-) single mutants, while in Igf-2(-)/Igf1r(-/-) and Igf-1(-/-)/Igf-2(-) double mutants, which are phenotypically identical, the dwarfism was further exacerbated (30% normal size). The roles of the IGFs in mouse embryonic development, as revealed from the phenotypic differences between these mutants, are discussed.
Robyn L. Tuttle Navdeep S. Gill W Pugh
Morris J Birnbaum
The physiological performance of an organ depends on an interplay between changes in cellular function and organ size, determined by cell growth, proliferation and death. Nowhere is this more evident than in the endocrine pancreas, where disturbances in function or mass result in severe disease. Recently, the insulin signal-transduction pathway has been implicated in both the regulation of hormone secretion from β cells in mammals as well as the determination of cell and organ size in Drosophila melanogaster. A prominent mediator of the actions of insulin and insulin-like growth factor 1 (IGF-1) is the 3′-phosphoinositide–dependent protein kinase Akt, also known as protein kinase B (PKB). Here we report that overexpression of active Akt1 in the mouse β cell substantially affects compartment size and function. There was a significant increase in both β-cell size and total islet mass, accompanied by improved glucose tolerance and complete resistance to experimental diabetes.
Rohit Kulkarni Jens C Bruning
Jonathon Winnay
C. Ronald Kahn
Dysfunction of the pancreatic β cell is an important defect in the pathogenesis of type 2 diabetes, although its exact relationship to the insulin resistance is unclear. To determine whether insulin signaling has a functional role in the β cell we have used the Cre-loxP system to specifically inactivate the insulin receptor gene in the β cells. The resultant mice exhibit a selective loss of insulin secretion in response to glucose and a progressive impairment of glucose tolerance. These data indicate an important functional role for the insulin receptor in glucose sensing by the pancreatic β cell and suggest that defects in insulin signaling at the level of the β cell may contribute to the observed alterations in insulin secretion in type 2 diabetes.
Catherine Mounier
Louis Lavoie
Victor Dumas
Barry Posner
Grb10 is a member of a family of adapter proteins that binds to tyrosine-phosphorylated receptors including the insulin receptor kinase (IRK). In this study recombinant adenovirus was used to over-express hGrb10ζ, a new Grb10 isoform, in primary rat hepatocytes and the consequences for insulin signaling were evaluated. Over-expression of hGrb10ζ resulted in 50% inhibition of insulin-stimulated IRK autophosphorylation and activation. Analysis of downstream events showed that hGrb10ζ over-expression specifically inhibits insulin-stimulated glycogen synthase (GS) activity and glycogen synthesis without affecting insulin-induced IRS1/2 phosphorylation, PI3-kinase activation, insulin like growth factor binding protein-1 (IGFBP-1) mRNA expression, and ERK1/2 MAP kinase activity. The classical pathway from PI3-kinase through Akt-PKB/GSK-3 leading to GS activation by insulin was also not affected by hGrb10ζ over-expression. These results indicate that hGrb10ζ inhibits a novel and presently unidentified insulin signaling pathway leading to GS activation in liver.