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Trends in Endocrinology and Metabolism:... Oct 2010Epidemiological studies have reported an increased risk of cancer in people with type 2 diabetes (T2DM) and obesity, related in part to hyperinsulinemia, secondary to... (Review)
Review
Epidemiological studies have reported an increased risk of cancer in people with type 2 diabetes (T2DM) and obesity, related in part to hyperinsulinemia, secondary to insulin resistance. Hyperinsulinemia leads to increased expression of insulin-like growth factor (IGF)-I expression. In fact, increased insulin, IGF-I and IGF-II levels are associated with tumor growth in vitro, in animal models, and in epidemiological studies in humans. In this paper, we discuss the roles of insulin, IGF-I and IGF-II, their interaction with the insulin receptor (IR) and IGF-I receptor (IGF-IR), and their signaling pathways and regulation as these pertain to tumor growth. We explain how these pathways have been deciphered by in vitro and in vivo studies, and how they are being exploited in the development of targeted cancer therapies.
Topics: Animals; Humans; Insulin; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Neoplasms; Receptor, IGF Type 1; Receptor, Insulin; Somatomedins
PubMed: 20663687
DOI: 10.1016/j.tem.2010.06.007 -
Cells Aug 2020Mammals have two insulin-like growth factors (IGF) that are key mediators of somatic growth, tissue differentiation, and cellular responses to stress. Thus, the... (Review)
Review
Mammals have two insulin-like growth factors (IGF) that are key mediators of somatic growth, tissue differentiation, and cellular responses to stress. Thus, the mechanisms that regulate the bioavailability of IGFs are important in both normal and aberrant development. IGF-I levels are primarily controlled via the growth hormone-IGF axis, in response to nutritional status, and also reflect metabolic diseases and cancer. One mechanism that controls IGF bioavailablity is the binding of circulating IGF to a number of binding proteins that keep IGF in a stable, but receptor non-binding state. However, even before IGF is released from the cells that produce it, it undergoes an obligatory association with a ubiquitous chaperone protein, GRP94. This binding is required for secretion of a properly folded, mature IGF. This chapter reviews the known aspects of the interaction and highlights the specificity issues yet to be determined. The IGF-GRP94 interaction provides a potential novel mechanism of idiopathic short stature, involving the obligatory chaperone and not just IGF gene expression. It also provides a novel target for cancer treatment, as GRP94 activity can be either inhibited or enhanced.
Topics: Animals; Biomarkers; HSP70 Heat-Shock Proteins; Humans; Insulin-Like Growth Factor I; Membrane Proteins; Molecular Chaperones; Protein Binding; Somatomedins
PubMed: 32781621
DOI: 10.3390/cells9081844 -
Endocrine Reviews Aug 2009The IGF system plays critical roles in somatic growth in an endocrine fashion (somatomedin hypothesis) as well as proliferation and differentiation of normal and... (Review)
Review
The IGF system plays critical roles in somatic growth in an endocrine fashion (somatomedin hypothesis) as well as proliferation and differentiation of normal and malignant cells in a paracrine/autocrine fashion. IGFBP-3 is known to modulate the actions of IGFs in circulation as well as the immediate extracellular environment. Interestingly, apart from the ability to inhibit or enhance IGF actions, IGFBP-3 also exhibits very clear, distinct biological effects independent of the IGF/IGF-I receptor axis. Over the past decade it has become widely appreciated that IGF/IGF-IR-independent actions of IGFBP-3 (antiproliferative and proapoptotic effects) contribute to improving the pathophysiology of a variety of human diseases, such as cancer, diabetes, and malnutrition. Recent studies have implicated interaction of IGFBP-3 with a variety of proteins or signaling cascades critical to cell cycle control and apoptosis; however, the actual mechanism of IGFBP-3 action is still unclear. This review reinforces the concept in support of the IGF/IGF-IR axis-independent actions of IGFBP-3 and delineates potential underlying mechanisms involved and subsequent biological significance, focusing in particular on functional binding partners and the clinical significance of IGFBP-3 in the assessment of cancer risk.
Topics: Active Transport, Cell Nucleus; Animals; Cell Differentiation; Cell Nucleus; Cell Proliferation; Conserved Sequence; Gene Expression; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Proteins; Neoplasms; Polymorphism, Genetic; Protein Binding; Receptor, IGF Type 1; Receptors, Cell Surface; Risk Factors; Somatomedins
PubMed: 19477944
DOI: 10.1210/er.2008-0028 -
Acta Obstetricia Et Gynecologica... Sep 2013Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are key regulators of fetal growth. However, the literature is inconsistent. Our objective was to... (Meta-Analysis)
Meta-Analysis Review
Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are key regulators of fetal growth. However, the literature is inconsistent. Our objective was to systematically and objectively evaluate the available literature and to develop a balanced opinion on the relation between maternal and fetal IGF-axes and birthweight. A systematic review and a meta-analysis were conducted according to the published Moose (Meta-analysis of Observational Studies in Epidemiology) guidelines. A robust recognized systematic methodology was used in the literature search and analysis to avoid bias. Weighted mean difference and 95% confidence intervals of cord/maternal IGFs and IGFBP-1 and -3 were calculated. Eleven observational studies were included. Cord IGF-I (p < 0.0001) and IGFBP-3 (p = 0.003) were significantly higher in large-for-gestational age (LGA) than appropriate-for-gestational age (AGA) babies. Cord IGFBP-1 was significantly higher in small-for-gestational age (SGA) than AGA babies (p < 0.0001). LGA and AGA babies had similar IGF-II levels, whereas SGA and AGA babies had comparable IGF-I levels. IGF-I was significantly higher in mothers of AGA than SGA babies (p < 0.0001). The assay methods and background population marginally affect the overall homogeneity and the direction of the primary analysis. Fetal IGFs and their binding proteins play different roles in fetal growth at either end of the growth spectrum. Fetal IGF-I and IGFBP-3 may be influential in LGA. However, fetal IGFBP-1 has a more prominent role in SGA.
Topics: Female; Fetal Development; Humans; Insulin-Like Growth Factor Binding Proteins; Pregnancy; Somatomedins
PubMed: 23745729
DOI: 10.1111/aogs.12192 -
Hormone Research 2008It is well known that the insulin-like growth factor (IGF) axis is an important regulator of foetal growth and in recent years, it has been suggested that the ligands... (Review)
Review
It is well known that the insulin-like growth factor (IGF) axis is an important regulator of foetal growth and in recent years, it has been suggested that the ligands IGF-I and IGF-II may, in part, mediate this effect by promoting proper placental development and function. In other tissues, IGF effects on metabolism, proliferation and differentiation are primarily mediated via IGF binding protein-regulated interaction of IGFs with the type 1 IGF receptor and therefore here, we review the placental expression and postulated role, of each of the IGF axis components and discuss the cellular mechanisms through which these effects are exerted.
Topics: Animals; Female; Fetal Development; Humans; Insulin-Like Growth Factor Binding Proteins; Models, Biological; Placenta; Placentation; Pregnancy; Receptors, Somatomedin; Signal Transduction; Somatomedins
PubMed: 18219215
DOI: 10.1159/000112585 -
Diabetes Research and Clinical Practice May 2007Mechanisms contributing to development of diabetic nephropathy (DN) remain unclear. High ambient glucose level transforms intracellular pathways, promoting stable... (Review)
Review
Mechanisms contributing to development of diabetic nephropathy (DN) remain unclear. High ambient glucose level transforms intracellular pathways, promoting stable phenotypic changes in the glomerulus such as mesangial cell hypertrophy, podocyte apoptosis, and matrix expansion. Insulin-like growth factors (IGFs) and the high affinity IGF binding proteins (IGFBPs) exert major effects on cell growth and metabolism. Compared with diabetic patients without microalbuminuria (MA), MA diabetic patients display perturbed GH-IGF-IGFBP homeostasis, including increased circulating IGF-I and IGFBP-3 protease activity, increased excretion of bioactive GH, IGF-I, and IGFBP-3, but decreased circulating IGFBP-3 levels. In diabetic animal models, expression of IGF-I and IGFBP-1 to -4 increases in key renal tissues and glomerular ulrafiltrate. Epithelial, mesangial, and endothelial cells derived from the kidney respond to IGF-I binding with increased protein synthesis, migration, and proliferation. This article reviews classic and emerging concepts for the roles of the GH-IGF-IGFBP axis in the etiopathophysiology, treatment, and prevention of diabetic renal disease. We report IGF-independent actions of IGFBP-3 in the podocyte for the first time.
Topics: Animals; Diabetes Mellitus; Diabetic Nephropathies; Humans; Insulin-Like Growth Factor Binding Proteins; Somatomedins
PubMed: 17011663
DOI: 10.1016/j.diabres.2006.09.012 -
Ageing Research Reviews Jan 2011The insulin/insulin growth factor (IGF) pathway is a critical mediator of longevity and aging. Efforts to extend longevity by altering the insulin/IGF pathway may have... (Review)
Review
The insulin/insulin growth factor (IGF) pathway is a critical mediator of longevity and aging. Efforts to extend longevity by altering the insulin/IGF pathway may have varying effects on other physiological processes. Reduced insulin/IGF levels may decrease the incidence of certain cancers as well as the risk of developing metastatic disease. However, it may also increase the risk of developing cardiovascular disease as well as cardiovascular related mortality. Pursuing the right insulin/IGF pathway targets will require striking a balance between inhibiting cancer cell development and progression and avoiding damage to tissues under normal insulin/IGF-mediated control. This review will discuss the roles of the insulin/IGF pathway in aging and longevity and the development of cancer cell metastasis and considerations in taking insulin/IGF directed targets to the oncology clinic.
Topics: Aging; Animals; Caenorhabditis elegans; Cardiovascular Diseases; Cell Movement; Drosophila melanogaster; Humans; Insulin; Insulin-Like Growth Factor Binding Protein 1; Mice; Neoplasms; Signal Transduction; Somatomedins
PubMed: 19896561
DOI: 10.1016/j.arr.2009.10.007 -
European Neuropsychopharmacology : the... Dec 2014The involvement of insulin, the insulin-like growth factors (IGF1, IGF2) and their receptors in central nervous system development and function has been the focus of... (Review)
Review
The involvement of insulin, the insulin-like growth factors (IGF1, IGF2) and their receptors in central nervous system development and function has been the focus of scientific interest for more than 30 years. The insulin-like peptides, both locally-produced proteins as well as those transported from the circulation into the brain via the blood-brain barrier, are involved in a myriad of biological activities. These actions include, among others, neuronal survival, neurogenes, angiogenesis, excitatory and inhibitory neurotransmission, regulation of food intake, and cognition. In recent years, a linkage between brain insulin/IGF1 and certain neuropathologies has been identified. Epidemiological studies have demonstrated a correlation between diabetes (mainly type 2) and Alzheimer׳s disease. In addition, an aberrant decline in IGF1 values was suggested to play a role in the development of Alzheimer׳s disease. The present review focuses on the expression and function of insulin, IGFs and their receptors in the brain in physiological and pathological conditions.
Topics: Animals; Appetite; Brain; Diabetes Mellitus; Disease Models, Animal; Glucose; Humans; Insulin; Life Expectancy; Lipid Metabolism; Receptor, Insulin; Receptors, Somatomedin; Somatomedins
PubMed: 24529663
DOI: 10.1016/j.euroneuro.2014.01.020 -
Trends in Endocrinology and Metabolism:... May 2012Twenty-five years after it was identified as a circulating protein of unknown function derived from the placenta, pregnancy-associated plasma protein-A (PAPP-A) was... (Review)
Review
Twenty-five years after it was identified as a circulating protein of unknown function derived from the placenta, pregnancy-associated plasma protein-A (PAPP-A) was discovered to be a novel zinc metalloproteinase expressed by a variety of cell types. Great progress has been made in understanding the biology of PAPP-A and its regulation during recent years, especially in regard to physiological and pathophysiological inflammatory injury responses. However, much remains to be learned about this complex protein and its potential clinical implications outside pregnancy. In this article we address some of the outstanding questions about PAPP-A, in particular about its newly emerging role in the insulin-like growth factor (IGF) system.
Topics: Female; Humans; Pregnancy; Pregnancy-Associated Plasma Protein-A; Somatomedins
PubMed: 22463950
DOI: 10.1016/j.tem.2012.02.008 -
The Indian Journal of Medical Research Apr 2007The insulin-like growth factor (IGF) is a complex system of peptide hormones (insulin-like growth factors of type 1 and 2, IGF-1 and IGF-2), cell surface receptors... (Review)
Review
The insulin-like growth factor (IGF) is a complex system of peptide hormones (insulin-like growth factors of type 1 and 2, IGF-1 and IGF-2), cell surface receptors (insulin receptor, IR; insulin-like growth factor receptors of type 1 and 2, IGF-R1, IGF-R2) and circulating binding proteins (insulinlike growth factor binding proteins, IGF-BP 1-6). IGF-1 and -2 are mitogens that play a role in regulating cell proliferation, differentiation and apoptosis. Their effects are mediated through the IGF-R1 which initiates signaling cascades that result in regulation of a number of biological responses. IGF-R2, together with IGF-BPs is involved in binding, internalization and degradation of IGF-2. IGF proteins regulate cell proliferation in an interconnected action via autocrine, paracrine and endocrine regulatory mechanisms. Consequently, any perturbation in each level of the IGF signaling proteins has been shown to be implicated in development and progression of numerous cancer types. The most important single components in this processes are IGF ligands as well as IGF-R1 - when disturbed they act as oncogenes. It has been shown that: (i) high serum concentrations of IGF-1 and IGF-2 are associated with an increased risk of breast, prostate, colorectal and lung cancers; and (ii) IGF-R1 is commonly disturbed in many tumours (like gastric, lung, endometrial cancer) leading to a phenotype of anchorage-independent tumour growth. In contrast, IGF-R2 is considered to act as a tumour suppressor gene; it protects the cells from neoplastic impulses. Consistent with the IGFs autocrine/paracrine regulation of tumour growth, cancer treatment strategies interfering with IGF-R1 signaling have been developed, that may be useful in future diagnostic and therapeutic strategies.
Topics: Animals; Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor Binding Proteins; Neoplasms; Receptors, Somatomedin; Signal Transduction; Somatomedins
PubMed: 17598937
DOI: No ID Found