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Endocrine Reviews Oct 2017The insulin receptor (IR) gene undergoes differential splicing that generates two IR isoforms, IR-A and IR-B. The physiological roles of IR isoforms are incompletely... (Review)
Review
The insulin receptor (IR) gene undergoes differential splicing that generates two IR isoforms, IR-A and IR-B. The physiological roles of IR isoforms are incompletely understood and appear to be determined by their different binding affinities for insulin-like growth factors (IGFs), particularly for IGF-2. Predominant roles of IR-A in prenatal growth and development and of IR-B in metabolic regulation are well established. However, emerging evidence indicates that the differential expression of IR isoforms may also help explain the diversification of insulin and IGF signaling and actions in various organs and tissues by involving not only different ligand-binding affinities but also different membrane partitioning and trafficking and possibly different abilities to interact with a variety of molecular partners. Of note, dysregulation of the IR-A/IR-B ratio is associated with insulin resistance, aging, and increased proliferative activity of normal and neoplastic tissues and appears to sustain detrimental effects. This review discusses novel information that has generated remarkable progress in our understanding of the physiology of IR isoforms and their role in disease. We also focus on novel IR ligands and modulators that should now be considered as an important strategy for better and safer treatment of diabetes and cancer and possibly other IR-related diseases.
Topics: Aging; Alternative Splicing; Cell Proliferation; Diabetes Mellitus; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; MicroRNAs; Molecular Structure; Neoplasms; Proinsulin; Protein Isoforms; Receptor, Insulin; Signal Transduction; Somatomedins
PubMed: 28973479
DOI: 10.1210/er.2017-00073 -
Human adaptation to high altitude: a review of convergence between genomic and proteomic signatures.Human Genomics Jul 2022Both genomics- and proteomics-based investigations have identified several essential genes, proteins, and pathways that may facilitate human adaptive genotype/phenotype... (Review)
Review
Both genomics- and proteomics-based investigations have identified several essential genes, proteins, and pathways that may facilitate human adaptive genotype/phenotype in a population-specific manner. This comprehensive review provides an up-to-date list of genes and proteins identified for human adaptive responses to high altitudes. Genomics studies for indigenous high-altitude populations like Tibetans, Andeans, Ethiopians, and Sherpas have identified 169 genes under positive natural selection. Similarly, global proteomics studies have identified 258 proteins (± 1.2-fold or more) for Tibetan, Sherpa, and Ladakhi highlanders. The primary biological processes identified for genetic signatures include hypoxia-inducible factor (HIF)-mediated oxygen sensing, angiogenesis, and erythropoiesis. In contrast, major biological processes identified for proteomics signatures include 14-3-3 mediated sirtuin signaling, integrin-linked kinase (ILK), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), and integrin signaling. Comparing genetic and protein signatures, we identified 7 common genes/proteins (HBB/hemoglobin subunit beta, TF/serotransferrin, ANGPTL4/angiopoietin-related protein 4, CDC42/cell division control protein 42 homolog, GC/vitamin D-binding protein, IGFBP1/insulin-like growth factor-binding protein 1, and IGFBP2/insulin-like growth factor-binding protein 2) involved in crucial molecular functions like IGF-1 signaling, LXR/RXR activation, ferroptosis signaling, iron homeostasis signaling and regulation of cell cycle. Our combined multi-omics analysis identifies common molecular targets and pathways for human adaptation to high altitude. These observations further corroborate convergent positive selection of hypoxia-responsive molecular pathways in humans and advocate using multi-omics techniques for deciphering human adaptive responses to high altitude.
Topics: Altitude; Genomics; Humans; Hypoxia; Phosphatidylinositol 3-Kinases; Proteomics; Selection, Genetic; Somatomedins
PubMed: 35841113
DOI: 10.1186/s40246-022-00395-y -
European Journal of Pharmaceutics and... Nov 2015This review starts off outlining the control of Insulin-like growth factor I (IGF-I) kinetics in Nature and by virtue of a complex system of 6 binding proteins... (Review)
Review
This review starts off outlining the control of Insulin-like growth factor I (IGF-I) kinetics in Nature and by virtue of a complex system of 6 binding proteins controlling half-life and tissue distribution of this strong anabolic peptide. In addition, alternative splicing is known to result in IGF-I variants with modulated properties in vivo and this insight is currently translated into advanced IGF-I variants for therapeutic use. Insights into these natural processes resulted in biomimetic strategies with the ultimate goal to control pharmacokinetics and have recently propelled new developments leading to optimized pharmaceutical performance of this protein in vivo. Aside from parenteral administration routes, IGF-I was successfully delivered across various epithelial barriers from liquid as well as from solid pharmaceutical forms opening novel and more convenient delivery modalities. IGF-I decoration yielded effective targeting upon systemic administration expanding the options for optimally deploying the growth factor for therapy. This review summarizes the exciting biotechnological and pharmaceutical progress seen for IGF-I delivery in recent years and critically discusses outcome in light of translational application for future IGF-I therapeutics.
Topics: Amino Acid Sequence; Animals; Chemistry, Pharmaceutical; Drug Delivery Systems; Humans; Insulin-Like Growth Factor I; Molecular Sequence Data
PubMed: 25936856
DOI: 10.1016/j.ejpb.2015.04.026 -
Biochimica Et Biophysica Acta.... Nov 2019The insulin/insulin-like growth factor system (IIGFs) plays a fundamental role in the regulation of prenatal and postnatal growth, metabolism and homeostasis. As a... (Review)
Review
The insulin/insulin-like growth factor system (IIGFs) plays a fundamental role in the regulation of prenatal and postnatal growth, metabolism and homeostasis. As a consequence, dysregulation of this axis is associated with growth disturbance, type 2 diabetes, chronic inflammation and tumor progression. A functional crosstalk between IIGFs and discoidin domain receptors (DDRs) has been recently discovered. DDRs are non-integrin collagen receptors that canonically undergo slow and long-lasting autophosphorylation after binding to fibrillar collagen. While both DDR1 and DDR2 functionally interact with IIGFs, the crosstalk with DDR1 is so far better characterized. Notably, the IIGFs-DDR1 crosstalk presents a feed-forward mechanism, which does not require collagen binding, thus identifying novel non-canonical action of DDR1. Further studies are needed to fully explore the role of this IIGFs-DDRs functional loop as potential target in the treatment of inflammatory and neoplastic disorders.
Topics: Animals; Diabetes Mellitus, Type 2; Discoidin Domain Receptor 1; Discoidin Domain Receptor 2; Discoidin Domain Receptors; Fibrosis; Humans; Inflammation; Insulin; Insulin-Like Growth Factor II; Neoplasms; Phosphorylation; Protein Binding; Protein Isoforms; Receptor, Insulin; Receptors, Somatomedin; Signal Transduction; Somatomedins; Thyroid Neoplasms
PubMed: 31394114
DOI: 10.1016/j.bbamcr.2019.118522 -
Oncogene Jun 2022The insulin-like growth factors (IGFs) and their regulatory proteins-IGF receptors and binding proteins-are strongly implicated in cancer progression and modulate cell... (Review)
Review
The insulin-like growth factors (IGFs) and their regulatory proteins-IGF receptors and binding proteins-are strongly implicated in cancer progression and modulate cell survival and proliferation, migration, angiogenesis and metastasis. By regulating the bioavailability of the type-1 IGF receptor (IGF1R) ligands, IGF-1 and IGF-2, the IGF binding proteins (IGFBP-1 to -6) play essential roles in cancer progression. IGFBPs also influence cell communications through pathways that are independent of IGF1R activation. Noncoding RNAs (ncRNAs), which encompass a variety of RNA types including microRNAs (miRNAs) and long-noncoding RNAs (lncRNAs), have roles in multiple oncogenic pathways, but their many points of intersection with IGF axis functions remain to be fully explored. This review examines the functional interactions of miRNAs and lncRNAs with IGFs and their binding proteins in cancer, and reveals how the IGF axis may mediate ncRNA actions that promote or suppress cancer. A better understanding of the links between ncRNA and IGF pathways may suggest new avenues for prognosis and therapeutic intervention in cancer. Further, by exploring examples of intersecting ncRNA-IGF pathways in non-cancer conditions, it is proposed that new opportunities for future discovery in cancer control may be generated.
Topics: Humans; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; MicroRNAs; Neoplasms; RNA, Long Noncoding; RNA, Untranslated; Receptors, Somatomedin
PubMed: 35597813
DOI: 10.1038/s41388-022-02353-3 -
Journal of Cellular and Molecular... Aug 2016Cardiovascular disease (CVD) constitutes a major public health threat worldwide, accounting for 17.3 million deaths annually. Heart disease and stroke account for the... (Review)
Review
Cardiovascular disease (CVD) constitutes a major public health threat worldwide, accounting for 17.3 million deaths annually. Heart disease and stroke account for the majority of healthcare costs in the developed world. While much has been accomplished in understanding the pathophysiology, molecular biology and genetics underlying the diagnosis and treatment of CVD, we know less about the role of epigenetics and their molecular determinants. The impact of environmental changes and epigenetics in CVD is now emerging as critically important in understanding the origin of disease and the development of new therapeutic approaches to prevention and treatment. This review focuses on the emerging role of epigenetics mediated by insulin like-growth factors-I and -II in major CVDs such as heart failure, cardiac hypertrophy and diabetes.
Topics: Animals; Cardiovascular Diseases; Epigenesis, Genetic; Humans; Models, Biological; Nutritional Physiological Phenomena; Somatomedins
PubMed: 27061217
DOI: 10.1111/jcmm.12845 -
Cold Spring Harbor Perspectives in... Aug 2015Growth is a complex process that is intimately linked to the developmental program to form adults with proper size and proportions. Genetics is an important determinant... (Review)
Review
Growth is a complex process that is intimately linked to the developmental program to form adults with proper size and proportions. Genetics is an important determinant of growth, as exemplified by the role of local diffusible molecules setting up organ proportions. In addition, organisms use adaptive responses allowing modulating the size of individuals according to environmental cues, for example, nutrition. Here, we describe some of the physiological principles participating in the determination of final individual size.
Topics: Animals; Body Size; Drosophila; Growth; Growth Hormone; Insulin; Metamorphosis, Biological; Nutritional Physiological Phenomena; Signal Transduction; Somatomedins; Species Specificity
PubMed: 26261282
DOI: 10.1101/cshperspect.a019117 -
Advances in Biological Regulation Dec 2019T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer, characterized by an uncontrolled expansion and accumulation of T-cell progenitors. During leukemic... (Review)
Review
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer, characterized by an uncontrolled expansion and accumulation of T-cell progenitors. During leukemic progression, immature T cells grow abnormally and occupy the bone marrow compartment, thereby interfering with the production of normal blood cells. Pediatric T-ALL is curable with intensive chemotherapy, but there are significant, long-term side effects and ~20% of patients suffer relapse for which there are limited treatment options. Adult T-ALL in contrast is largely incurable and refractory/relapsed disease is common despite multi-agent chemotherapy (5-year overall survival of ~40%), and thus new therapeutic targets are needed. We have reported previously on the role of insulin-like growth factor (IGF) signaling in T-ALL, and shown that it exerts potent phenotypes in both leukemia stem cell and bulk tumor cell populations. Modulators of IGF signaling may thus prove useful in improving outcomes in patients with T-ALL. In this review, we summarize the most recent findings relating to IGF signaling in T-ALL and outline therapeutic options using clinically relevant IGF signaling modulators.
Topics: Humans; Neoplasm Proteins; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Signal Transduction; Somatomedins
PubMed: 31543360
DOI: 10.1016/j.jbior.2019.100652 -
Neurochemical Research Mar 2017Sirtuins (SIRT1-SIRT7) are unique histone deacetylases (HDACs) whose activity depends on NAD levels and thus on the cellular metabolic status. SIRTs regulate energy... (Review)
Review
Sirtuins (SIRT1-SIRT7) are unique histone deacetylases (HDACs) whose activity depends on NAD levels and thus on the cellular metabolic status. SIRTs regulate energy metabolism and mitochondrial function. They orchestrate the stress response and damage repair. Through these functions sirtuins modulate the course of aging and affect neurodegenerative diseases. SIRTSs interact with multiple signaling proteins, transcription factors (TFs) and poly(ADP-ribose) polymerases (PARPs) another class of NAD-dependent post-translational protein modifiers. The cross-talk between SIRTs TFs and PARPs is a highly promising research target in a number of brain pathologies. This review describes updated results on sirtuins in brain aging/neurodegeneration. It focuses on SIRT1 but also on the roles of mitochondrial SIRTs (SIRT3, 4, 5) and on SIRT6 and SIRT2 localized in the nucleus and in cytosol, respectively. The involvement of SIRTs in regulation of insulin-like growth factor signaling in the brain during aging and in Alzheimer's disease was also focused. Moreover, we analyze the mechanism(s) and potential significance of interactions between SIRTs and several TFs in the regulation of cell survival and death. A critical view is given on the application of SIRT activators/modulators in therapy of neurodegenerative diseases.
Topics: Aging; Animals; Brain; Cell Death; Cell Nucleus; Cell Survival; Cytosol; Energy Metabolism; Humans; Mitochondria; Neurodegenerative Diseases; Neuroprotection; Neuroprotective Agents; Signal Transduction; Sirtuins; Somatomedins; Transcription Factors
PubMed: 27882448
DOI: 10.1007/s11064-016-2110-y -
Trends in Endocrinology and Metabolism:... Oct 2014Dietary restriction (DR) extends the lifespan of many animals, including Drosophila melanogaster. Recent work with flies shows that longevity is controlled by the ratio... (Review)
Review
Dietary restriction (DR) extends the lifespan of many animals, including Drosophila melanogaster. Recent work with flies shows that longevity is controlled by the ratio of consumed protein relative to carbohydrates. Given that reduced insulin and/or insulin-like growth factor (IGF) and target of rapamycin (TOR) signaling increase Drosophila lifespan, these pathways are candidate mediators of DR. However, this idea has ambiguous experimental support. The Nutritional Geometric Framework (NGF), which dissects the impact of nutrient protein relative to carbohydrates, may provide an approach to resolving the roles for these pathways in DR. Nutrient sensing of protein and carbohydrate may occur in the fat body through signals to hypothalamic-like neurons in the fly brain and, thus, control secretion of insulin-like peptides that regulate longevity.
Topics: Animal Nutritional Physiological Phenomena; Animals; Caloric Restriction; Dietary Carbohydrates; Dietary Proteins; Drosophila; Drosophila Proteins; Eating; Insulin; Intercellular Signaling Peptides and Proteins; Longevity; Signal Transduction; Somatomedins
PubMed: 24685228
DOI: 10.1016/j.tem.2014.02.006