Document Detail

Human conditions of insulin-like growth factor-I (IGF-I) deficiency.
Jump to Full Text
MedLine Citation:
PMID:  23148873     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Insulin-like growth factor I (IGF-I) is a polypeptide hormone produced mainly by the liver in response to the endocrine GH stimulus, but it is also secreted by multiple tissues for autocrine/paracrine purposes. IGF-I is partly responsible for systemic GH activities although it possesses a wide number of own properties (anabolic, antioxidant, anti-inflammatory and cytoprotective actions). IGF-I is a closely regulated hormone. Consequently, its logical therapeutical applications seems to be limited to restore physiological circulating levels in order to recover the clinical consequences of IGF-I deficiency, conditions where, despite continuous discrepancies, IGF-I treatment has never been related to oncogenesis. Currently the best characterized conditions of IGF-I deficiency are Laron Syndrome, in children; liver cirrhosis, in adults; aging including age-related-cardiovascular and neurological diseases; and more recently, intrauterine growth restriction. The aim of this review is to summarize the increasing list of roles of IGF-I, both in physiological and pathological conditions, underlying that its potential therapeutical options seem to be limited to those proven states of local or systemic IGF-I deficiency as a replacement treatment, rather than increasing its level upper the normal range.
Authors:
Juan E Puche; Inma Castilla-Cortázar
Related Documents :
24676933 - The soluble vegfr1 concentration in the serum of patients with colorectal cancer.
23321463 - Impact of serum adiponectin and leptin levels in acute leukemia.
18056923 - Associations of serum sex hormone binding globulin (shbg) levels with shbg gene polymor...
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review     Date:  2012-11-14
Journal Detail:
Title:  Journal of translational medicine     Volume:  10     ISSN:  1479-5876     ISO Abbreviation:  J Transl Med     Publication Date:  2012  
Date Detail:
Created Date:  2013-01-14     Completed Date:  2013-06-25     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  101190741     Medline TA:  J Transl Med     Country:  England    
Other Details:
Languages:  eng     Pagination:  224     Citation Subset:  IM    
Affiliation:
Applied Molecular Medicine Institute, School of Medicine, Department of Medical Physiology, Universidad CEU San Pablo, Madrid, Spain.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Disease*
Growth and Development
Humans
Insulin-Like Growth Factor I / chemistry,  deficiency*,  metabolism
Organ Specificity
Chemical
Reg. No./Substance:
67763-96-6/Insulin-Like Growth Factor I
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): J Transl Med
Journal ID (iso-abbrev): J Transl Med
ISSN: 1479-5876
Publisher: BioMed Central
Article Information
Download PDF
Copyright ©2012 Puche and Castilla-Cortazar; licensee BioMed Central Ltd.
open-access:
Received Day: 11 Month: 7 Year: 2012
Accepted Day: 7 Month: 11 Year: 2012
collection publication date: Year: 2012
Electronic publication date: Day: 14 Month: 11 Year: 2012
Volume: 10First Page: 224 Last Page: 224
PubMed Id: 23148873
ID: 3543345
Publisher Id: 1479-5876-10-224
DOI: 10.1186/1479-5876-10-224

Human conditions of insulin-like growth factor-I (IGF-I) deficiency
Juan E Puche1 Email: quikepu@hotmail.com
Inma Castilla-Cortázar1 Email: iccortazar@ceu.es
1Applied Molecular Medicine Institute (IMMA), School of Medicine, Department of Medical Physiology, Universidad CEU San Pablo, Madrid, Spain

Introduction

Insulin-like growth factor I (IGF-I) is a 70 aa polypeptide hormone with endocrine, paracrine, and autocrine effects. It shares >60% homology with IGF-II and by 50% homology with proinsulin structures [1].

IGFs were first described in 1957 by Salmon and Daughaday [2] when they noted that direct addition of growth hormone (GH) to costal cartilage from hypophysectomized rats in vitro did not significantly stimulate growth (measured by radioactive sulfate uptake). Consistently, serum from these hypophysectomized rats was also ineffective. However, normal rat serum stimulated the in vitro uptake of sulfate into costal cartilage from hypophysectomized rats. These results demonstrated the existence in serum of a “sulfation factor” that stimulated incorporation of 35Sulfate by costal cartilage.

In parallel, Froesch et al. described the non-suppressible insulin-like activity (NSILA) of two soluble serum components (NSILA I and II) by the fact that they stimulated glucose uptake into isolated rat adipocytes, sharing “insulin-like” activity, while anti-insulin antibodies were not able to abrogate their hypoglycemic effects [3].

At the same time, other investigators found some other roles for these polypeptides. Among all, their mitogenic capability, that moved them to propose the term “fraction with multiplication stimulating activity” [4].

Only when Daughaday et al. pointed out that the sulfation factors were “identical with or very similar to the smaller molecular weight component of the non-suppressible insulin-like activity” in 1972, a new nomenclature was proposed for these two molecules: somatomedin A and C, denoting substances under control and mediating the effects of GH [5].

Finally, a more extensive research on NSILAs/somatomedins carried out by Rinderknecht and Humbel [6,7] culminated with the discovery that those molecules had identical amino acid sequences to “two forms of an insulin-like hormone whose effects on cell and tissue growth predominate over those on metabolic parameters” [8]. Therefore, accordingly to their structural resemblance to proinsulin, they were finally renamed “insulin-like growth factor I and II” (IGF-I and II), molecules that also fulfill all the criteria of a somatomedin: 1) they possess insulin-like activity in the presence of insulin antibodies [3,9]; 2) they are sulfation factors [9,10]; 3) they could act as mitogens [9,11]; and 4) at least, IGF-I is growth-hormone dependent [5].

The consensus about their nomenclature [12] together with the milestone in the discovery of their amino acid sequences, which made possible the subsequent recombinant synthesis [8], opened the door to many new areas of research, and boosted the number of articles from that moment up to more than 32,500 works currently indexed in PubMed.

This historical perspective provides us a list of actions carried out by IGF-I, among others: tissue growth and development, insulin-like activity, proliferative, pro-survival/anti-aging, antioxidant, etc.

As an hormone with a wide range of physiological roles, IGF-I levels must be strictly controlled, as it has been demonstrated from in vivo results: six forms of high affinity IGF binding proteins (IGFBPs 1 to 6), either promoting or inhibiting IGF-I actions; a yearly increasing list of IGFBPs proteases; allelic variations and an alternative splicing are some of the mechanisms by which IGF-I is tightly maintained in a close physiological range (~286.1±52.4 ng/mL, adults between 21–40 years old) [13,14].

On the other hand, majority of IGF-I actions are mediated through the union of IGF-I to its putative receptor, IGF-IR, a tyrosine kinase that is one of the most potent natural activators of Akt pathway, involving among others: mTOR, MAPK, GSK3β, FOXO, HDM2, Grb2 and Shc systems, all of them closely related with cell survival, growth and proliferation [15-17]. However, IGF-I can also bind to the insulin receptor (with a lower affinity), as a secondary via through which this hormone mediates some of its metabolic functions [6], due to their high homology. Complementarily, insulin can also bind to IGF-IR with a lower specificity than insulin receptor (Figure 1).

Under this scenario, a review about the increasing list of IGF-I roles, both in physiological and pathological conditions, and its therapeutical potential, arises as a promising field of work.


Physiological roles of IGF-I

IGF-I is a relevant hormone both in embryological and postnatal states. Although it is mainly produced by the liver, virtually every tissue is able to secrete IGF-I for autocrine/paracrine purposes [18].

Pituitary (GH) and liver (IGF-I) establish negative feedback mechanisms common to any other endocrine gland. The pituitary somatotrophs (GH-secreting cells) are under a delicate controlled balance between stimulatory growth horomone-releasing hormone and inhibitory somatostatin, both generated by the hypothalamus as a result of systemic and cortical neurogenic, metabolic, and hormonal factors [19]. In another hand, IGF-I inhibits GH secretion acting on the hypothalamus by two feedback mechanisms: firstly, inhibiting GH gene expression [20] and secondly by stimulating the secretion of somatostatin [21,22], that inhibits GH production.

Secreted GH can exist in both free and bound states by the GHBP (the secondary domain of the GH receptor) [19]. Also, activation of liver GH receptor, promotes IGF-I synthesis which, in turn, is released to the circulation and can be found in its free form but mainly bound to IGFBPs (overall IGFBP-3, which binds ~90% of circulating IGF-I) [23].

The role of IGF-I in physiological conditions is still being uncovered and continuously unfastened from GH actions as an independent, self-sufficient peptide. For example, it is known that GH and nutrition are the major factors that regulate hepatic IGF-I expression, as well as in other organs [24,25]. However, in some other tissues, IGF-I expression appears to be regulated by tissue specific trophic factors, as for example in uterus, where estrogens (and not GH) stimulate IGF-I expression [26], while follicle stimulating hormone is a major IGF-I regulator in ovary [27].

In an attempt to provide a coherent and integrated review of certain physiological conditions where the role of IGF-I has been well established, we have summarized them in this review (cfr. Figure 2).

Body growth

IGFs have been shown to play a very important role in fetal growth and differentiation [24,28,29], although their pattern of expression and abundance varies among organs. For instance, in fetal liver, kidney and heart are lower than IGF-II, while they progressively increase after birth (as serum IGF-I concentration does). However, expression of IGF-I in fetal lung, muscle, and stomach is higher than it is postnatally [29].

Of interest, while the actions of IGF-I after birth are being continuously recognized, the physiologic role of IGF-II is still poorly understood at this stage [1,30]. Interestingly, it was reported that GH is not required for normal intrauterine growth, a finding supported by evidence that GH deficiency/insensitivity does not associate with a significant reduced size at birth [31-35]. In contrast, inactivating mutations of IGF-I or its receptor, have clearly established that IGF-I is a major regulator of intrauterine growth [36-41]. Thus, these findings suggest that the stimulatory role of IGF-I on intrauterine growth is GH-independent.

With this perspective, Daughaday et al. [5,42] proposed the somatomedin hypothesis for the postnatal growth, where GH stimulated skeletal growth by stimulating liver production of IGF-I, which in turn promotes longitudinal bone growth in an endocrine manner. However, a noteworthy direct action of GH on bone growth has also been reported [43,44]. Nevertheless, the discovery of an extra-hepatic IGF-I production in the following years [18,45], made it necessary to spand the conception of the GH/IGF-I axis, being well accepted nowadays that pituitary GH is able to induce IGF-I synthesis in both liver (~75%) and other tissues [23,46,47], which subsequently, is able to act in an endocrine/paracrine/autocrine manner.

So, taking into account all these data, we can conclude that both GH and IGF-I has independent and synergic effects in promoting postnatal body growth. This idea was also confirmed by comparing the weight of transgenic mice with GH receptor inactivation, IGF-I knockout and the double inactivation [36]. As expected, double knockout mice presented a more severe reduction in body length than the other two models (~20% more).

Finally, GH and IGF-I (both liver/endocrine and locally produced) are essential for normal body growth. The role of other molecules for this control is also important and may increase the complexity in the understanding of these mechanisms. Acid-labile subunit (ALS) and IGFBP-3 are two proteins that bind IGF-I (~90% of total serum IGF-I) in a ternary complex which transports and prolong IGF-I half-life in circulation [23]. Although the liver is also the principal source of circulating IGFBP-3 and ALS, other tissues have been proposed to produce these factors [48,49]. The importance of IGFBP-3 relies also on its capability to act independently from IGF-I, regulating growth, apoptosis and metabolism of target cells [50-52]. Therefore, the expression of ALS and IGFBP-3 in non-hepatic tissues and possible IGF-I-independent effects of IGFBP-3, should be considered when analyzing findings. To go through IGFBP-3 roles/effects in depth the review by Ohlsson C et al. is recommended [23].

Central nervous system (CNS) development

Although the action mechanisms of IGF-I in neurons have not been fully elucidated, it has been shown that IGF-I stimulates the autophosphorylation of IGF-IR [53] in a different manner to insulin [54]. Furthermore, as it will be further discussed, we have reported a neuroprotective role for IGFs associated to mitochondrial protection and antioxidant defenses in aging animals [55-58]. Both mechanistic pathways, that may be linked, are currently being studied in more detail.

IGF-I is harmonically produced by peaks that coincide with periods of neuron progenitor proliferation and differentiation, neuritic outgrowth (increasing the number of dendrites, axonal cones, synapse number…) or post-injury conditions [59]. However, the possibility of IGF-I to influence neural stem cells (NSC) is still on debate despite the fact that IGF-I and IGF-IR are expressed in cultured NSC [60,61], and that in response to IGF-I, cultured NSC proceed toward specific lineages, such as neurons [62] or oligodendrocytes [63].

Interestingly, not only neural-produced IGF-I is involved in these processes. It was first reported 20 years ago that systemic IGFs could cross the blood–brain barrier (BBB), when labeled IGFs were infused into the common carotid arteries of adult rats, and they were later on detected in the choroid plexus, median eminence, brain arterioles, and parenchyma [64]. In fact, this work was based on previous data confirming the presence of IGF-I receptors in brain capillary endothelial cells (which constitute the BBB), and their role in internalizing IGFs to the CNS from the circulation [65,66]. A more recent work by Torres-Aleman’s group, elegantly demonstrated that this process is initiated by the release of glutamate at active regions, triggering two secondary processes: a vasodilation to increase local serum IGF-I availability and an increased activity of matrix metalloprotease 9, together with cleavage from IGFBP-3. The combined action of these events results in an increased local availability of free serum IGF-I, which is then transported by transcytosis using an endothelial transporter (lipoprotein related receptor 1) dependent mechanism [67]. This research may shed light on previous data identifying liver-derived IGF-I as one of the main factors in regulating the clearance of brain amyloid-β (Aβ) levels [68] and its potential implications in Alzheimer’s Disease (what will be further discussed in III.4.3.). However, it is noteworthy that there is no significant correlation between serum and cerebrospinal fluid IGFs concentrations [69] and therefore, it seems that systemic IGFs are not a major source of IGFs for CNS.

On the other hand, little is known about those factors and mechanisms that regulate IGF-I expression in the brain, but there is evidence, however, that growth factors (i.e. GH, epidermal growth factor, basic fibroblast growth factor) [70-72], nutrition [73,74], and injury (hypoxic/ischemic, stereotactic, electrolytic and cryogenic injuries, as well as induced demyelination and experimental autoimmune encephalomyelitis) [75-81], influence its in vivo brain expression. Nevertheless, IGF-I mRNA abundance is reduced in the brain of hypophysectomized rats and, intracerebral infusion of GH restores IGF-I mRNA to 80% of normal levels [70], which points out that GH has a clear role in modulating brain IGF-I.

Additionaly, IGF-I may promote proliferation and/or survival of oligodendrocytes and their precursors, but it also could be involved in the modulation of BBB permeability [81]. The latter would limit accessibility of T lymphocytes and soluble destructive immune factors to the brain. Other possibilities are also plausible, as for instance, IGF-I may influence the peripheral immune reaction, what in turn could reduce CNS inflammation, demyelination, and BBB permeability [82]. These findings, taken together with the neuroprotective actions of IGF-I [55,56], suggest that astrocytes are relevant in ameliorating brain injury.

In another hand, in vivo experiments with transgenic mice have clarified some aspects about the topic. Transgenic (Tg) mice that overexpress IGF-I in the brain exhibit postnatal brain overgrowth without anatomic abnormality (up to 85%) via an increase in cell number [83] and myelination [84]. A complementary experiment [83] excluded the possibility of GH in directly promoting these effects, since GH-overexpressing Tg mice did not exhibit those changes. However, as stated before, a role for GH in brain growth cannot be underestimated, since GH-deficient mice have significantly smaller brains than normal mice [23]. Consistently, transgenic mice with ablated IGF-I expression barely survive postnatally. Survivals have very small brains (−60% of normal size) but remain morphologically normal [85]. These brains are characterized by a paucity of white matter owing to markedly decreased myelination [86] and an apparent decrease in the number of axons [85].

These IGF-I actions, taken together with its neuroprotective effects following CNS and peripheral nerve injury, suggest that it may be of therapeutic benefit in a wide variety of disorders affecting the nervous system.

Liver regeneration

The liver is the main source of circulating insulin-like growth factor I, accounting for ~75% of circulating IGF-I levels secondary to the GH stimulation on hepatocytes [23,46,47]. Of interest, although liver-derived IGF-I has endocrine effects on extrahepatic tissues, there are only few data regarding local effects of this hormone in the liver [87] probably due to the very low amount of IGF-I receptors on the hepatocytes membrane [46,88,89]. However, there are IGF-I receptors on the nonparenchymal cells [89,90] and it has been reported that IGF-I stimulates both DNA synthesis [91,92] and the production of hepatocyte growth factor (HGF) in hepatic stellate cells in vitro[87].

The lack of IGF-I receptors on hepatocytes would also mean that liver-derived IGF-I would be unable to stimulate liver growth during adulthood. Accordingly, mice with liver-specific IGF-I deficiency, instead of displaying decreased hepatic growth, showed disproportionally large livers, likely due to direct stimulation by an unsuppressed GH secretion [47,93]. In line with this finding, GH receptor deficient mice have reduced relative liver weight [94], and transgenic mice overexpressing GH presented disproportional growth of the liver, whereas this is less apparent in mice overexpressing IGF-I [95,96].

Nevertheless, during liver regeneration, where it is required an explosive burst of hepatocyte renewal (i.e. after partial hepatectomy), IGF-I may play a role in supporting hepatocyte proliferation and accelerating DNA synthesis [97,98], together with IL-6, TNF-α, HGF and TGF-α/EGF [99,100]. It remains unknown why IGF-I stimulates liver regeneration more effectively than growth of intact liver.

Gametogenesis
Ovarian folliculogenesis

The process of folliculogenesis can be divided into three developmental phases: I) preantral follicle growth: primordial to primary follicle transition, and formation and growth of secondary follicles; II) basal antral follicle growth: antrum formation and development of early antral follicles to the gonadotrophin-dependent stage; and III) terminal antral follicle growth: development of antral to preovulatory follicles [101].

The involvement of the IGF system as intraovarian regulators of folliculogenesis has been intensively studied in a variety of mammal species, and it is now established that the ovary is a site of IGF-I gene expression and reception [102]. However, this huge amount of data could be somehow distractive since different species may produce distinct IGFs (or their relative binding proteins and receptors) at different stages of follicular development. For this reason, in this review, we will focus on murine and primate data.

In primate, mRNA expression patterns of IGF-I and its putative receptor have been deeply studied during folliculogenesis. IGF-I is expressed in primordial follicles, primary follicles, secondary follicles and growing antral follicles (oocyte and theca), but not in preovulatory follicles (mural granulose and theca) [101]. Of interest, IGF-IR mRNA is temporally consistent with the IGF-I expression, except from the mural granulose cells, where IGF-IR production is preserved, suggesting a paracrine/endocrine dependence for the IGF-I effects at this level [101].

The lack of information regarding the role of IGFs in a specific time point of human folliculogenesis, hinder its correlation with the expression patterns of IGF-I. Fortunately, murine models provide us a useful tool to elucidate its possible implications. This approach suggest that IGF-I may play a role at different stages of follicular development: a) initiation of growth of the primordial follicle; b) at a secondary follicle stage, IGF-I may be involved on induction of FSH-R expression on granulose cell and their differentiation, theca cell survival and cortical granules formation in oocytes [103-106]; and c) at antral follicular stage, IGF-I may increase follicle sensitivity to gonadotrophin, oocyte maturation and LH-R expression in granulose and theca cells enhancing their proliferation and steroidogenic activity [107-111]. In humans, IGF-I also stimulates vascular endothelial growth factor production by granulose cells [112].

Despite recent progresses, the precise mechanisms underlying ovarian follicular growth are not yet fully elucidated. In most mammalian species studied, although GH and IGFs do not appear to be required for primordial to primary follicles transition, they are responsible for promoting secondary follicle growth and antrum formation. In brief, GH enhances the development of small antral follicles to the gonadotrophin-dependent stages and stimulates oocyte maturation, whereas IGFs increase granulose cell proliferation, steroidogenesis and oocyte growth in most mammalian species [101].

Testicular function

Although it is well established that testicular function is mainly controlled by the gonadotropins LH and FSH [113,114], there is now considerable evidence pointing to locally produced factors as important key regulators of testicular function [115]. Among those, IGF-I has been reported to be a potent candidate due to its para/autocrine functions. Immunostainable IGF-I has been found in adult human testes [116]. Cultures of Sertoli and Leydig cells from adult rats and immature pigs secrete immunoreactive IGF-I into the medium, and this secretion is enhanced by FSH (Sertoli cells) or LH (Leydig cells) [117,118]. IGF-IR has also been found on human, pig, and rat Leydig cells [119-121], where it enhances the differentiated functions of Leydig cells [122,123].

The crucial role of IGF-I in the development and function of Leydig cells was obtained from studies in IGF-I knockout mice [124]. The testes of these animals were reduced in size and although epididymides were overall nearly allometric to the reduced body weight, the distal regions of the duct, vas deferens, seminal vesicles, and prostate were vestigial. These transgenic mice showed significantly reduced plasma testosterone levels (18% of normal) [124] and the IGF-I deficiency was correlated with an ultrastructural analysis of mutant Leydig cells revealing a significant developmental delay, with fewer and smaller Leydig cells than normal. Importantly, it is noteworthy that those reduced testosterone levels in serum were inadequate for perinatal androgenization. And secondly, androgen deficiency in the mutants can be correlated with an apparently retarded differentiation of Leydig cells (in concrete, their second phase) [124]. In vitro studies also suggested a relationship between IGF-I and LH-androgen production in rodents [125], through a direct effect on Leydig cells.

Consistently, a large number of studies have previously suggested that the IGF system is involved in mammalian reproductive functions [108,126,127]. First, it has been emphasized the importance of insulin receptor family for the induction of testicular differentiation by Sry-dependent processes [128]. In addition, IGF-I regulates the expression of key steroidogenic enzymes during prenatal development, which in turn lead to establishment of the male phenotype and fertility [129]. Moreover, male gonads cultured in the presence of IGF-I increased testosterone production during testicular development [130]. Postnatally, in vitro studies have also demonstrated that the IGF-I regulates the expression rate of genes encoding steroidogenic enzymes that involved in the biotransformation of steroid hormones in the testis [131-133]. Secondly, a role for IGF-I on sperm number has been reported since in IGF-I deficient mice there is a dramatic reduction of sperm number [124]. Moreover, the vast majority of these males that were caged with wild type females did not exhibit mating behavior.

In another hand, it is notable that the role of GH, if any, on the regulation of intratesticular IGF-I may not be significant, since GH receptor gene may not be expressed in the testis [134,135] and GHI animals are fertile (normal steroidogenesis and spermatogenesis) [136,137]. Interestingly, despite GH deficiency and low serum IGF-I concentration, they exhibit normal levels of testicular IGF-I [119]. Thus, in addition to being apparently GH-independent, the testicular functions of IGF-I seem to be served by its local production (autocrine/paracrine action) without a major endocrine contribution by the circulating form of this factor.

Kidney development and function

Several lines of evidence support the role of the GH/IGF-I system in normal kidney development and function. IGFs, IGFBPs and IGF receptors (along with GH receptors) are all expressed in specific locations along the nephron, suggesting that IGFs have paracrine and autocrine actions at these sites [138,139].

Both IGF-I and the IGF-IR are expressed in glomerulus development being their patterns of expression disrupted in animal models and in human examples of renal disease [140]. Indeed, it has been demonstrated a role for IGF signaling in maintaining glomerular integrity, by preserving podocytes and the glomerular basement membrane from damage. Consistently, IGF-I administration to rodents increases kidney growth, renal blood flow and glomerular filtration rate (GFR) [138,141,142], and similarly, GH and IGF-I also increase renal blood flow and GFR in humans [143], suggesting that IGF-I may be a physiologic regulator of renal function.

Furthermore, a possible role for the IGF system in compensatory renal growth was proposed since renal IGF-I levels are increased in the remaining kidney following uninephrectomy and compensatory renal growth [144] in an age-dependent manner [145]. However, by using IGF-I deficient mice, it has been recently reported that uninephrectomy in these mice induces a significant and proportional increase in renal mass, as compared to normal mice, despite markedly decreased kidney IGF-I levels and no significant changes in receptor phosphorylation [146]. Therefore, the implications of IGF-I in this process may be elucidated in following years.

Cardiovascular development

Cardiovascular system is an important target organ for GH and IGF-I actions. There is evidence that IGF-I and its receptor are expressed in the myocardium and both aortic smooth muscle and endothelial cells [45,147-149], being all of them more sensitive to IGF-I than to insulin [150,151]. In addition, cardiac IGF-I production increases in response to GH [45]. Consequently, there are different possibilities of direct actions of GH as well as endocrine or autocrine/paracrine effects of IGF-I on the cardiovascular system.

Previous studies indicate that IGF-I is a potent vasodilator [152], and that this effect may be partly mediated by increased NO release from the endothelium [153,154]. Accumulating evidence would also suggest that insufficient IGF-I levels play a role in vascular diseases such as atherosclerosis and restenosis [155], what will be discussed in further sections (cardiovascular diseases).

Immune modulation

The potential relationship between immune function and growth factors such as IGF-I has remained poorly characterized until recently. However, the realization that diverse regulatory pathways often converge, motivated a number of studies that eventually demonstrated the importance of GH, IGF-I, and IGF-IR in many processes of immune function [156].

Complex interactions between cytokines and growth factors, including IGF-I, has been properly reviewed by O’Connor et al. [157]. In brief, pro-inflammatory cytokines seem to damp several components of the IGF-I pathway. Many of the cytokines share common signaling components, such as Erk1/2 MAPK.

The role of IGF-I on thymus development and function, hematopoiesis and immune system reconstitution is well documented [158-161].

The role of IGF-I on different immune cell lineages has also been reported. Both IGF-I plays important roles in T lymphocytes development and function. Specifically, IGF-I can increase the number of CD4+CD8+ immature T cells in rat thymus and spleen [162], promotes T cell survival [163], proliferation, chemotaxis and maturation, and blocks spontaneous and induced programmed cell death [163,164], although it has also been reported to block IL-2-dependent lymphocyte growth and function [165]. The possibility for IGF-I to determine how T-cell compartments are filled throughout life remains an open question. However, given the importance of IL-7 in that process and how IGF-I potentiates the actions of IL-7 in pro-B cell expansion [166], a similar influence on T cells seems likely.

Aging rodents exhibit diminished responsiveness to pathogens. This shift is associated with reduced cellularity and significant thymus involution [167,168]. As will be further discussed in section “Aging and age retaled diseases”, IGF-I and GH levels also decrease with aging (somatopause) [169], reason why a potential strategy for reversing these senile changes in thymic vitality may involve administration of either GH or IGF-I, which have been examined for their potential to expand T-cell populations in animals [170].

B cells play diverse roles in immune function by virtue of their further differentiation into immunoglobulin-secreting plasma cells, generation of cytokines, and their importance in antigen presentation. IGF-I has been reported to drive B-cell differentiation, to enhance IL-7-dependent B-cell proliferation in parallel with c-kit ligand [171], as well as to potentiate IL-7 promotion of pro-B-cell expansion [166]. When administered in vivo, IGF-I also enhances the population of intrasplenic B cells through increased proliferation of mature cells [172,173] together with an influence on antibody expression and class switching by plasma cells [174].

Human macrophages and granulocytes are also sensitive to IGF-I by displaying IGF-IR [156]. It was documented that IGF-I attenuated spontaneous apoptosis in these populations [175].

Finally, neutrophils seems to be a potential target for IGF-I actions, since it was able to delay Fas-mediated apoptosis through the PI3K pathway. Moreover, this effect was conserved even in the presence of pro-apototic cytokines, suggesting that it may play a dominant role, even within the context of an active inflammation [156].


Conditions of IGF-I deficiency

An increasing list of animal models has been reported highlighting the role of this molecule in many different organs and systems. In this review, we will focus on the best characterized models of IGF-I deficiency, where the substitutive therapy may be an effective strategy.

Intrauterine growth restriction (IUGR)

Fetal growth is a complex process involving maternal, placental, and fetal factors from genetic, environmental, and nutritional nature. Intrauterine growth restriction is an important obstetric issue affecting ~5% of pregnancies and refers to a fetus that has not reached its growth potential [176]. The growth-restricted fetus/newborn is characterized by an increased fetal and neonatal mortality and morbidity [177,178] and an increased risk of clinical disorders in adult life, such as cardiovascular disease, diabetes and obesity [179,180].

In the prenatal period, differences between GH and IGF-I are clearly shown. Whereas GH insensitivity, both in humans and in transgenic mice, have only mild retardation of growth at birth as previously stated [31-35], IGF-I deficiency in gestational state reveals serious postnatal growth retardation, as has been reported both in humans and in transgenic animal models of IGF-I deletion [36-40]. Interestingly, in contrast to growth hormone insensitivity (GHI), the IGF-I deficient animals are neurologically impaired, as was also reported in a single patient with a defect in the IGF-I gene [40]. Thus it appears that IGF-I is necessary for normal brain development in uterus while GH insensitivity may be recovered by an intrauterine GH-independent production of IGF-I [181,182].

Fetal progress is widely controlled by the oxygenated blood reaching the uterine circulation, the placental integrity and function, and the fetus ability to get the required nutrients [183]. It has been estimated that progenitor’s genes account for only 20% of the variation of human birth weight. Nevertheless, majority of the variation (62%) is due to the intrauterine environment [184]. Placentas from IUGR pregnancies have been shown to have poor invasion of the trophoblastic cells into the maternal decidual tissues, particularly the maternal spiral arteries [185,186]. Studies into the pathological process of IUGR have pointed to an abnormal placental function as a common mechanism [187]. However, it is known that the placental dysfunction is often gradual and it can occur much earlier than any demonstrable IUGR [188], thus difficulting the resolution of this hypothesis.

In the same way, IGFs control growth directly, and circulating IGF-I appears to be virtually independent of fetal GH secretion [182]. However, under this condition, placental growth hormone may take this role as the prime regulator of maternal serum IGF-I during pregnancy [189], being of particular interest the positive expression of IGF-IR in placenta [190] and the lower expression of placental-derived IGF-I during IUGR [191]. In general, endocrine milieu of the human fetus with growth retardation is also characterized by low circulating levels of insulin, IGF-I, IGF-II, and IGFBP-3, and high levels of GH and IGFBP-1 [185,192,193]. At this point, an elegant study in zebrafish demonstrated that knockdown of IGFBP-1 significantly alleviated the hypoxia-induced growth retardation and developmental delay. And consistently, overexpression of IGFBP-1 caused growth and developmental retardation under normoxia conditions [194].

In the last years, it is being proposed a role of fetal programming for an altered GH/IGF axis in IUGR, constituting the so-call Thrifty Phenotype Hypothesis [185], with an already proven inverse association between IGF-I levels at 9 months and 17 years. Under this perspective, GH/IGF-I axis may be programmed early in life. This fetal programming could be involved in, at least, two pathological conditions in later life, as insulin resistance and hypertension. Firstly, children with IUGR show an impaired GH/IGF-I axis, which might be contributing to reduced insulin sensitivity and IGF-I resistance, as higher basal and GH-induced IGF-I levels are required to achieve a growth velocity similar to that of other children, what secondarily leads to a compensatory hyperinsulinemia to counteract insulin antagonistic effects of GH [195] and, an impaired regulation of glucose transporter-4 expression by insulin in muscle and adipose tissue [196].

In another hand, fetal responses to IUGR-related hypoxia include downregulation of insulin, IGF-I, and IGF-II and increased expression of inhibitory IGFBPs. Hypoxia also activates the hypothalamo-pituitary-adrenal (HPA) axis, raising plasma levels of adrenocorticotropic hormone and cortisol, another mechanism that regulates IGFBP expression [197]. Moreover, as previously stated, kidney growth is under IGF-I control; and a reduced IGF action, parallel to increased cortisol levels, results in a smaller number of glomeruli [198]. Alterations in the renin-angiotensin system are also frequent, probably downstream to activation of the HPA axis. These changes together with compensatory responses for the reduced kidney function probably account for the predisposition to adult hypertension.

Laron syndrome (LS)

In 1966, Zvi Laron et al. described the first condition of IGF-I deficiency as a new type of dwarfism indistinguishable from genetic isolated GH deficiency, but with unexpected high serum GH levels [199,200] and inability to synthesize IGF-I and other related molecules, as IGFBP-3 [34,35,201]. This heterogeneous condition was finally named as Laron Syndrome or primary Growth Hormone insensitivity (GHI), and it includes: GH receptor deficiency (the most common), GH-GH receptor signal transduction defect, IGF-I synthetic defect, IGF-I receptor deficiency and IGF-I/IGF-I receptor signal transduction defects.

Epidemiologically, this pathological entity is closely related to an ethnic origin (>90% of cases) [19]. Clinically, overall growth in uterus is slightly shorter at birth in LS (42–47 cm) than in healthy babies (49–52 cm), suggesting a potential role of IGF-I in controlling intrauterine linear growth [34] as will be discussed ahead. This condition is more dramatic throughout childhood, where both skeletal maturation and organ growth are retarded [19,34,202] probably due to a lower impact of GH on gestational growth as compared to IGF-I [31-40]. These growth abnormalities in LS patients without IGF-I substitutive treatment includes postnatal average growth rates of one-half the expected during the first years of life [19], a small brain (with prominent forehead, reduced vertical dimension of the face and hypoplasia of the midfacies and the nasal bridge), a small heart and acromicria [203] together with underdevelopment of the muscular system that delays walking in three-fourth of patients [204,205], osteopenia at all stages (despite normal sex hormone status) with increased occurrence of avascular necrosis of the femoral head [206], impair and weaken skin, hair and nail growth [207], blue sclera due to the decreased thickness of its connective tissue, allowing visualization of the underlying choroid [205], a puberty delay from 3 to 7 years [206], retardation in the maturation of dentition [206] and high-pitched voice [208]. Of interest, normal reproductive function and behavior are widely preserved [202].

This condition of IGF-I deficiency highlight the critical role of IGF-I on brain development and function, as also will be stated in section “Neurodegenerative diseases”.

Animal models of GHI are available since 1997 [31], helping us to better understanding the patho-physiological changes and potentially improved strategies for treating these patients. Nowadays, this is the unique condition of IGF-I deficiency where rhIGF-I is approved (as will be stated in “Current therapeutic options” section).

Chronic liver disease

Cirrhosis is a consequence of chronic and diffuse liver disease characterized by replacement of liver tissue by fibrosis, necrosis and regenerative nodules, leading to loss of functional liver mass. Cirrhosis is most usually caused by alcoholism, hepatitis B and C, and fatty liver disease, among other possible causes [209].

Most common complications of advanced cirrhosis include jaundice and coagulopathy from hepatocellular insufficiency, gastrointestinal bleeding from esophageal varices, ascites, hepatorenal syndrome, spontaneous bacterial peritonitis, liver-related encephalopathy, and malnutrition [209]. Although survival in patients with compensated cirrhosis is relatively high (90% at 5 years after diagnosis), occurrence of complications worsen this scenario to 30% at 3 years [210,211].

Liver cirrhosis was firstly associated with IGF-I in the late ‘80s, proposing this hormone as a good indicator for functional hepatocellular capability [212-214] with a marked decline from early cirrhosis stages (Child-Pugh A) [215]. Since then, the idea of liver cirrhosis as a condition of IGF-I deficiency during adult age has been yearly consolidated from a number of publications establishing the origin of this lack from a decrease in GH receptors seen in cirrhotic livers [216] and a progressive reduction of liver synthesis capability from decreased hepatocellular mass in advanced stages [209]. Furthermore, a marked decline of IGF-I has also been related to a higher probability of hepatocarcinoma [217] and poorer prognosis in patients requiring liver surgery [218]. As a result IGF-I levels are considered of prognostic value regarding survival in cirrhotic patients [215,218].

The availability of animal models for experimental liver cirrhosis (carbon tetrachloride, thioacetamide, bile duct ligation, D-galactosamine…) helped us to better elucidate the role of IGF-I in this pathology. In concrete terms, our group of work has reported that cirrhotic animals treated with rhIGF-I showed: increased food ingestion and efficiency with increased nitrogen uptake and balance (resulting in an increase in muscle weight) [219], normalization of intestinal amino acid and sugar absorption [220,221] (including in animals with advanced cirrhosis and ascites [222]), glucose metabolism [223], reduced portal pressure, endotoxemia and bacterial translocation [224], improved osteopenia both in compensated and ascetic cirrhosis [225,226] and testicular morphology and function [227,228], recovered somatostatinergic tone [229] with improved liver function (increased albumin and coagulation factor levels) and decreased hepatic fibrosis [223]. We have also reported that the hepatic restoration was associated to antioxidant, antiapoptotic, antifibrogenic and mitochondrial-protective effects of IGF-I [230-234].

Aging and age-related diseases

Aging is a universal, intrinsic, irreversible, heterogeneous and multidimensional process of progressive involution characterized by a gradual loss of physiological functions that increases the probability of death. Although related, longevity is different from aging, since the first one is simply considered as the length of the life span independent of the biological aging process. Average lifespan has being (hopefully) continuously growing: from ~27 years in the Greco-Roman era, to ~47 years in 1900, and ~77 years by the end of 20th century [235]. However, it is very interesting that maximum lifespan (longevity) has not dramatically changed and seems to rest at about 120 years, despite the increase in the number of centenarians [236].

Circulating GH and IGF-I levels are maximal during peripubertal growth and early adulthood; however, they progressively decline with age [169]. This decline during human aging is sometimes referred to as somatopause, in analogy with the menopause and andropause. Reduced GH/IGF-I secretion in the elderly is believed to be responsible for or contribute to many symptoms of aging, including loss of muscle mass, increased adiposity, reduced bone mineral density, and decline in energy levels, along with alterations in psychological indicators of the quality of life [237].

There are diverse theories of aging [238] that basically point to few broad physiological processes important for longevity: genetic stability, telomere shortening, stress resistance and metabolic control. Interestingly, IGF-I is somehow related to all of them (Figure 3). Firstly, assuming that mitochondria are the main source of endogenous free radicals [239,240], it has been previously reported that species with higher metabolic rates have shorter maximum lifespan due to superoxide anion radical accumulation that lead to cell damage, hastening aging [241]. At this point, we have previously shown that IGF-I is a main character in restoring mitochondrial dysfunction during aging by increasing mitochondrial membrane potential, reducing oxygen consumption, and increasing ATP synthesis what in turn minimize the c-cytochrome release to the cytoplasm and subsequently promote neural survival by decreasing caspase-induced apoptosis [55,56], in agreement with in vitro reported works from others [242-244]. Furthermore IGF-I’s antioxidant capability in brain cortex and hippocampus was assessed as improving antioxidant enzymes activities (superoxide dismutase, catalase and glutathione peroxidase) and parameters of oxidative damage (MDA and PCC) [55,56]. Thus, by improving mitochondrial function and decreasing oxidative insults, IGF-I may be protecting DNA, proteins and lipids.

Secondly, IGF-I has been proposed as an index of healthy aging, due to the finding that it directly correlates with the leukocyte telomere length [245,246], a biomarker of human aging associated with increased risk of developing vascular diseases, metabolic disorders, and other age associated phenotypes [247,248].

And thirdly, another aspect where IGF-I may play a role in delaying aging symptoms is by controlling metabolism, together with insulin [249]. The best characterized intracellular substrates for the insulin and IGF-I receptors are the insulin receptor substrate proteins 1 to 4 [250]. Following tyrosine phosphorylation, each of these substrates associates with Src homology 2 (SH2) domains of intracellular molecules to generate downstream signals (cfr. Figure 4). The two most important SH2 molecules at this point are the adaptor molecule Grb2 and the enzyme PI3K [251,252]. Grb2 links insulin action to the Ras-MAPK pathway, stimulating cell growth and differentiation. PI3K, on the other hand, is responsible for the insulin-like actions of the hormones by activating Akt/protein-kinase B (PKB) and protein-kinase C (PKC), which subsequently leads to activation of p70 S6K and glycogen-synthase kinase 3 [252]. This, eventually results in stimulation of glycogen, lipid and protein synthesis, as well as in glucose transporter translocation to the plasma membrane with an increase in glucose transport [253]. Importantly, Akt/PKB also phosphorylates forkhead transcription factors of the FOXO subfamily, and this leads to their inactivation and retention in cytoplasm [254,255] resulting in a reduced transcriptional activity [256]. As a final step, depending on the nature of the activation signal, FOXO can regulate apoptosis [257], cell cycle [258], differentiation [256], or the expression of genes involved in DNA repair [259] and oxidative stress resistance [260].

In addition, insulin sensitivity normally decreases during aging, and insulin resistance is a well established human risk factor for a variety of illnesses that affect morbidity and mortality among the elderly, including hypertension, atherosclerosis, obesity, diabetes and neurodegenerative disorders [261-265]. In our group, we have demonstrated that low doses of IGF-I restored circulating IGF-I levels, which improves insulin resistance and lipid metabolism in aging rats [55], thus becoming a potential beneficial agent to prevent insulin resistance-related pathologies.

As stated before, aging and longevity are different concepts. And this is also evident at the IGF-I function level. Despite all the beneficial effects of IGF-I described up to now and the following ones reporting its role in aging-related pathologies as musculoskeletal, neurodegenerative, cardiovascular diseases, IGF-I has been paradoxically negatively related to lifespan [266,267], probably due, at least in part, to its downstream molecule Akt and its interactions with FOXO, mTOR and SIRT-1, among others [268,269]. These outcomes demand much more work to elucidate the apparently contradictory actions of IGF-I on aging and longevity.

Cardiovascular diseases (CVD)

Cardiovascular diseases remain the biggest cause of deaths worldwide, though over the last two decades, cardiovascular mortality rates have declined in many high-income countries. At the same time cardiovascular deaths and disease evolution have increased at an astonishingly fast rate in low- and middle-income countries due to the increase in obesity, sedentary lifestyles and unhealthy habits [262].

Over the last years, low circulating IGF-I levels have been correlated with an increased risk for CVD in humans [270-274]. In cross-sectional studies, low circulating IGF-I levels were found to be associated with angiographically documented coronary artery disease [275] and may predict fatal ischemic heart disease [272], a significantly increased risk of ischemic stroke and congestive heart failure in elderly patients [276,277], as well as a worse prognosis of recovery after an acute myocardial infarction [278]. Additionally, it has been reported a positive correlation between circulating IGF-I levels and both coronary flow reserve [279] and successful cardiovascular aging in healthy centenarians [280].

Available data from transgenic mice with liver-derived IGF-I deficiency clarified that IGF-I deficiency per se can promote the development of an accelerated cardiovascular aging phenotype. Particularlly, contractility of cardiac myocytes is significantly impaired [281,282] together with a deficient compensatory hypertrophic response, following experimental aortic constriction [281]. This animal model also exhibit a dysregulation of Nrf2-dependent antioxidant responses in the vasculature, which promotes the development of marked endothelial dysfunction and endothelial apoptosis in the presence of increased oxidative stress [281], mimicking the aging phenotype.

Consistently, a complementary strategy showed that in aged mice, where IGF-I levels are decreased, cardiac overexpression of IGF-I significantly improved cardiomyocyte contractile function [283], attenuating oxidative stress-mediated protein damage, normalizing Ca2+ homeostasis, reversing age-related alterations in the expression of pro-apoptotic proteins, and decreasing the apoptosis rate [284].

In a similar way, a role for locally produced IGF-I have also been documented. It was recently demonstrated that the paracrine IGF-I system confers vasoprotection and cardioprotection [285] and contributes to the maintenance of microvasculature structural and functional integrity. However, vascular paracrine IGF-I system cannot compensate for deficiency of circulating IGF-I [286].

Beneficial effects of the IGF-I/IGF-IR system in cardiac progenitor cells are also starting to be documented. Due to its great potential, this is a new field that deserves more recognition and study. The recent identification of a subpopulation of human cardiac stem cells expressing IGF-IR and secreting autocrine IGF-I with a secondary therapeutic potential for myocardial regeneration [287,288], may be an important step toward this direction. Among others, actions of IGF-I on cardiac stem cells include antioxidant effects, upregulation of telomerase activity, a delay in replicative senescence [288], and migration and homing of cardiac stem cells facilitating neovascularization in damaged hearts [287].

Aging is associated with functional and phenotypic alterations in the microcirculation, including endothelial dysfunction, oxidative stress, chronic low-grade inflammation, and microvascular rarefaction (reduced number and combined length of small vessels in a given volume of tissue) [289]. Our current understanding is that both, circulating IGF-I levels and locally produced IGF-I, contribute to the maintenance of microcirculation functional and structural integrity, increasing NO bioavailability, decreasing reactive oxygen species (ROS) production, and exerting antiinflammatory, antiapoptotic, and pro-angiogenic effects. The mechanisms by which IGF-I reverses and/or prevents microvascular rarefaction and improves tissue blood supply are likely multifaceted, and may involve, among others: 1) Apoptosis, since IGF-I inhibits oxidative stress-induced apoptosis by preserving the functional integrity of the mitochondria [56,290]; 2) Angiogenesis, because IGF-I is known to exert significant pro-angiogenic effects, inducing proliferation of microvascular endothelial cells in culture through HIF-1α and VEGF [291]; 3) Endothelial cell turnover, as it was reported that age-dependent impairment of endothelial progenitor cells is restored by the GH-mediated increase in circulating IGF-I levels [292]; and 4) Oxidative stress and NO bioavailability, since age-related oxidative stress and downregulation of endothelial nitric oxide synthase (eNOS) impair the bioavailability of NO [293], which is likely to contribute to decreased microvascular density. Those facts were confirmed in animal models of IGF-I deficiency as they often exhibit increased ROS production and decreased NO bioavailability, mimicking the vascular aging phenotype [294]. Of interest, treatment of aged rats with IGF-I was shown to upregulate eNOS and improve bioavailability of NO [295], and in vitro experiments in cultured endothelial cells demonstrated that IGF-I treatment reduce ROS production and upregulate eNOS [294].

In the same way, it has been postulated that majority of these cardiovascular events related to low IGF-I levels may be due to a possible insulin resistance and accelerated atherosclerosis [296]. Also, the endothelial dysfunction and subintimal modified lipoprotein deposition are frequently consequence of oxidative stress [297] and inflammatory cells activity [298]. Antioxidant and anti-inflammatory effects of IGF-I have been documented to reduce atherosclerotic burden, mainly both via cytokine response modulation (attenuating IL-6 and TNF-α pro-inflammatory responses) [299] and/or eNOS activity regulation [295].

Metabolic syndrome

The metabolic syndrome was defined as a combination of clinical features that predispose to enhanced CVD risk, morbidity, and mortality [300]. In some populations, it is present in ~50% of adults [301]. It is thought that an important underlying pathogenetic basis for the metabolic syndrome is insulin resistance and accompanying compensatory hyperinsulinemia [301].

Although without total consensus, six components have been proposed to constitute the metabolic syndrome [300]: Abdominal obesity (or increased waist circumference), atherogenic dyslipidemia (hypertriglyceridemia and low high-density lipoprotein cholesterol concentrations), raised blood pressure, insulin resistance with glucose intolerance, pro-inflammatory state (elevated C-reactive protein) and a pro-thrombotic state (with increased plasminogen activator inhibitor-1 and fibrinogen).

On the other hand, similarities between insulin and IGF-I (molecular homology, shared receptors…) point to the possibility of IGF-I participation in the phenotypic expression of this disorder [301]. The high insulin levels could probably cause a downregulation of IGF-I production by the liver and other tissues, as a compensatory homeostatic mechanism, induced most likely through a differential modulation of IGFBPs production. This might be responsible for the low IGF-I levels seen in association with states of insulin resistance, as the metabolic syndrome [301].

IGF-I’s action on insulin suppression via somatostatine [1] has been tried in diabetes. In type 1 diabetes, where IGF-I and IGFBP-3 levels are decreased [302], substitutive rhIGF-I/IGFBP-3 therapy enhances protein [303] and glucose metabolism by controlling both endogenous glucose output and peripheral glucose uptake [304]. In type 2 diabetic patients, co-treatment with rhIGF-I can significantly reduce glucose levels and insulin requirement [305] while improving glucose tolerance, hyperinsulinemia, and hypertriglyceridemia [306]. Even in nondiabetic subjects, rhIGF-I enhances insulin sensitivity, suppresses lipolysis, clears postprandial lipemia, and increases oxidative and nonoxidative glucose metabolism [223,307,308]. The higher prevalence of insulin resistance and metabolic syndrome in older people compared with younger population may also be attributable, at least in part, to the decline of serum and tissue IGF-I concentrations with advancing age [55,307]. Reduced IGF-I levels are independently associated with glucose intolerance, diabetes, abdominal obesity [309,310] and atherogenic dyslipidemia [311,312]. Overall, these data suggest an important and independent role for IGF-I in protecting against the development of CVD.

Indeed, many of the traditional CVD risk factors, including oxidized low-density lipoprotein [313], hyperlipidemia (hypercholesterolemia or mixed dyslipidemia) [314] insulin resistance [309,310,312], diabetes [315], obesity [309,311], elevated C-reactive protein [316], waist-to-hip ratio [309], reduced coronary flow reserve [279], smoking [317], sedentary life [318] and psychological distress [319], which act via effects on endothelial dysfunction, apoptosis and impaired endothelial-dependent vascular reactivity, have been associated with low serum IGF-I levels and reduced IGF-I and IGF-IR mRNA as well as protein expression in vascular smooth muscle cells (VSMC) [313]. Initially described as a pro-atherogenic molecule due to its proliferative role in VSMC, it was further demonstrated that the effect of IGF-I on VSMC was to compensate for local apoptosis, and that, overall, IGF-I is not pro-atherogenic in native arteries but anti-atherogenic [320], mainly through enhanced nitric oxide production [308]. In addition, IGF-I induces vasodilatation [279,321,322], thereby influencing the regulation of vascular tone and arterial blood pressure and preserving coronary flow reserve [279,321], platelet function, and glucose uptake [323].

Finally, it was recently suggested that IGF-I has significant characteristics to be a good marker for the insulin resistance syndrome and risk of cardiovascular disease, since logistic regression analysis showed that each unit increase in log-transformed IGF-I concentrations was associated with a 90.5% reduction in the risk of metabolic syndrome [274].

Neurodegenerative diseases

Neurodegenerative diseases are a heterogeneous group of disorders from virtually unknown etiology, which eventually lead to neuronal degeneration and dysfunction. As described before, since GH/IGF-I axis is involved in many aspects of brain development, growth and function, their progressive decrease during aging could be involved in a variety of human cerebrovascular diseases, comprising Alzheimer’s disease (AD), vascular dementia (VD), amyotrophic lateral sclerosis (ALS) and stroke.

Alzheimer’s disease and vascular dementia are the most common forms of dementia in elderly [324]. A decrease in IGF-I levels in AD and VD has been widely documented and it may be involved in the development of neurofibrillary tangles, abnormal amyloid β metabolism and aberrant Tau phosphorylation, cognitive loss, neural inflammation, oxidative stress or mitochondrial dysfunction, among others [68,325].

Specifically, IGF-I has been proposed as a physiological regulator of brain amyloid levels [68] by the entrance/production through the brain barrier of different proteins involved in Aβ transport, which eventually enhances its brain efflux [68,326]. In fact, blockade of systemic IGF-I action at the choroid plexus was sufficient to induce brain amyloidosis [326].

Another well recognised neuropathological finding in AD is the accumulation of abnormally hyperphosphorylated Tau in degenerating neurons [325]. Based on the known role of insulin/IGF-I as inhibitors of Tau phosphorylation by inhibiting a major Tau kinase, such as glycogen synthase kinase-β, numerous observations demonstrated that IGF-I controls the levels of hyperphosphorylated Tau in brain [326,327]. Two other pathological processes underlying neuronal decline in AD are gaining attention: oxidative stress and inflammation [328,329]. Again, antiinflammatory and antioxidant effects of IGF-I, together with its antiapoptotic capability, endorse IGF-I as a suitable candidate for AD treatment. Thus, although more work in animal models are required, the available evidence strongly indicates that IGF-I therapy in Alzheimer’s dementia may address etiopathogenic processes and could be a potential candidate for clinical trials.

On the other hand, amyotrophic lateral sclerosis is the most common motor neuron disorder in human adults. In this pathology, IGF-I levels diverge between studies, from increased to decreased IGF-I concentrations [330-332], probably due to differences in samples origin (serum/cerebrospinal fluid vs spinal cord/musculoskeletal) and could be explained as a physiological defensive mechanism promoted in response to the neural degeneration and/or muscle atrophy. Beneficial effects of IGF-I treatment in ALS have been demonstrated both in vivo and in vitro, from which IGF-I has been postulated as an important factor for the maintenance and survival of motor neurons in the spinal cord by activating clue pathways as PI3K/Akt and p44/42 MAPK [333] and ameliorating the superoxide effect [334]. Based on the strength of the pre-clinical evidence, two randomized double-blind placebo-controlled phase III trials examining the efficacy of subcutaneous rhIGF-I in the treatment of ALS have been completed [335,336]; however, the results of these two trials conflict, concluding, that more complex studies to set the potential role of IGF-I in ALS disease are required.

Along with this, cerebrovascular accident (CVA) is currently the second leading cause of death in the Western world, ranking after heart disease and before cancer [337], and experts predict that it is likely to be soon the most common cause of death worldwide [338]. Studies on patients with ischemic stroke suggest that high circulating IGF-I levels are associated with neurological recovery and a better functional outcome [339], probably due to its neuroprotective and pro-angiogenic effects. In fact, increased cerebrovacular mortality in patients with hypopituitarism was documented last century [340]. Importantly, as the nervous system ages, there is also a rarefaction of the microvasculature in different regions of the brain, as well as alterations in the structure of the remaining vessels, which have been causally linked to cognitive dysfunction in older humans [341,342]. This age-related microvascular rarefaction contributes to a decline in regional cerebral blood flow that reduces metabolic support for neural signaling, especially when neuronal activity is high. Of great interest, infusion of IGF-I was shown to elicit a significant (~40%) increase in cerebromicrovascular density in the adult mouse brain [343], via stimulation of HIF-1α and its downstream effector, VEGF.

Menupause and insulin resistance have independently been involved in the incidence of neurodegenerative diseases [344]. Several studies have pointed to PI3K activation as a pivotal event for estradiol effects, a common pathway for IGF-I and insulin [344]. Therefore, it seems possible that estrogen receptor alpha may interact with IGF-I/insulin signaling pathways, to promote neuroprotective effects in brain. Current investigations are also evidencing the role exerted by other key signalling molecules, such as glycogen synthase kinase 3 and beta-catenin, in the cross-talk of estrogen receptors and IGF-I receptors in neural cells [345].

Cognition and memory also decline with age, and they have been correlated to low IGF-I levels as well [346-349], through a proposed mechanism that may include its role in angiogenesis and neurogenesis in the hippocampus. Interestingly, the phosphodiesterase inhibitor Cilostazol (used in peripheral vascular disease treatment) is able to improve cognitive function in mice by increasing the hippocampal production of IGF-I through stimulation of sensory neurons [350].

Musculoskeletal disorders

Aging is associated with a decline in skeletal muscle mass, sometimes referred to as “sarcopenia of old age”. There are several underlying mechanisms that have been implicated in this age-related muscle wasting: decreased protein synthesis, reduced enzymatic activity (especially in glycolytic and glycogenolytic pathways), depletion in energy reserves, increased oxidative damage, and changes in ion content [351], among others. GH and IGF-I have a significant anabolic effect on skeletal muscle and so their decline with aging likely contributes to the decline in muscle mass. For example, they can promote mitosis, protein synthesis, satellite cell proliferation and nerve sprouting, while preventing apoptosis [352,353]. However, in general, tissue responsiveness to IGF-I is altered with aging. Thus, it was reported that median IGF-I and IGFBP-5 mRNA levels in resting young muscle are more than twice higher than those in elderly muscle [354], and aging is associated with decreases in IGF-IR content and IGF-IR phosphorylation in muscle [355].

Skeletal health may also be compromised in vertebrates with reduced GH/IGF-I signaling. Like muscle, normal aging is associated with both quantitative and qualitative changes in bone, including alterations in trabecular architecture, mineralization, protein content and the accumulations of microfractures [356]. IGF-I, which mediates most of the effects of GH on skeletal metabolism, promotes chondrogenesis and increases bone formation by regulating the functions of the differentiated osteoblasts [357,358]. Furthermore, in fibroblasts, DNA synthesis and cell proliferation in response to IGF-I decrease with elderly [359]. Bone responsiveness to IGF-I also decreases with aging, requiring higher doses to reach the same anabolic effect [360]. These studies suggest that low circulating IGF-I bioactivity and/or abnormalities of IGF-I signaling in elderly subjects, may play an important role in age-related sarcopenia and osteopenia, where the substitutive IGF-I treatment may be a suitable therapeutic strategy, although this apparent IGF-I resistance may dampen this aim.

Other IGF-I deficiency conditions
Renal diseases

As previously stated, the IGF system is involved in normal kidney development, and age-related dysregulation of this system may play a role in kidney and vascular diseases, including hypertension [138]. In addition, under renal dysfunction conditions there are profound changes in renal responses to GH/IGF-I system as well as in the circulating levels of these hormones, despite the limited role of the kidney for removing IGF-I from the circulation (since negligible amounts of the IGFBP-3/ALS/IGF-I ternary complex crosses the glomerular barrier in healthy individuals) [361].

In mice with global inactivation of the IGF-I gene, the proportionally reduced kidney size associates with reduced glomerular size and decreased numbers of nephrons [362]. In addition, IGF-I has rapid effects on renal hemodynamics, including an increased renal blood flow and glomerular filtration rate [138,141,142]. Furthermore, both IGF-I and the IGF-IR are expressed in the developing glomerulus and patterns of expression are disrupted in animal models and in human examples of renal disease [140]. Indeed, it has been demonstrated a role of IGF-I signaling for maintaining glomerular integrity, restoring podocyte abnormalities, inhibiting podocyte apoptosis, and alterations in the glomerular basement membrane and the adjacent endothelial cell layer [140,363].

In humans, IGF-I also increases renal blood flow and GFR by ~25% and causes volume expansion and sodium retention by a direct action on the renal tubules, with stimulation of rennin release and suppression of atrial natriuretic peptide secretion [364]. IGF-I administered to GH deficient rats (or to patients with GH receptor defects) normalizes the low GFR as does GH replacement in GH deficiency. Curiously, the effects of GH on kidney function are similar to those observed with IGF-I, except that the functional response to GH is delayed several days, correlating with the secondary increase in serum IGF-I levels, and thus indicating that the GH effects are mediated by IGF-I. However, it is noteworthy that GH receptors are present in the proximal tubule, a site where IGF-I mRNA is not normally expressed, suggesting that GH also may have direct actions on tubular function [364].

In another hand, while most reports appear to implicate IGF-I as a potential mediator of pathological changes in the diabetic kidney [364,365], IGF-I is also protective against oxidative stress and apoptosis induced by high levels of glucose in cultured mesangial cells. This protection appears to be mediated by Akt/PKB and MAPK signalling pathways [366], and it has been suggested that stimulation of this survival pathways may be turned to therapeutic advantage for protection against cell death and progression of nephropathy.

Catabolic states

Clinical investigators have shown that IGF-I levels are often significantly altered in catabolic states, including the acute postoperative period [367], burn patients [368] and chronic catabolic illnesses, such as cystic fibrosis [369] and HIV with wasting [370]. These conditions result in low IGF-I concentrations, and changes in IGF-I positively correlate with changes in lean body mass [369,370], as well as reversal of acute catabolic states is associated with an increase in IGF-I levels [371,372]. In clinical use, children with extensive thermal burns who were treated with IGF-I in combination with IGFBP-3, presented a reduction in serum levels of IL-1β, TNF-α, C-reactive protein, α1-acid glycoprotein, and complement C-3 [299]. In contrast, the serum levels of retinol-binding proteins, prealbumin, and transferrin were increased by the infusion. From these results, authors concluded that attenuating the pro-inflammatory acute phase with IGF-I/IGFBP-3 may prevent multiple organ failure and improve clinical outcomes after thermal injury without any detectable adverse side effects.

Also, when IGF-I was used to monitor total parenteral nutrition therapy in catabolic patients, the changes correlate with improvements in protein metabolism [373]. Consistently, a close correlation between IGF-I and protein synthesis in patients with burns was reported [368]. Similarly, extremely low IGF-I levels observed in severe malnutrition improved with caloric repletion [374].


Current therapeutic options and limitations

The pluripotential roles of IGF-I may explain the interest and wide availability of IGF-I assays from different laboratories. However, standard methods of IGF-I measurement are not well characterized yet. Recombinant human IGF-I was first available for experimental therapy in the late 1980s, what allowed the development of long-term studies in children with severe primary IGF-I deficiency (defined as a height SDS and IGF-I SDS less than or equal to −3 and normal or elevated GH levels) [375]. These studies followed the children for up to 12 years and reported a significant dose-dependent increase in mean first-year height velocity over baseline (~3.0 cm/year at baseline, ~8.5 cm/year at first year, p<0.001) [376-380]. Mean height velocity decreased during the subsequent years of treatment, but remained higher than the pretreatment height velocity for up to 8 years [376]. A complementary aspect of the rhIGF-I treatment in these patients was an increase in testosterone levels, testicular size and stretched penile length, which indicates a direct effect of IGF-I on sex hormones and organs in male patients [381].

These studies supported the 2005 US Food and Drug Administration (FDA) approval of rhIGF-I, being commercially available in 2005 for treatment of patients with severe primary IGF-I deficiency due to genetic GH resistance from mutations in the GH receptor, defects in the GH receptor signaling pathway (including STAT5b gene mutations), mutations in the IGF-I gene, or in rare patients with GH gene deletions in whom inactivating antibodies develop to exogenous rhGH [382-384], but not for other conditions of (secondary) IGF-I deficiency such as malnutrition, hypothyroidism and chronic illnesses [383]:

• Active or suspected neoplasia.

• Allergy to rhIGF-I (mecasermin, Increlex®) or any of its ingredients.

• Chronic illness (i.e. diabetes, cystic fibrosis, etc.).

• Growth failure associated with other identifiable causes (i.e. Prader-Willi syndrome, Russell-Silver syndrome, Turner syndrome, Noonan syndrome or chromosomal abnormalities).

• Patients with closed epiphyses (for promoting growth treatments).

By the same time, FDA also approved the use of the combination of IGF-I and IGFBP-3. Theoretically, it might be a better choice as a more physiological strategy (which would require lower doses). However, the results were not as promising as expected and legal issues led to its discontinuation. Interestingly, a recent work developed in two brothers with insulin-like growth factor deficiency, where one was treated with IGF-I plus IGFBP-3 and the other with just IGF-I, showed that both modalities improved determinants of hepatic insulin sensitivity, body composition and linear growth rate; however, IGF-I alone seemed to be more efficient [385].

A complete review by Laron in 2008 [386] summarizes the experience by several groups worldwide. The main conclusions were: 1) The one or two injections regimen result in the same growth velocity; 2) The growth speed obtained with IGF-I administration is smaller than that observed with hGH in children with congenital isolated GH deficiency; 3) Overdosage of IGF-I causes a series of adverse effects which can be avoided by carefully monitoring the serum IGF-I and GH levels. The optimal dosing guidelines are still on debate. Firstly stated on the basis of IGF-I tolerance, two more recent studies presented at the International Congress of Endocrinology (2008) showed the safety and efficacy of both twice-daily (80–120 μg/Kg) or once-daily (240 μg/Kg) rhIGF-I treatment for primary IGF-I deficiency [387,388]. Interestingly, it was also reported a certain degree of heterogeneity in the serum IGF-I responses, probably influenced on the IGFBP-3 levels [389].

Another disturbing aspects are the difficulties found when collecting, storing and monitoring IGF-I serum samples [389,390]. In contrast to GH, circulating levels of IGF-I remain relatively stable during daytime with minimum oscillations, being unaffected by meal intake [391,392]. However, IGFBP-3 levels showed acute changes with meal intake [391-393], what has direct consequences on IGF-I bioavailability, and it was reported a nocturnal decline of IGF-I levels from midnight to 4 am [393], probably due to shifts in plasma volume. Despite this, the lack of any major diurnal variation in circulating IGF-I levels, combined with the long half-life of ternary complex constituting IGF-I [393] has led to the concept that a single measurement of IGF-I is representative for an individual IGF-I level. On the other hand, the serum half-life of rhIGF-I is less than 24 hours, what suggests that serum IGF-I monitoring may be worth for detecting a single missing dose on the day, but it is not useful for identifying long term treatment noncompliance [394]. Furthermore, there is no clear indication to date that routine serum IGF-I monitoring is informative or useful for children taking rhIGF-I treatment, as it has not been linked to the occurrence of adverse events or efficacy outcomes [387-389].

Safety is the paramount aim when developing new drugs. In this case, as previously happened with recombinant technologies for GH and insulin, IGF-I is a natural peptide already produced in humans, what facilitates the elucidation of possible secondary effects due to rhIGF-I therapy. However, a number of clinical trials monitoring long-term rhIGF-I treatment have reported different adverse events [372,377,387-389,395-398], although they were transient, well tolerated and easy managed without treatment discontinuation (Table 1). In brief, it has been reported episodes of tachycardia (self-resolved and probably due to the inotropic effect of rhIGF-I), transient increase of intracranial pressure with headache and vomiting (consistent with the safety profile of rhGH treatment), lipohypertrophy at injection site, tonsillar/adenoidal hypertrophy, facial edema, arthralgia, myalgia, asthenia, orthostatic hypotension and hypoglycemia. This decrease in blood sugar could be a consequence of the insulin like action of IGF-I per se, and the binding of IGF-I to the insulin receptor. However, a placebo controlled study by Guevara-Aguirre et al. in 1995 reported no statistically significant difference in the frequency of hypoglycemia in those who received IGF-I vs. placebo for 6 months (86% in IGF-I group vs. 67% in the placebo group) [379]. Interestingly, as previously stated by Laron [386], doses lower than 60 μg/Kg/day did not show these described adverse effects, both in human clinical trials [398,399] and in animal experimental models [55,56,219-221,223].

Another outcome from the rhIGF-I treatment in Laron syndrome is the significant increase in body adipose tissue (to double or triple the normal values) concomitantly with the increase in growth [400] although, due to the underdevelopment of the muscular and skeletal systems, body mass index did not accurately reflect the degree of obesity. From these data, authors concluded that IGF-I, similar to insulin, exerts an adipogenic effect. However, another study in insulin resistance, reported a reduction in both intramyocellular lipids and intrahepatic fat in a patient treated with rhIGF-I/IGFBP-3 (together with a post-treatment normalization of % HbA1C value) [401]. These data, although very preliminary, may indicate different mechanistic pathways by which IGF-I controls lipid metabolism.

Consistently, despite these known effects, we still must be alert due to the reported potential role of IGF-I in neoplasias development (a recommended review is available at ref. [402]). Fortunately, a recent study shed some light on this topic by reporting the malignancies occurrence in patients with congenital IGF-I deficiency and insensitivity to GH. They found that this condition seemed to be protective against future cancer development, but more interesting, even when treated with IGF-I [403]. Furthermore, no current data in the literature suggest the malignant transformation of a normal cell in association with IGF-I administration, what may reassure possible concerns about its long-term safety and use in replacement therapies.

Nowadays, rhIGF-I therapy is also being tested or proposed in other pathological conditions as chronic liver disease, insulin resistances/hyperinsulinemia, diabetes, neurological disorders (Alzheimer’s disease and amyotrophic lateral sclerosis) and stroke, cysticfibrosis, wound healing, AIDS muscle wasting and HIV-associated adipose redistribution syndrome, burns, osteoporosis, Crohn’s disease, Werner syndrome, X-linked severe combined immunodeficiency, myotonic muscular dystrophy, hearing loss prevention, spinal cord injury, cardiovascular protection, anorexia nervosa, fetal growth restriction and prevention of retinopathy of prematurity [182,303-306,384,399,401,404-423], although some of the treatment’s contraindications may limit its potential applicability (Table 2).

Nonetheless, in spite of the great amount of data obtained from these studies, there is still a necessity for further studies to either elucidate the right doses to achieve the expected results, clarify the rhIGF-I therapy effectiveness or even exclude any potential adverse event. For example, the effect of rhIGF-I in chronic liver injury (20 μg/Kg/day with dose escalation up to 50–100 μg/Kg/day for 4 months) was mainly reduced to an increase in albumin levels [399], probably due to the low number of subjects and treatment guidelines, which could not achieve normal IGF-I values, as was also reported in a recent study [387] where doses by 40 μg/Kg/day did were not able to normalize serum IGF-I.

In our experience, the most important goal is to prove the presence of IGF-I deficiency. However, in some cases like compensated liver cirrhosis, IGF-I circulating levels are normal, but if low doses of this hormone are administrated, many beneficial effects are induced [219-221,223,225,228,232]. This finding suggests that the bioavailability of IGF-I is reduced from early stages of liver disease. However, without hepatopathy, IGF-I levels and bioavailability are not diminished. Thus, IGF-I treatment failed to induce the desired effects, like was reported in a model of testicular dysfunction secondary to epinephrine intra-scrotal injections (but without liver cirrhosis or any other condition of IGF-I deficiency) [424].

At this point, it is also crucial to state that testicular dysfunction was only restored when it was associated to IGF-I deficiency conditions, since IGF-I treatment of rats with testicular damage secondary to epinephrine intra-scrotal injections (but without liver cirrhosis or any other condition of IGF-I deficiency) was not able to adequately recover their morphology and function.

On the other side, therapeutic use of rhIGF-I has been debated in ALS, since a Cochrane systematic evidence review found that the available randomized placebo controlled trials [335,336] did not permit a definitive assessment of its clinical efficacy [407], with just a small significant benefit in favor of recombinant IGF-I, which clinical relevance is unclear. The authors concluded that more research is needed, noting that one trial is in progress, and they recommended that future trials may include survival rates as another outcome measure.

And thirdly, although Rosenbloom [384] stated that the rhIGF-I insulin-sensitizing effect may be beneficial for diabetic patients to reduce hemoglobin A1C levels, there are no current ongoing clinical trials because of concern about risk of retinopathy and other complications [425], thus limiting the theoretically wide spectrum of potential IGF-I treatment indications.


Conclusions

Briefly, IGF-I deficiency states –as it is the case with every other hormone- produce effects that culminate in recognizable syndromes with significant clinical consequences. Until now, the best known conditions of IGF-I deficiency are: Laron Syndrome, in children; advanced liver cirrhosis, in adults; and aging including cardiovascular and neurological diseases associated to aging. More recently, intrauterine growth restriction seems to appear as another state of IGF-I deficiency. In these four conditions, the replacement therapy can logically induce beneficial actions. Apart from these, many other diseases have been recently proposed to be either consequence or cause of both a systemic or partial IGF-I deficiency. However, more in-depth studies are needed to properly characterize these potential new conditions of IGF-I deficiency and their future clinical perspectives.

On the other hand, the multiple physiological properties of IGF-I may generate excessive prospects if basic concepts about this topic are not adequately considered:

1. IGF-I is a closed regulated hormone. Its therapeutic applications should, in principle, be limited to restore physiological levels, but not over its normal range, as it is the usual practice in endocrinology diseases (hypothyroidism, diabetes, etc.).

2. Exogenous administration of IGF-I in conditions without IGF-I deficiency, usually responds to an attempt to exploit its anti-inflammatory, hematopoietic, antioxidant, metabolic or anabolic properties. However, despite the limited results of these strategies, it may entail obvious risks. In the best of cases, these strategies would require prudence and short periods of treatment, as in the corticotherapy.

3. Low doses of IGF-I seem to be able to restore circulating levels of this hormone promoting beneficial effects without secondary effects (including hypoglycemia). Secondary adverse effects from IGF-I therapy were reported after administration of doses higher than 60–80 μg/Kg/day.

4. The axis GH/IGF-I is claiming a particular physiological understanding. Usually IGF-I deficiency is associated to “GH resistance” or “GH insensibility” states. IGF-I replacement therapy induced a restoration of the altered GH/IGF-I axis by reducing circulating GH levels and improving somatostatinergic tone. Thus, IGF-I therapy would need to be considered as a different strategy from GH treatment, avoiding past inadequate procedures when both GH/IGF-I therapies were considered equivalent.

5. Finally, a concern about the potential relationship between IGF-I and cancer is an awkward issue that may require a deeper approach. For instance, a question may arise: are the higher circulating IGF-I levels a marker or a causal factor? In our experience, IGF-I at low doses is a cytoprotective factor that, exerting effective mitochondrial protection, anti-inflammatory and antioxidant activities, could prevent oncogenesis and cancer development by acting in the earliest stages of these pathogenic mechanisms. In addition, despite permanent reservations relating cancer and IGF-I, no current data suggest an IGF-I related malignant transformation from a normal cell.

In conclusion, on the basis of the available evidence, and despite the current limitations in this matter, it seems reasonable that IGF-I therapies may be designed only to restore its physiological levels as a replacement treatment, but never elevating IGF-I levels above its upper normal range.


Abbreviations

ALS: Acid-labile subunit; Aβ: Amyloid β; BBB: Blood–brain barrier; CVA: Cerebrovascular accident; EGF: Epidermal growth factor; CNS: Central nervous system; CVD: Cardiovascular diseases; EAE: Experimental autoimmune encephalomyelitis; FDA: Food and drug administration; FSH: Follicle-stimulating hormone; GFR: Glomerular filtration rate; GH: Growth hormone; GHBP: Growth hormone binding protein; GHI: Growth Hormone Insensitivity; HGF: Hepatocyte growth factor; HIF: Hypoxia inducible factor; HPA: Hypothalamo-pituitary-adrenal; IGF: Insulin-like growth factor; IGF-IR: Receptor de IGF-I; IGFBP: Insulin-like growth factor binding protein; IL: Interleukin; IUGR: Intrauterine growth restriction; LH: Luteinizing hormone; LS: Laron syndrome; MAPK: Mitogen-activated protein kinase; MDA: Malon-dialdehyde; NO: Nitric oxide; NSILA: Non-suppressible insulin-like activity; NSC: Neural stem cells; PCC: Protein carbonyl content; PI3K: Phosphatidyl-inositol-3-kinase; Rh: Recombinant human; ROS: Reactive oxygen species; SDS: Standard deviation score; SH2: Src homology 2; TNF-α: Tumor necrosis factor-alpha; VEGF: Vascular endothelial growth factor; VSMC: Vascular smooth muscle cells.


Competing interests

Authors have nothing to disclose.


Authors’ contributions

JEP participated in compiling data and elaborating the manuscript. ICC critically revised the intellectual content of the review, and gave the final approval. All authors read and approved the final manuscript.


Acknowledgements

The authors would like to thank every researcher that contributed to the better understanding of the IGF-I role both in physiological and pathological conditions. We also appreciate Mr. Gonzalo Cañas Guevara imaging processing, and Mrs. Amalia Calderón and Mrs. Susana Arahuetes for their generous and expert secretarial and technical assistance. Special thanks to Kabi Pharmacia (Drs. Anna Sköttner and Jan Holmberg) and Chiron Company (Dr. Bruce Scharschmidt) for kindly providing the recombinant human insulin-like growth factor used in our studies. This work was supported by the Spanish “I+D Program” SAF 2009-08319.


References
Le Roith D,Seminars in medicine of the beth israel deaconess medical center. Insulin-like growth factorsN Engl J MedYear: 1997336963364010.1056/NEJM1997022733609079032050
Salmon WD Jr,Daughaday WH,A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitroJ Lab Clin MedYear: 195749682583613429201
Froesch ER,Buergi H,Ramseier EB,Bally P,Labhart A,Antibody-suppressible and nonsuppressible insulin-like activities in human serum and their physiologic significance. An insulin assay with adipose tissue of increased precision and specificityJ Clin InvestYear: 1963421816183410.1172/JCI10486614083170
Pierson RW Jr,Temin HM,The partial purification from calf serum of a fraction with multiplication-stimulating activity for chicken fibroblasts in cell culture and with non-suppressible insulin-like activityJ Cell PhysiolYear: 197279331933010.1002/jcp.10407903024339122
Daughaday WH,Hall K,Raben MS,Salmon WD Jr,van den Brande JL,van Wyk JJ,Somatomedin: proposed designation for sulphation factorNatureYear: 1972235533310710.1038/235107a04550398
Rinderknecht E,Humbel RE,The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulinJ Biol ChemYear: 1978253827692776632300
Rinderknecht E,Humbel RE,Primary structure of human insulin-like growth factor IIFEBS LettYear: 197889228328610.1016/0014-5793(78)80237-3658418
Klapper DG,Svoboda ME,Van Wyk JJ,Sequence analysis of somatomedin-C: confirmation of identity with insulin-like growth factor IEndocrinologyYear: 198311262215221710.1210/endo-112-6-22156343062
Zapf J,Schoenle E,Froesch ER,Insulin-like growth factors I and II: some biological actions and receptor binding characteristics of two purified constituents of nonsuppressible insulin-like activity of human serumEuropean journal of biochemistry / FEBSYear: 197887228529610.1111/j.1432-1033.1978.tb12377.x668694
Froesch ER,Zapf J,Audhya TK,Ben-Porath E,Segen BJ,Gibson KD,Nonsuppressible insulin-like activity and thyroid hormones: major pituitary-dependent sulfation factors for chick embryo cartilageProc Natl Acad Sci U S AYear: 19767382904290810.1073/pnas.73.8.29041066701
Rinderknecht E,Humbel RE,Polypeptides with nonsuppressible insulin-like and cell-growth promoting activities in human serum: isolation, chemical characterization, and some biological properties of forms I and IIProc Natl Acad Sci U S AYear: 19767372365236910.1073/pnas.73.7.23651065887
Daughaday WH,Hall K,Salmon WD Jr,Van den Brande JL,Van Wyk JJ,On the nomenclature of the somatomedins and insulin-like growth factorsJ Clin Endocrinol MetabYear: 19876551075107610.1210/jcem-65-5-10753667879
Clemmons DR,Role of insulin-like growth factor binding proteins in controlling IGF actionsMol Cell EndocrinolYear: 19981401–219249722163
Clemmons DR,Busby W,Clarke JB,Parker A,Duan C,Nam TJ,Modifications of insulin-like growth factor binding proteins and their role in controlling IGF actionsEndocr JYear: 199845SupplS1S810.1507/endocrj.45.Suppl_S19790222
Annenkov A,The insulin-like growth factor (IGF) receptor type 1 (IGF1R) as an essential component of the signalling network regulating neurogenesisMol NeurobiolYear: 200940319521510.1007/s12035-009-8081-019714501
Chitnis MM,Yuen JS,Protheroe AS,Pollak M,Macaulay VM,The type 1 insulin-like growth factor receptor pathwayClin Cancer ResYear: 200814206364637010.1158/1078-0432.CCR-07-487918927274
LeRoith D,Werner H,Beitner-Johnson D,Roberts CT Jr,Molecular and cellular aspects of the insulin-like growth factor I receptorEndocr RevYear: 19951621431637540132
D’Ercole AJ,Applewhite GT,Underwood LE,Evidence that somatomedin is synthesized by multiple tissues in the fetusDev BiolYear: 198075231532810.1016/0012-1606(80)90166-97372001
Rosenbloom AL,Guevara-Aguirre J,Rosenfeld RG,Pollock BH,Growth in growth hormone insensitivityTrends in endocrinology and metabolism: TEMYear: 19945729630310.1016/1043-2760(94)P3205-L18407222
Ghigo MC,Torsello A,Grilli R,Luoni M,Guidi M,Cella SG,Locatelli V,Muller EE,Effects of GH and IGF-I administration on GHRH and somatostatin mRNA levels: I. A study on ad libitum fed and starved adult male ratsJ Endocrinol InvestYear: 19972031441509186821
Berelowitz M,Szabo M,Frohman LA,Firestone S,Chu L,Hintz RL,Somatomedin-C mediates growth hormone negative feedback by effects on both the hypothalamus and the pituitaryScienceYear: 198121245001279128110.1126/science.62629176262917
Bertherat J,Bluet-Pajot MT,Epelbaum J,Neuroendocrine regulation of growth hormoneEur J EndocrinolYear: 19951321122410.1530/eje.0.13200127850005
Ohlsson C,Mohan S,Sjogren K,Tivesten A,Isgaard J,Isaksson O,Jansson JO,Svensson J,The role of liver-derived insulin-like growth factor-IEndocr RevYear: 200930549453510.1210/er.2009-001019589948
Daughaday WH,Rotwein P,Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrationsEndocr RevYear: 1989101689110.1210/edrv-10-1-682666112
Clemmons DR,Underwood LE,Nutritional regulation of IGF-I and IGF binding proteinsAnnu Rev NutrYear: 19911139341210.1146/annurev.nu.11.070191.0021411716449
Murphy LJ,Friesen HG,Differential effects of estrogen and growth hormone on uterine and hepatic insulin-like growth factor I gene expression in the ovariectomized hypophysectomized ratEndocrinologyYear: 1988122132533210.1210/endo-122-1-3253335211
Adashi EY,Resnick CE,Hurwitz A,Ricciarelli E,Hernandez ER,Roberts CT,Leroith D,Rosenfeld R,Insulin-like growth factors: the ovarian connectionHum ReprodYear: 199169121312191721620
Cohick WS,Clemmons DR,The insulin-like growth factorsAnnu Rev PhysiolYear: 19935513115310.1146/annurev.ph.55.030193.0010238466170
Adamo M,Lowe WL Jr,LeRoith D,Roberts CT Jr,Insulin-like growth factor I messenger ribonucleic acids with alternative 5’-untranslated regions are differentially expressed during development of the ratEndocrinologyYear: 198912462737274410.1210/endo-124-6-27372721444
Wolf E,Hoeflich A,Lahm H,What is the function of IGF-II in postnatal life? Answers from transgenic mouse modelsGrowth Horm IGF ResYear: 19988318519310.1016/S1096-6374(98)80110-X10984306
Zhou Y,Xu BC,Maheshwari HG,He L,Reed M,Lozykowski M,Okada S,Cataldo L,Coschigamo K,Wagner TE,et al. A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse)Proc Natl Acad Sci U S AYear: 19979424132151322010.1073/pnas.94.24.132159371826
Wit JM,van Unen H,Growth of infants with neonatal growth hormone deficiencyArch Dis ChildYear: 199267792092410.1136/adc.67.7.9201519958
Savage MO,Blum WF,Ranke MB,Postel-Vinay MC,Cotterill AM,Hall K,Chatelain PG,Preece MA,Rosenfeld RG,Clinical features and endocrine status in patients with growth hormone insensitivity (laron syndrome)J Clin Endocrinol MetabYear: 19937761465147110.1210/jc.77.6.14657505286
Laron Z,Jameson JLLaron syndrome—primary growth hormone resistanceHormone resistance syndromes contemporary endocrinologyYear: 1999Humana Press, NJ1737 vol. 2.
Savage MO,Burren CP,Blair JC,Woods KA,Metherell L,Clark AJ,Camacho-Hubner C,Growth hormone insensitivity: pathophysiology, diagnosis, clinical variation and future perspectivesHorm ResYear: 200155Suppl 2323511684873
Lupu F,Terwilliger JD,Lee K,Segre GV,Efstratiadis A,Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growthDev BiolYear: 2001229114116210.1006/dbio.2000.997511133160
Baker J,Liu JP,Robertson EJ,Efstratiadis A,Role of insulin-like growth factors in embryonic and postnatal growthCellYear: 199375173828402902
Liu JP,Baker J,Perkins AS,Robertson EJ,Efstratiadis A,Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r)CellYear: 199375159728402901
Abuzzahab MJ,Schneider A,Goddard A,Grigorescu F,Lautier C,Keller E,Kiess W,Klammt J,Kratzsch J,Osgood D,et al. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardationN Eng J MedYear: 2003349232211222210.1056/NEJMoa010107
Woods KA,Camacho-Hubner C,Savage MO,Clark AJ,Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I geneN Eng J MedYear: 1996335181363136710.1056/NEJM199610313351805
Leal Ade C,Canton AP,Montenegro LR,Coutinho DC,Arnhold IJ,Jorge AA,Mutations in insulin-like growth factor receptor 1 gene (IGF1R) resulting in intrauterine and postnatal growth retardationArq Bras Endocrinol MetabolYear: 201155854154910.1590/S0004-2730201100080000722218435
Daughaday WH,Daughaday WHGrowth hormone and the somatomedinsEndocrine control of growthYear: 1981Elsevier, New York124
Savage MO,Attie KM,David A,Metherell LA,Clark AJ,Camacho-Hubner C,Endocrine assessment, molecular characterization and treatment of growth hormone insensitivity disordersNat Clin Pract Endocrinol MetabYear: 20062739540710.1038/ncpendmet019516932322
Backeljauw PF,Underwood LE,syndrome GCGGhiTherapy for 6.5-7.5 years with recombinant insulin-like growth factor I in children with growth hormone insensitivity syndrome: a clinical research center studyJ Clin Endocrinol MetabYear: 20018641504151010.1210/jc.86.4.150411297575
D’Ercole AJ,Stiles AD,Underwood LE,Tissue concentrations of somatomedin C: further evidence for multiple sites of synthesis and paracrine or autocrine mechanisms of actionProc Natl Acad Sci U S AYear: 198481393593910.1073/pnas.81.3.9356583688
Froesch ER,Schmid C,Schwander J,Zapf J,Actions of insulin-like growth factorsAnnu Rev PhysiolYear: 19854744346710.1146/annurev.ph.47.030185.0023032986538
Sjogren K,Liu JL,Blad K,Skrtic S,Vidal O,Wallenius V,LeRoith D,Tornell J,Isaksson OG,Jansson JO,et al. Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in miceProc Natl Acad Sci U S AYear: 199996127088709210.1073/pnas.96.12.708810359843
Yakar S,Rosen CJ,Bouxsein ML,Sun H,Mejia W,Kawashima Y,Wu Y,Emerton K,Williams V,Jepsen K,et al. Serum complexes of insulin-like growth factor-1 modulate skeletal integrity and carbohydrate metabolismFASEB JYear: 200923370971910.1096/fj.08-11897618952711
Chin E,Zhou J,Dai J,Baxter RC,Bondy CA,Cellular localization and regulation of gene expression for components of the insulin-like growth factor ternary binding protein complexEndocrinologyYear: 199413462498250410.1210/en.134.6.24987515002
Jaques G,Noll K,Wegmann B,Witten S,Kogan E,Radulescu RT,Havemann K,Nuclear localization of insulin-like growth factor binding protein 3 in a lung cancer cell lineEndocrinologyYear: 199713841767177010.1210/en.138.4.17679075742
Schedlich LJ,Le Page SL,Firth SM,Briggs LJ,Jans DA,Baxter RC,Nuclear import of insulin-like growth factor-binding protein-3 and −5 is mediated by the importin beta subunitJ Biol ChemYear: 200027531234622347010.1074/jbc.M00220820010811646
Lee KW,Ma L,Yan X,Liu B,Zhang XK,Cohen P,Rapid apoptosis induction by IGFBP-3 involves an insulin-like growth factor-independent nucleomitochondrial translocation of RXRalpha/Nur77J Biol ChemYear: 200528017169421694810.1074/jbc.M41275720015731112
Kenner KA,Heidenreich KA,Insulin and insulin-like growth factors stimulate in vivo receptor autophosphorylation and tyrosine phosphorylation of a 70K substrate in cultured fetal chick neuronsEndocrinologyYear: 1991129130131110.1210/endo-129-1-3011711464
Begum N,Robinson LJ,Draznin B,Heidenreich KA,Protein phosphatase-1 and -2a activities in cultured fetal chick neurons: differential regulation by insulin and insulin-like growth factor-IEndocrinologyYear: 199313352085209010.1210/en.133.5.20858404657
Garcia-Fernandez M,Delgado G,Puche JE,Gonzalez-Baron S,Castilla Cortazar I,Low doses of insulin-like growth factor I improve insulin resistance, lipid metabolism, and oxidative damage in aging ratsEndocrinologyYear: 200814952433244210.1210/en.2007-119018187555
Puche JE,Garcia-Fernandez M,Muntane J,Rioja J,Gonzalez-Baron S,Castilla Cortazar I,Low doses of insulin-like growth factor-I induce mitochondrial protection in aging ratsEndocrinologyYear: 200814952620262710.1210/en.2007-156318276748
Garcia-Fernandez M,Sierra I,Puche JE,Guerra L,Castilla-Cortazar I,Liver mitochondrial dysfunction is reverted by insulin-like growth factor II (IGF-II) in aging ratsJ Transl MedYear: 2011912310.1186/1479-5876-9-12321798010
Castilla-Cortazar I,Garcia-Fernandez M,Delgado G,Puche JE,Sierra I,Barhoum R,Gonzalez-Baron S,Hepatoprotection and neuroprotection induced by low doses of IGF-II in aging ratsJ Transl MedYear: 2011910310.1186/1479-5876-9-10321733157
Joseph D’Ercole A,Ye P,Expanding the mind: insulin-like growth factor I and brain developmentEndocrinologyYear: 2008149125958596210.1210/en.2008-092018687773
Drago J,Murphy M,Carroll SM,Harvey RP,Bartlett PF,Fibroblast growth factor-mediated proliferation of central nervous system precursors depends on endogenous production of insulin-like growth factor IProc Natl Acad Sci U S AYear: 19918862199220310.1073/pnas.88.6.21992006157
Popken GJ,Dechert-Zeger M,Ye P,D’Ercole AJ,Brain developmentAdv Exp Med BiolYear: 200556718722010.1007/0-387-26274-1_816372399
Brooker GJ,Kalloniatis M,Russo VC,Murphy M,Werther GA,Bartlett PF,Endogenous IGF-1 regulates the neuronal differentiation of adult stem cellsJ Neurosci ResYear: 200059333234110.1002/(SICI)1097-4547(20000201)59:3<332::AID-JNR6>3.0.CO;2-210679768
Hsieh J,Aimone JB,Kaspar BK,Kuwabara T,Nakashima K,Gage FH,IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytesJ Cell BiolYear: 2004164111112210.1083/jcb.20030810114709544
Reinhardt RR,Bondy CA,Insulin-like growth factors cross the blood–brain barrierEndocrinologyYear: 199413551753176110.1210/en.135.5.17537525251
Rosenfeld RG,Pham H,Keller BT,Borchardt RT,Pardridge WM,Demonstration and structural comparison of receptors for insulin-like growth factor-I and -II (IGF-I and -II) in brain and blood–brain barrierBiochem Biophys Res CommunYear: 1987149115916610.1016/0006-291X(87)91618-42961336
Duffy KR,Pardridge WM,Rosenfeld RG,Human blood–brain barrier insulin-like growth factor receptorMetab Clin ExpYear: 198837213614010.1016/S0026-0495(98)90007-52963191
Nishijima T,Piriz J,Duflot S,Fernandez AM,Gaitan G,Gomez-Pinedo U,Verdugo JM,Leroy F,Soya H,Nunez A,et al. Neuronal activity drives localized blood–brain-barrier transport of serum insulin-like growth factor-I into the CNSNeuronYear: 201067583484610.1016/j.neuron.2010.08.00720826314
Carro E,Trejo JL,Gomez-Isla T,LeRoith D,Torres-Aleman I,Serum insulin-like growth factor I regulates brain amyloid-beta levelsNat MedYear: 20028121390139710.1038/nm1202-79312415260
Backstrom M,Hall K,Sara V,Somatomedin levels in cerebrospinal fluid from adults with pituitary disordersActa EndocrinolYear: 198410721711786388207
Hynes MA,Van Wyk JJ,Brooks PJ,D’Ercole AJ,Jansen M,Lund PK,Growth hormone dependence of somatomedin-C/insulin-like growth factor-I and insulin-like growth factor-II messenger ribonucleic acidsMol EndocrinolYear: 19871323324210.1210/mend-1-3-2333453890
Chernausek SD,Insulin-like growth factor-I (IGF-I) production by astroglial cells: regulation and importance for epidermal growth factor-induced cell replicationJ Neurosci ResYear: 199334218919710.1002/jnr.4903402068450562
Pons S,Torres-Aleman I,Basic fibroblast growth factor modulates insulin-like growth factor-I, its receptor, and its binding proteins in hypothalamic cell culturesEndocrinologyYear: 199213152271227810.1210/en.131.5.22711385099
Lowe WL Jr,Adamo M,Werner H,Roberts CT Jr,LeRoith D,Regulation by fasting of rat insulin-like growth factor I and its receptor. Effects on gene expression and bindingJ Clin InvestYear: 198984261962610.1172/JCI1142072547834
Hall KS,Lien B,Paulsen JE,Clausen OP,Bergan A,Rugstad HE,Effect of preoperative 4’-epidoxorubicin (epi-adriamycin) treatment on the regeneration and function of the liver in partially hepatectomized ratsEuropean surgical research Europaische chirurgische Forschung Recherches chirurgicales europeennesYear: 1989213–41962042806348
Lee WH,Clemens JA,Bondy CA,Insulin-like growth factors in the response to cerebral ischemiaMol Cell NeurosciYear: 199231364310.1016/1044-7431(92)90006-N19912843
Garcia-Estrada J,Garcia-Segura LM,Torres-Aleman I,Expression of insulin-like growth factor I by astrocytes in response to injuryBrain ResYear: 19925921–23433471280521
Yamaguchi F,Itano T,Miyamoto O,Janjua NA,Ohmoto T,Hosokawa K,Hatase O,Increase of extracellular insulin-like growth factor I (IGF-I) concentration following electrolytical lesion in rat hippocampusNeurosci LettYear: 1991128227327610.1016/0304-3940(91)90278-21945047
Yao DL,West NR,Bondy CA,Brenner M,Hudson LD,Zhou J,Collins GH,Webster HD,Cryogenic spinal cord injury induces astrocytic gene expression of insulin-like growth factor I and insulin-like growth factor binding protein 2 during myelin regenerationJ Neurosci ResYear: 199540564765910.1002/jnr.4904005107541476
Komoly S,Hudson LD,Webster HD,Bondy CA,Insulin-like growth factor I gene expression is induced in astrocytes during experimental demyelinationProc Natl Acad Sci U S AYear: 19928951894189810.1073/pnas.89.5.18941371885
Yao DL,Liu X,Hudson LD,Webster HD,Insulin-like growth factor I treatment reduces demyelination and up-regulates gene expression of myelin-related proteins in experimental autoimmune encephalomyelitisProc Natl Acad Sci U S AYear: 199592136190619410.1073/pnas.92.13.61907541143
Liu X,Yao DL,Webster H,Insulin-like growth factor I treatment reduces clinical deficits and lesion severity in acute demyelinating experimental autoimmune encephalomyelitisMult SclerYear: 199511299345463
D’Ercole AJ,Ye P,Calikoglu AS,Gutierrez-Ospina G,The role of the insulin-like growth factors in the central nervous systemMol NeurobiolYear: 199613322725510.1007/BF027406258989772
Behringer RR,Lewin TM,Quaife CJ,Palmiter RD,Brinster RL,D’Ercole AJ,Expression of insulin-like growth factor I stimulates normal somatic growth in growth hormone-deficient transgenic miceEndocrinologyYear: 199012731033104010.1210/endo-127-3-10332387246
Carson MJ,Behringer RR,Brinster RL,McMorris FA,Insulin-like growth factor I increases brain growth and central nervous system myelination in transgenic miceNeuronYear: 199310472974010.1016/0896-6273(93)90173-O8386530
Beck KD,Powell-Braxton L,Widmer HR,Valverde J,Hefti F,Igf1 gene disruption results in reduced brain size, CNS hypomyelination, and loss of hippocampal granule and striatal parvalbumin-containing neuronsNeuronYear: 199514471773010.1016/0896-6273(95)90216-37718235
Ye P,Li L,Richards RG,DiAugustine RP,D’Ercole AJ,Myelination is altered in insulin-like growth factor-I null mutant miceJ NeurosciYear: 200222146041605112122065
Skrtic S,Wallenius V,Ekberg S,Brenzel A,Gressner AM,Jansson JO,Insulin-like growth factors stimulate expression of hepatocyte growth factor but not transforming growth factor beta1 in cultured hepatic stellate cellsEndocrinologyYear: 1997138114683468910.1210/en.138.11.46839348194
Caro JF,Poulos J,Ittoop O,Pories WJ,Flickinger EG,Sinha MK,Insulin-like growth factor I binding in hepatocytes from human liver, human hepatoma, and normal, regenerating, and fetal rat liverJ Clin InvestYear: 198881497698110.1172/JCI1134512832449
Skrtic S,Waññenius V,Ekberg S,Brenzel A,Gressner AJOJ,Wisse E, Knook D, Balabaud CExpression pattern of growth hormone/insulin-like growth factor associated genes in rat liverCells of the hepatic sinusoidYear: 1997The Kupffer Foundation, The Netherlands131133
Brenzel A,Gressner AM,Characterization of insulin-like growth factor (IGF)-I-receptor binding sites during in vitro transformation of rat hepatic stellate cells to myofibroblastsEur J Clin Chem Clin: J Forum Eur Clin Chem SocYear: 1996345401409
Pinzani M,Abboud HE,Aron DC,Secretion of insulin-like growth factor-I and binding proteins by rat liver fat-storing cells: regulatory role of platelet-derived growth factorEndocrinologyYear: 199012752343234910.1210/endo-127-5-23431699746
Gressner AM,Brenzel A,Vossmeyer T,Hepatocyte-conditioned medium potentiates insulin-like growth factor (IGF) 1 and 2 stimulated DNA synthesis of cultured fat storing cellsLiverYear: 199313286948510491
Yakar S,Liu JL,Stannard B,Butler A,Accili D,Sauer B,LeRoith D,Normal growth and development in the absence of hepatic insulin-like growth factor IProc Natl Acad Sci U S AYear: 199996137324732910.1073/pnas.96.13.732410377413
Sjogren K,Bohlooly YM,Olsson B,Coschigano K,Tornell J,Mohan S,Isaksson OG,Baumann G,Kopchick J,Ohlsson C,Disproportional skeletal growth and markedly decreased bone mineral content in growth hormone receptor −/− miceBiochem Biophys Res CommunYear: 2000267260360810.1006/bbrc.1999.198610631109
Shea BT,Hammer RE,Brinster RL,Growth allometry of the organs in giant transgenic miceEndocrinologyYear: 198712161924193010.1210/endo-121-6-19243678132
Quaife CJ,Mathews LS,Pinkert CA,Hammer RE,Brinster RL,Palmiter RD,Histopathology associated with elevated levels of growth hormone and insulin-like growth factor I in transgenic miceEndocrinologyYear: 19891241404810.1210/endo-124-1-402642417
Pennisi PA,Kopchick JJ,Thorgeirsson S,LeRoith D,Yakar S,Role of growth hormone (GH) in liver regenerationEndocrinologyYear: 2004145104748475510.1210/en.2004-065515242989
Desbois-Mouthon C,Wendum D,Cadoret A,Rey C,Leneuve P,Blaise A,Housset C,Tronche F,Le Bouc Y,Holzenberger M,Hepatocyte proliferation during liver regeneration is impaired in mice with liver-specific IGF-1R knockoutFASEB JYear: 200620677377516484330
Fausto N,Laird AD,Webber EM,Liver regeneration. 2. Role of growth factors and cytokines in hepatic regenerationFASEB JYear: 1995915152715368529831
Cressman DE,Greenbaum LE,DeAngelis RA,Ciliberto G,Furth EE,Poli V,Taub R,Liver failure and defective hepatocyte regeneration in interleukin-6-deficient miceScienceYear: 199627452911379138310.1126/science.274.5291.13798910279
Silva JR,Figueiredo JR,van den Hurk R,Involvement of growth hormone (GH) and insulin-like growth factor (IGF) system in ovarian folliculogenesisTheriogenologyYear: 20097181193120810.1016/j.theriogenology.2008.12.01519193432
Adashi EY,The IGF family and folliculogenesisJ Reprod ImmunolYear: 1998391–213199786450
Zhao J,Taverne MA,Van Der Weijden GC,Bevers MM,Van Den Hurk R,Insulin-like growth factor-I (IGF-I) stimulates the development of cultured rat pre-antral folliclesMol Reprod DevYear: 200158328729610.1002/1098-2795(200103)58:3<287::AID-MRD7>3.0.CO;2-G11170270
Zhao J,Taverne MA,van der Weijden GC,Bevers MM,van den Hurk R,Immunohistochemical localisation of growth hormone (GH), GH receptor (GHR), insulin-like growth factor I (IGF-I) and type I IGF-I receptor, and gene expression of GH and GHR in rat pre-antral folliclesZygoteYear: 2002101859411964096
Demeestere I,Gervy C,Centner J,Devreker F,Englert Y,Delbaere A,Effect of insulin-like growth factor-I during preantral follicular culture on steroidogenesis, in vitro oocyte maturation, and embryo development in miceBiol ReprodYear: 20047061664166910.1095/biolreprod.103.02331714960488
Zhou J,Kumar TR,Matzuk MM,Bondy C,Insulin-like growth factor I regulates gonadotropin responsiveness in the murine ovaryMol EndocrinolYear: 199711131924193310.1210/me.11.13.19249415397
Monget P,Fabre S,Mulsant P,Lecerf F,Elsen JM,Mazerbourg S,Pisselet C,Monniaux D,Regulation of ovarian folliculogenesis by IGF and BMP system in domestic animalsDomest Anim EndocrinolYear: 2002231–213915412142233
Giudice LC,Insulin-like growth factors and ovarian follicular developmentEndocr RevYear: 19921346416691281087
Magoffin DA,Weitsman SR,Insulin-like growth factor-I regulation of luteinizing hormone (LH) receptor messenger ribonucleic acid expression and LH-stimulated signal transduction in rat ovarian theca-interstitial cellsBiol ReprodYear: 199451476677510.1095/biolreprod51.4.7667529576
Tsuchiya M,Minegishi T,Kishi H,Tano M,Kameda T,Hirakawa T,Ibuki Y,Mizutani T,Miyamoto K,Control of the expression of luteinizing hormone receptor by local factors in rat granulosa cellsArch Biochem BiophysYear: 1999367218519210.1006/abbi.1999.124110395734
Yu Y,Yan J,Li M,Yan L,Zhao Y,Lian Y,Li R,Liu P,Qiao J,Effects of combined epidermal growth factor, brain-derived neurotrophic factor and insulin-like growth factor-1 on human oocyte maturation and early fertilized and cloned embryo developmentHum ReprodYear: 20122772146215910.1093/humrep/des09922532606
Stanek MB,Borman SM,Molskness TA,Larson JM,Stouffer RL,Patton PE,Insulin and insulin-like growth factor stimulation of vascular endothelial growth factor production by luteinized granulosa cells: comparison between polycystic ovarian syndrome (PCOS) and non-PCOS womenJ Clin Endocrinol MetabYear: 20079272726273310.1210/jc.2006-284617488794
Hall P,Knobil E, Neill JTesticular steroid synthesis: organization and regulationThe physiology of reproductionYear: 1994Raven Press, New York13351362 vol. 1.
Rouiller-Fabre V,Lecref L,Gautier C,Saez JM,Habert R,Expression and effect of insulin-like growth factor I on rat fetal Leydig cell function and differentiationEndocrinologyYear: 199813962926293410.1210/en.139.6.29269607803
Saez J,Lejeune H,Payne A, Hardy M, Russell LRegulation of Leydig cell function by hormones and growth factors other than LH and IGF-IThe leydig cellYear: 1996Cache River Press, Vienna383406 vol. 1.
Vannelli BG,Barni T,Orlando C,Natali A,Serio M,Balboni GC,Insulin-like growth factor-I (IGF-I) and IGF-I receptor in human testis: an immunohistochemical studyFertil SterilYear: 19884946666692965033
Cailleau J,Vermeire S,Verhoeven G,Independent control of the production of insulin-like growth factor I and its binding protein by cultured testicular cellsMol Cell EndocrinolYear: 1990691798910.1016/0303-7207(90)90091-L2157618
Naville D,Chatelain PG,Avallet O,Saez JM,Control of production of insulin-like growth factor I by pig Leydig and Sertoli cells cultured alone or together. Cell-cell interactionsMol Cell EndocrinolYear: 199070321722410.1016/0303-7207(90)90212-Q2113875
Spiteri-Grech J,Bartlett JM,Nieschlag E,Regulation of testicular insulin-like growth factor-I in pubertal growth hormone-deficient male ratsJ EndocrinolYear: 1991131227928510.1677/joe.0.13102791744573
Perrard-Sapori MH,Chatelain PG,Jaillard C,Saez JM,Characterization and regulation of somatomedin-C/insulin-like growth factor I (Sm-C/IGF-I) receptors on cultured pig Leydig cells. Effects of Sm-C/IGF-I on luteotropin receptors and steroidogenesisEur J Biochem / FEBSYear: 1987165120921410.1111/j.1432-1033.1987.tb11213.x
Lin T,Haskell J,Vinson N,Terracio L,Characterization of insulin and insulin-like growth factor I receptors of purified Leydig cells and their role in steroidogenesis in primary culture: a comparative studyEndocrinologyYear: 198611941641164710.1210/endo-119-4-16412944738
Saez JM,Leydig cells: endocrine, paracrine, and autocrine regulationEndocr RevYear: 19941555746267843069
Lin T,Payne A, Hardy M, Russell LInsulin-like growth factor-I regulation of the leydig cellThe leyding cellYear: 1996Cache River Press, Vienna477491 vol. 1.
Baker J,Hardy MP,Zhou J,Bondy C,Lupu F,Bellve AR,Efstratiadis A,Effects of an Igf1 gene null mutation on mouse reproductionMol EndocrinolYear: 199610790391810.1210/me.10.7.9038813730
Gelber SJ,Hardy MP,Mendis-Handagama SM,Casella SJ,Effects of insulin-like growth factor-I on androgen production by highly purified pubertal and adult rat Leydig cellsJ AndrolYear: 19921321251301597396
Adashi EY,Resnick CE,Hurwitz A,Ricciardelli E,Hernandez ER,Roberts CT,LeRoith D,Rosenfeld R,Nieschlag E, Habenicht UFThe ovarian and testicular IGF-I system: a comparative analysisSpermatogenesis-Fertilization-Contraception: Molecular, Cellular and Endocrine Events in Male ReproductionYear: 1992Springer-Verlag, Berlin143168
Giudice LC,Saleh W,Growth factors in reproductionTrends in endocrinology and metabolism: TEMYear: 199562606910.1016/1043-2760(94)00205-I18406685
Nef S,Verma-Kurvari S,Merenmies J,Vassalli JD,Efstratiadis A,Accili D,Parada LF,Testis determination requires insulin receptor family function in miceNatureYear: 2003426696429129510.1038/nature0205914628051
Villalpando I,Lopez-Olmos V,Insulin-like growth factor I (IGF-I) regulates endocrine activity of the embryonic testis in the mouseJ Steroid Biochem Mol BiolYear: 200386215115810.1016/S0960-0760(03)00265-614568566
Tapanainen J,Kuopio T,Pelliniemi LJ,Huhtaniemi I,Rat testicular endogenous steroids and number of leydig cells between the fetal period and sexual maturityBiol ReprodYear: 19843151027103510.1095/biolreprod31.5.10276518225
Lin T,Blaisdell J,Haskell JF,Type I IGF receptors of leydig cells are upregulated by human chorionic gonadotropinBiochem Biophys Res CommunYear: 1987149385285810.1016/0006-291X(87)90486-42962579
Moore A,Morris ID,The involvement of insulin-like growth factor-I in local control of steroidogenesis and DNA synthesis of leydig and non-leydig cells in the rat testicular interstitiumJ EndocrinolYear: 1993138110711410.1677/joe.0.13801077531750
Chuzel F,Clark AM,Avallet O,Saez JM,Transcriptional regulation of the lutropin/human choriogonadotropin receptor and three enzymes of steroidogenesis by growth factors in cultured pig leydig cellsEuropean journal of biochemistry/FEBSYear: 1996239181610.1111/j.1432-1033.1996.0008u.x8706722
Tiong TS,Herington AC,Tissue distribution, characterization, and regulation of messenger ribonucleic acid for growth hormone receptor and serum binding protein in the ratEndocrinologyYear: 199112931628163410.1210/endo-129-3-16281874192
Lobie PE,Breipohl W,Aragon JG,Waters MJ,Cellular localization of the growth hormone receptor/binding protein in the male and female reproductive systemsEndocrinologyYear: 199012642214222110.1210/endo-126-4-22142156686
Godfrey P,Rahal JO,Beamer WG,Copeland NG,Jenkins NA,Mayo KE,GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor functionNat GenetYear: 19934322723210.1038/ng0793-2278395283
Chubb C,Sexual behavior and fertility of little miceBiol ReprodYear: 198737356456910.1095/biolreprod37.3.5643676404
Bach LA,The insulin-like growth factor system in kidney disease and hypertensionCurr Opin Nephrol HypertensYear: 2012211869110.1097/MNH.0b013e32834dc1a222123209
Rabkin R,Schaefer F,New concepts: growth hormone, insulin-like growth factor-I and the kidneyGrowth Horm IGF ResYear: 200414427027610.1016/j.ghir.2004.02.00115231295
Bridgewater DJ,Dionne JM,Butt MJ,Pin CL,Matsell DG,The role of the type I insulin-like growth factor receptor (IGF-IR) in glomerular integrityGrowth Horm IGF ResYear: 2008181263710.1016/j.ghir.2007.06.00317689124
Martin AA,Tomas FM,Owens PC,Knowles SE,Ballard FJ,Read LC,IGF-I and its variant, des-(1–3)IGF-I, enhance growth in rats with reduced renal massAm J PhysiolYear: 19912614 Pt 2F626F6331928375
Hirschberg R,Insulin-like growth factor I in the kidneyMiner Electrolyte MetabYear: 1996221–31281328676803
Kumar PA,Brosius FC III,Menon RK,The glomerular podocyte as a target of growth hormone action: implications for the pathogenesis of diabetic nephropathyCurr Diabetes RevYear: 201171505510.2174/15733991179427390021067510
Yildiz B,Kural N,Colak O,Ak I,Akcar N,IGF-1, IGFBP-3, VEGF and MMP-9 levels and their potential relationship with renal functions in patients with compensatory renal growthClin Physiol Funct ImagingYear: 200828210711210.1111/j.1475-097X.2007.00783.x18093232
Mulroney SE,Haramati A,Werner H,Bondy C,Roberts CT Jr,LeRoith D,Altered expression of insulin-like growth factor-I (IGF-I) and IGF receptor genes after unilateral nephrectomy in immature ratsEndocrinologyYear: 1992130124925610.1210/en.130.1.2491309331
Landau D,Biada J,Chen Y,Sood S,Yakar S,Leroith D,Segev Y,Rabkin R,A marked deficiency in circulating and renal IGF-I peptide does not inhibit compensatory renal enlargement in uninephrectomized miceGrowth Horm IGF ResYear: 201121527928410.1016/j.ghir.2011.07.00821862442
Delafontaine P,Bernstein KE,Alexander RW,Insulin-like growth factor I gene expression in vascular cellsHypertensionYear: 199117569369910.1161/01.HYP.17.5.6931708744
Guler HP,Zapf J,Scheiwiller E,Froesch ER,Recombinant human insulin-like growth factor I stimulates growth and has distinct effects on organ size in hypophysectomized ratsProc Natl Acad Sci U S AYear: 198885134889489310.1073/pnas.85.13.48893387445
Wickman A,Isgaard J,Adams MA,Friberg P,Inhibition of nitric oxide in rats. Regulation of cardiovascular structure and expression of insulin-like growth factor I and its receptor messenger RNAJ HypertensYear: 199715775175910.1097/00004872-199715070-000079222943
Chisalita SI,Johansson GS,Liefvendahl E,Back K,Arnqvist HJ,Human aortic smooth muscle cells are insulin resistant at the receptor level but sensitive to IGF1 and IGF2J Mol EndocrinolYear: 200943623123910.1677/JME-09-002119589910
Johansson GS,Chisalita SI,Arnqvist HJ,Human microvascular endothelial cells are sensitive to IGF-I but resistant to insulin at the receptor levelMol Cell EndocrinolYear: 20082961–2586318708119
Pete G,Hu Y,Walsh M,Sowers J,Dunbar JC,Insulin-like growth factor-I decreases mean blood pressure and selectively increases regional blood flow in normal ratsExp Biol MedYear: 19962132187192
Walsh MF,Barazi M,Pete G,Muniyappa R,Dunbar JC,Sowers JR,Insulin-like growth factor I diminishes in vivo and in vitro vascular contractility: role of vascular nitric oxideEndocrinologyYear: 199613751798180310.1210/en.137.5.17988612517
Copeland KC,Nair KS,Recombinant human insulin-like growth factor-I increases forearm blood flowJ Clin Endocrinol MetabYear: 199479123023210.1210/jc.79.1.2308027233
Delafontaine P,Song YH,Li Y,Expression, regulation, and function of IGF-1, IGF-1R, and IGF-1 binding proteins in blood vesselsArterioscler Thromb Vasc BiolYear: 200424343544410.1161/01.ATV.0000105902.89459.0914604834
Smith TJ,Insulin-like growth factor-I regulation of immune function: a potential therapeutic target in autoimmune diseases?Pharmacol RevYear: 201062219923610.1124/pr.109.00246920392809
O’Connor JC,McCusker RH,Strle K,Johnson RW,Dantzer R,Kelley KW,Regulation of IGF-I function by proinflammatory cytokines: at the interface of immunology and endocrinologyCell ImmunolYear: 20082521–29111018325486
Tsarfaty G,Longo DL,Murphy WJ,Human insulin-like growth factor I exerts hematopoietic growth-promoting effects after in vivo administrationExp HematolYear: 19942213127312777957713
Murphy WJ,Durum SK,Longo DL,Human growth hormone promotes engraftment of murine or human T cells in severe combined immunodeficient miceProc Natl Acad Sci U S AYear: 199289104481448510.1073/pnas.89.10.44811584780
Murphy WJ,Durum SK,Longo DL,Role of neuroendocrine hormones in murine T cell developmentGrowth hormone exerts thymopoietic effects in vivo. Journal of immunologyYear: 19921491238513857
de Mello-Coelho V,Villa-Verde DM,Dardenne M,Savino W,Pituitary hormones modulate cell-cell interactions between thymocytes and thymic epithelial cellsJ NeuroimmunolYear: 1997761–239499184631
Hinton PS,Peterson CA,Dahly EM,Ney DM,IGF-I alters lymphocyte survival and regeneration in thymus and spleen after dexamethasone treatmentAm J PhysiolYear: 19982744 Pt 2R912R9209575951
Walsh PT,Smith LM,O’Connor R,Insulin-like growth factor-1 activates Akt and Jun N-terminal kinases (JNKs) in promoting the survival of T lymphocytesImmunologyYear: 2002107446147110.1046/j.1365-2567.2002.01525.x12460191
Tu W,Cheung PT,Lau YL,Insulin-like growth factor 1 promotes cord blood T cell maturation and inhibits its spontaneous and phytohemagglutinin-induced apoptosis through different mechanismsJ ImmunolYear: 200016531331133610903734
Hunt P,Eardley DD,Suppressive effects of insulin and insulin-like growth factor-1 (IGF1) on immune responsesJ ImmunolYear: 198613611399439993517163
Gibson LF,Piktel D,Landreth KS,Insulin-like growth factor-1 potentiates expansion of interleukin-7-dependent pro-B cellsBloodYear: 19938210300530117693033
Hadden JW,Malec PH,Coto J,Hadden EM,Thymic involution in aging. Prospects for correctionAnn N Y Acad SciYear: 199267323123910.1111/j.1749-6632.1992.tb27458.x1485720
Miller RA,The aging immune system: primer and prospectusScienceYear: 19962735271707410.1126/science.273.5271.708658199
Lamberts SW,van den Beld AW,van der Lely AJ,The endocrinology of agingScienceYear: 1997278533741942410.1126/science.278.5337.4199334293
Chu YW,Schmitz S,Choudhury B,Telford W,Kapoor V,Garfield S,Howe D,Gress RE,Exogenous insulin-like growth factor 1 enhances thymopoiesis predominantly through thymic epithelial cell expansionBloodYear: 200811272836284610.1182/blood-2008-04-14943518658030
Landreth KS,Narayanan R,Dorshkind K,Insulin-like growth factor-I regulates pro-B cell differentiationBloodYear: 1992805120712121515639
Jardieu P,Clark R,Mortensen D,Dorshkind K,In vivo administration of insulin-like growth factor-I stimulates primary B lymphopoiesis and enhances lymphocyte recovery after bone marrow transplantationJ ImmunolYear: 19941529432043278157955
Clark R,The somatogenic hormones and insulin-like growth factor-1: stimulators of lymphopoiesis and immune functionEndocr RevYear: 199718215717910.1210/er.18.2.1579101135
Robbins K,McCabe S,Scheiner T,Strasser J,Clark R,Jardieu P,Immunological effects of insulin-like growth factor-I–enhancement of immunoglobulin synthesisClin Exp ImmunolYear: 19949523373428306510
Rom WN,Paakko P,Activated alveolar macrophages express the insulin-like growth factor-I receptorAm J Respir Cell Mol BiolYear: 1991454324391850606
Resnik R,Intrauterine growth restrictionObstet GynecolYear: 200299349049610.1016/S0029-7844(01)01780-X11864679
Low JA,Handley-Derry MH,Burke SO,Peters RD,Pater EA,Killen HL,Derrick EJ,Association of intrauterine fetal growth retardation and learning deficits at age 9 to 11 yearsAm J Obstet GynecolYear: 19921676149915051471654
Kramer MS,Olivier M,McLean FH,Willis DM,Usher RH,Impact of intrauterine growth retardation and body proportionality on fetal and neonatal outcomePediatricsYear: 19908657077132235224
Hattersley AT,Tooke JE,The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular diseaseLancetYear: 199935391661789179210.1016/S0140-6736(98)07546-110348008
Barker DJ,The developmental origins of well-beingPhilos Trans R Soc Lond B Biol SciYear: 200435914491359136610.1098/rstb.2004.151815347527
Rosenfeld RG,Rosenbloom AL,Guevara-Aguirre J,Growth hormone (GH) insensitivity due to primary GH receptor deficiencyEndocr RevYear: 19941533693908076588
Randhawa R,Cohen P,The role of the insulin-like growth factor system in prenatal growthMol Genet MetabYear: 2005861–2849016165387
Gluckman PD,Hanson MA,Maternal constraint of fetal growth and its consequencesSemin Fetal Neonatal MedYear: 20049541942510.1016/j.siny.2004.03.00115691778
Penrose LS,Data on the genetics of birth weightAnn EugenYear: 195216437838114953134
Setia S,Sridhar MG,Changes in GH/IGF-1 axis in intrauterine growth retardation: consequences of fetal programming?Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolismeYear: 2009411179179810.1055/s-0029-123102619623512
Brosens JJ,Pijnenborg R,Brosens IA,The myometrial junctional zone spiral arteries in normal and abnormal pregnancies: a review of the literatureAm J Obstet GynecolYear: 200218751416142310.1067/mob.2002.12730512439541
Miller HC,Prenatal factors affecting intrauterine growth retardationClin PerinatolYear: 19851223073184017405
Voigt HJ,Becker V,Doppler flow measurements and histomorphology of the placental bed in uteroplacental insufficiencyJ Perinat MedYear: 199220213914710.1515/jpme.1992.20.2.1391501057
Verhaeghe J,Bougoussa M,Van Herck E,de Zegher F,Hennen G,Igout A,Placental growth hormone and IGF-I in a pregnant woman with Pit-1 deficiencyClin EndocrinolYear: 200053564564710.1046/j.1365-2265.2000.01044.x
Reece EA,Wiznitzer A,Le E,Homko CJ,Behrman H,Spencer EM,The relation between human fetal growth and fetal blood levels of insulin-like growth factors I and II, their binding proteins, and receptorsObstet GynecolYear: 199484188957516515
Koutsaki M,Sifakis S,Zaravinos A,Koutroulakis D,Koukoura O,Spandidos DA,Decreased placental expression of hPGH, IGF-I and IGFBP-1 in pregnancies complicated by fetal growth restrictionGrowth Horm IGF ResYear: 2011211313610.1016/j.ghir.2010.12.00221212012
de Zegher F,Francois I,van Helvoirt M,Van den Berghe G,Clinical review 89: Small as fetus and short as child: from endogenous to exogenous growth hormoneJ Clin Endocrinol MetabYear: 19978272021202610.1210/jc.82.7.20219215266
Giudice LC,de Zegher F,Gargosky SE,Dsupin BA,de las Fuentes L,Crystal RA,Hintz RL,Rosenfeld RG,Insulin-like growth factors and their binding proteins in the term and preterm human fetus and neonate with normal and extremes of intrauterine growthJ Clin Endocrinol MetabYear: 19958051548155510.1210/jc.80.5.15487538146
Kajimura S,Aida K,Duan C,Insulin-like growth factor-binding protein-1 (IGFBP-1) mediates hypoxia-induced embryonic growth and developmental retardationProc Natl Acad Sci U S AYear: 200510241240124510.1073/pnas.040744310215644436
Woods KA,van Helvoirt M,Ong KK,Mohn A,Levy J,de Zegher F,Dunger DB,The somatotropic axis in short children born small for gestational age: relation to insulin resistancePediatr ResYear: 2002511768010.1203/00006450-200201000-0001411756643
Jaquet D,Vidal H,Hankard R,Czernichow P,Levy-Marchal C,Impaired regulation of glucose transporter 4 gene expression in insulin resistance associated with in utero undernutritionJ Clin Endocrinol MetabYear: 20018673266327110.1210/jc.86.7.326611443199
Han VK,Carter AM,Control of growth and development of the feto-placental unitCurr Opin PharmacolYear: 20011663264010.1016/S1471-4892(01)00108-411757820
Vehaskari VM,Aviles DH,Manning J,Prenatal programming of adult hypertension in the ratKidney IntYear: 200159123824510.1046/j.1523-1755.2001.00484.x11135076
Laron Z,Pertzelan A,Mannheimer S,Genetic pituitary dwarfism with high serum concentation of growth hormone–a new inborn error of metabolism?Israel J Med SciYear: 1966221521555916640
Laron Z,Laron syndrome (primary growth hormone resistance or insensitivity): the personal experience 1958–2003J Clin Endocrinol MetabYear: 20048931031104410.1210/jc.2003-03103315001582
Laron Z, Parks JSLessons from Laron Syndrome (LS) 1996-1992Pediatr Adolesc EndocrinolYear: 1993Karger, Basel237243
Rosenbloom AL,Growth hormone insensitivity: physiologic and genetic basis, phenotype, and treatmentJ PediatrYear: 1999135328028910.1016/S0022-3476(99)70121-610484790
Feinberg MS,Scheinowitz M,Laron Z,Echocardiographic dimensions and function in adults with primary growth hormone resistance (laron syndrome)Am J CardiolYear: 200085220921310.1016/S0002-9149(99)00642-610955379
Brat O,Ziv I,Klinger B,Avraham M,Laron Z,Muscle force and endurance in untreated and human growth hormone or insulin-like growth factor-I-treated patients with growth hormone deficiency or laron syndromeHorm ResYear: 1997472454810.1159/0001854299030966
Guevara-Aguirre J,Rosenbloom AL,Vaccarello MA,Fielder PJ,de la Vega A,Diamond FB Jr,Rosenfeld RG,Growth hormone receptor deficiency (laron syndrome): clinical and genetic characteristicsActa Paediatr Scand SupplYear: 1991377961031785320
Laron Z,Frick P, Harnack GA, Kochsieck K, Martini GA, Prader ALaron-type dwarfism (hereditary somatomedin deficiency): a reviewAdvances in internal medicine and pediatricsYear: 1984Springer, Berlin117150
Lurie R,Ben-Amitai D,Laron Z,Laron syndrome (primary growth hormone insensitivity): a unique model to explore the effect of insulin-like growth factor 1 deficiency on human hairDermatologyYear: 2004208431431810.1159/00007783915178913
Johnston LB,Woods KA,Rose SJ,Clark AJ,Savage MO,The broad spectrum of inherited growth hormone insensitivity syndromeTrends Endocrin Met: TEMYear: 19989622823210.1016/S1043-2760(98)00062-9
Quiroga J,Beloqui O,Castilla A,Prieto J, Rodes J, Shafritz DACirrhosisHepatobilliary diseasesYear: 1992Springer-Verlag, Berlin323415
Bruguera-Cortada M,Rodes-Teixidor J,Bruguera-Cortada M, Mino-Fugarolas G, Pons-Romero F, Moreno-Otero RCirrosis hepática compensadaTratamiento de las enfermedades hepáticasYear: 1997Asociación Española para el Estudio del Hígado, Spain4550
Gines P,Quintero E,Arroyo V,Teres J,Bruguera M,Rimola A,Caballeria J,Rodes J,Rozman C,Compensated cirrhosis: natural history and prognostic factorsHepatologyYear: 19877112212810.1002/hep.18400701243804191
Sheppard MS,Minuk GY,Bhaumick B,Bala RM,Insulin-like growth factors (IGF) in liver disease: differential changes of IGF-I and IGF-IIClin Invest Med Medecine clinique et experimentaleYear: 19871024953
Caufriez A,Reding P,Urbain D,Golstein J,Copinschi G,Insulin-like growth factor I: a good indicator of functional hepatocellular capacity in alcoholic liver cirrhosisJ Endocrinol InvestYear: 19911443173211865082
Assy N,Hochberg Z,Amit T,Shen-Orr Z,Enat R,Baruch Y,Growth hormone-stimulated insulin-like growth factor (IGF) I and IGF-binding protein-3 in liver cirrhosisJ HepatolYear: 199727579680210.1016/S0168-8278(97)80315-79382965
Caregaro L,Alberino F,Amodio P,Merkel C,Angeli P,Plebani M,Bolognesi M,Gatta A,Nutritional and prognostic significance of insulin-like growth factor 1 in patients with liver cirrhosisNutritionYear: 19971331851909131676
Chang TC,Lin JJ,Yu SC,Chang TJ,Absence of growth-hormone receptor in hepatocellular carcinoma and cirrhotic liverHepatologyYear: 199011112312610.1002/hep.18401101212153093
Inaba T,Saito H,Inoue T,Han I,Furukawa S,Matsuda T,Ikeda S,Muto T,Growth hormone/insulin-like growth factor 1 axis alterations contribute to disturbed protein metabolism in cirrhosis patients after hepatectomyJ HepatolYear: 199931227127610.1016/S0168-8278(99)80224-410453940
Moller S,Becker U,Juul A,Skakkebaek NE,Christensen E,Prognostic value of insulinlike growth factor I and its binding protein in patients with alcohol-induced liver disease. EMALD groupHepatologyYear: 19962351073107810.1002/hep.5102305218621136
Picardi A,de Oliveira AC,Muguerza B,Tosar A,Quiroga J,Castilla-Cortazar I,Santidrian S,Prieto J,Low doses of insulin-like growth factor-I improve nitrogen retention and food efficiency in rats with early cirrhosisJ HepatolYear: 199726119120210.1016/S0168-8278(97)80026-89148011
Pascual M,Castilla-Cortazar I,Urdaneta E,Quiroga J,Garcia M,Picardi A,Prieto J,Altered intestinal transport of amino acids in cirrhotic rats: the effect of insulin-like growth factor-IAm J Physiol Gastrointest Liver PhysiolYear: 20002792G319G32410915640
Castilla-Cortazar I,Prieto J,Urdaneta E,Pascual M,Nunez M,Zudaire E,Garcia M,Quiroga J,Santidrian S,Impaired intestinal sugar transport in cirrhotic rats: correction by low doses of insulin-like growth factor IGastroenterologyYear: 199711341180118710.1053/gast.1997.v113.pm93225139322513
Castilla-Cortazar I,Pascual M,Urdaneta E,Pardo J,Puche JE,Vivas B,Diaz-Casares A,Garcia M,Diaz-Sanchez M,Varela-Nieto I,et al. Jejunal microvilli atrophy and reduced nutrient transport in rats with advanced liver cirrhosis: improvement by insulin-like growth factor IBMC GastroenterolYear: 200441210.1186/1471-230X-4-1215196310
Castilla-Cortazar I,Garcia M,Muguerza B,Quiroga J,Perez R,Santidrian S,Prieto J,Hepatoprotective effects of insulin-like growth factor I in rats with carbon tetrachloride-induced cirrhosisGastroenterologyYear: 199711351682169110.1053/gast.1997.v113.pm93528739352873
Lorenzo-Zuniga V,Rodriguez-Ortigosa CM,Bartoli R,Martinez-Chantar ML,Martinez-Peralta L,Pardo A,Ojanguren I,Quiroga J,Planas R,Prieto J,Insulin-like growth factor I improves intestinal barrier function in cirrhotic ratsGutYear: 20065591306131210.1136/gut.2005.07998816434425
Cemborain A,Castilla-Cortazar I,Garcia M,Quiroga J,Muguerza B,Picardi A,Santidrian S,Prieto J,Osteopenia in rats with liver cirrhosis: beneficial effects of IGF-I treatmentJ HepatolYear: 199828112213110.1016/S0168-8278(98)80211-09537849
Cemborain A,Castilla-Cortazar I,Garcia M,Muguerza B,Delgado G,Diaz-Sanchez M,Picardi A,Effects of IGF-I treatment on osteopenia in rats with advanced liver cirrhosisJ Physiol BiochemYear: 2000562919910.1007/BF0317990411014614
Castilla-Cortazar I,Garcia M,Quiroga J,Diez N,Diez-Caballero F,Calvo A,Diaz M,Prieto J,Insulin-like growth factor-I reverts testicular atrophy in rats with advanced cirrhosisHepatologyYear: 200031359260010.1002/hep.51031030810706548
Castilla-Cortazar I,Diez N,Garcia-Fernandez M,Puche JE,Diez-Caballero F,Quiroga J,Diaz-Sanchez M,Castilla A,Casares AD,Varela-Nieto I,et al. Hematotesticular barrier is altered from early stages of liver cirrhosis: effect of insulin-like growth factor 1World J Gastroentero: WJGYear: 2004101725292534
Castilla-Cortazar I,Aliaga-Montilla MA,Salvador J,Garcia M,Delgado G,Gonzalez-Baron S,Quiroga J,Prieto J,Insulin-like growth factor-I restores the reduced somatostatinergic tone controlling growth hormone secretion in cirrhotic ratsLiverYear: 200121640540910.1034/j.1600-0676.2001.210607.x11903885
Garcia-Fernandez M,Castilla-Cortazar I,Diaz-Sanchez M,Navarro I,Puche JE,Castilla A,Casares AD,Clavijo E,Gonzalez-Baron S,Antioxidant effects of insulin-like growth factor-I (IGF-I) in rats with advanced liver cirrhosisBMC GastroenterolYear: 20055710.1186/1471-230X-5-715745444
Muguerza B,Castilla-Cortazar I,Garcia M,Quiroga J,Santidrian S,Prieto J,Antifibrogenic effect in vivo of low doses of insulin-like growth factor-I in cirrhotic ratsBiochim Biophys ActaYear: 200115362–318519511406353
Perez R,Garcia-Fernandez M,Diaz-Sanchez M,Puche JE,Delgado G,Conchillo M,Muntane J,Castilla-Cortazar I,Mitochondrial protection by low doses of insulin-like growth factor- I in experimental cirrhosisWorld J Gastroentero: WJGYear: 200814172731273910.3748/wjg.14.2731
Tutau F,Rodriguez-Ortigosa C,Puche JE,Juanarena N,Monreal I,Garcia Fernandez M,Clavijo E,Castilla A,Castilla-Cortazar I,Enhanced actions of insulin-like growth factor-I and interferon-alpha co-administration in experimental cirrhosisLiver International: official journal of the International Association for the Study of the LiverYear: 2009291374610.1111/j.1478-3231.2008.01770.x18544128
Mirpuri E,Garcia-Trevijano ER,Castilla-Cortazar I,Berasain C,Quiroga J,Rodriguez-Ortigosa C,Mato JM,Prieto J,Avila MA,Altered liver gene expression in CCl4-cirrhotic rats is partially normalized by insulin-like growth factor-IInt J Biochem Cell BiolYear: 200234324225210.1016/S1357-2725(01)00123-611849991
Futterman LG,Lemberg L,The framingham heart study: a pivotal legacy of the last millenniumAmerican journal of critical care: an official publication, American Association of Critical-Care NursesYear: 200092147151
Fries JF,Aging, natural death, and the compression of morbidityN Eng J MedYear: 1980303313013510.1056/NEJM198007173030304
Bartke A,Chandrashekar V,Dominici F,Turyn D,Kinney B,Steger R,Kopchick JJ,Insulin-like growth factor 1 (IGF-1) and aging: controversies and new insightsBiogerontologyYear: 2003411810.1023/A:102244853224812652183
Weinert BT,Timiras PS,Invited review: theories of agingJ Appl PhysiolYear: 20039541706171612970376
Boveris A,Oshino N,Chance B,The cellular production of hydrogen peroxideBiochem JYear: 197212836176304404507
Giulivi C,Boveris A,Cadenas E,Gilbert D, Colton CReactive oxygen species in biological systems: an interdisciplinary approachYear: 1999Kluwer Academic/Plenum Publishers, New York77102
Van Raamsdonk JM,Meng Y,Camp D,Yang W,Jia X,Benard C,Hekimi S,Decreased energy metabolism extends life span in Caenorhabditis elegans without reducing oxidative damageGeneticsYear: 2010185255957110.1534/genetics.110.11537820382831
Hodge RD,D’Ercole AJ,O’Kusky JR,Insulin-like growth factor-I (IGF-I) inhibits neuronal apoptosis in the developing cerebral cortex in vivoInternational journal of developmental neuroscience: the official journal of the International Society for Developmental NeuroscienceYear: 200725423324110.1016/j.ijdevneu.2007.03.00417459648
Ye P,Xing Y,Dai Z,D’Ercole AJ,In vivo actions of insulin-like growth factor-I (IGF-I) on cerebellum development in transgenic mice: evidence that IGF-I increases proliferation of granule cell progenitorsBrain Res Dev Brain ResYear: 19969514454
Chrysis D,Calikoglu AS,Ye P,D’Ercole AJ,Insulin-like growth factor-I overexpression attenuates cerebellar apoptosis by altering the expression of Bcl family proteins in a developmentally specific mannerJ NeurosciYear: 20012151481148911222638
Moverare-Skrtic S,Svensson J,Karlsson MK,Orwoll E,Ljunggren O,Mellstrom D,Ohlsson C,Serum insulin-like growth factor-I concentration is associated with leukocyte telomere length in a population-based cohort of elderly menJ Clin Endocrinol MetabYear: 200994125078508410.1210/jc.2009-145019846733
Barbieri M,Paolisso G,Kimura M,Gardner JP,Boccardi V,Papa M,Hjelmborg JV,Christensen K,Brimacombe M,Nawrot TS,et al. Higher circulating levels of IGF-1 are associated with longer leukocyte telomere length in healthy subjectsMech Ageing DevYear: 200913011–1277177619913048
Fitzpatrick AL,Kronmal RA,Gardner JP,Psaty BM,Jenny NS,Tracy RP,Walston J,Kimura M,Aviv A,Leukocyte telomere length and cardiovascular disease in the cardiovascular health studyAm J EpidemiolYear: 20071651142117043079
Vasan RS,Demissie S,Kimura M,Cupples LA,Rifai N,White C,Wang TJ,Gardner JP,Cao X,Benjamin EJ,et al. Association of leukocyte telomere length with circulating biomarkers of the renin-angiotensin-aldosterone system: the framingham heart studyCirculationYear: 200811791138114410.1161/CIRCULATIONAHA.107.73179418268147
Blakesley VA,Butler AA,Koval AP,Okubo Y,LeRoith D,Rosenfeld R, Roberts CIGF-1 receptor function: transducing the igf-1 signal into intracellular eventsThe IGF systemYear: 1999Humana Press, New Jersey143164
White MF,The IRS-signalling system: a network of docking proteins that mediate insulin actionMol Cell BiochemYear: 19981821–23119609109
Skolnik EY,Batzer A,Li N,Lee CH,Lowenstein E,Mohammadi M,Margolis B,Schlessinger J,The function of GRB2 in linking the insulin receptor to Ras signaling pathwaysScienceYear: 199326051161953195510.1126/science.83168358316835
Cheatham B,Vlahos CJ,Cheatham L,Wang L,Blenis J,Kahn CR,Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp 70 S6 kinase, DNA synthesis, and glucose transporter translocationMol Cell BiolYear: 1994147490249118007986
Kohn AD,Summers SA,Birnbaum MJ,Roth RA,Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocationJ Biol ChemYear: 199627149313723137810.1074/jbc.271.49.313728940145
Zhang X,Gan L,Pan H,Guo S,He X,Olson ST,Mesecar A,Adam S,Unterman TG,Phosphorylation of serine 256 suppresses transactivation by FKHR (FOXO1) by multiple mechanisms. Direct and indirect effects on nuclear/cytoplasmic shuttling and DNA bindingJ Biol ChemYear: 200227747452764528410.1074/jbc.M20806320012228231
Van Der Heide LP,Hoekman MF,Smidt MP,The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulationBiochem JYear: 2004380Pt 229730915005655
Hribal ML,Nakae J,Kitamura T,Shutter JR,Accili D,Regulation of insulin-like growth factor-dependent myoblast differentiation by Foxo forkhead transcription factorsJ Cell BiolYear: 2003162453554110.1083/jcb.20021210712925703
Gilley J,Coffer PJ,Ham J,FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neuronsJ Cell BiolYear: 2003162461362210.1083/jcb.20030302612913110
Martinez-Gac L,Marques M,Garcia Z,Campanero MR,Carrera AC,Control of cyclin G2 mRNA expression by forkhead transcription factors: novel mechanism for cell cycle control by phosphoinositide 3-kinase and forkheadMol Cell BiolYear: 20042452181218910.1128/MCB.24.5.2181-2189.200414966295
Tran H,Brunet A,Grenier JM,Datta SR,Fornace AJ Jr,DiStefano PS,Chiang LW,Greenberg ME,DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 proteinScienceYear: 2002296556753053410.1126/science.106871211964479
Brunet A,Sweeney LB,Sturgill JF,Chua KF,Greer PL,Lin Y,Tran H,Ross SE,Mostoslavsky R,Cohen HY,et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylaseScienceYear: 200430356662011201510.1126/science.109463714976264
Facchini FS,Hua N,Abbasi F,Reaven GM,Insulin resistance as a predictor of age-related diseasesJ Clin Endocrinol MetabYear: 20018683574357810.1210/jc.86.8.357411502781
DeFronzo RA,Ferrannini E,Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular diseaseDiabetes CareYear: 199114317319410.2337/diacare.14.3.1732044434
Reaven GM,Banting lecture 1988. Role of insulin resistance in human diseaseDiabetesYear: 198837121595160710.2337/diabetes.37.12.15953056758
Umegaki H,Neurodegeneration in diabetes mellitusAdv Exp Med BiolYear: 201272425826510.1007/978-1-4614-0653-2_1922411248
Bosco D,Plastino M,Cristiano D,Colica C,Ermio C,De Bartolo M,Mungari P,Fonte G,Consoli D,Consoli A,et al. Dementia is associated with insulin resistance in patients with Parkinson’s diseaseJ Neurol SciYear: 20123151–2394322265943
Longo VD,Linking sirtuins, IGF-I signaling, and starvationExp GerontolYear: 2009441–2707418638538
Rincon M,Muzumdar R,Atzmon G,Barzilai N,The paradox of the insulin/IGF-1 signaling pathway in longevityMech Ageing DevYear: 2004125639740315272501
Barzilai N,Huffman DM,Muzumdar RH,Bartke A,The critical role of metabolic pathways in agingDiabetesYear: 20126161315132210.2337/db11-130022618766
Tang BL,SIRT1, neuronal cell survival and the insulin/IGF-1 aging paradoxNeurobiol AgingYear: 200627350150510.1016/j.neurobiolaging.2005.02.00116464659
Ungvari Z,Csiszar A,The emerging role of IGF-1 deficiency in cardiovascular aging: recent advancesThe journals of gerontology Series A, Biological sciences and medical sciencesYear: 2012676599610
Rosen T,Bengtsson BA,Premature mortality due to cardiovascular disease in hypopituitarismLancetYear: 1990336871028528810.1016/0140-6736(90)91812-O1973979
Laughlin GA,Barrett-Connor E,Criqui MH,Kritz-Silverstein D,The prospective association of serum insulin-like growth factor I (IGF-I) and IGF-binding protein-1 levels with all cause and cardiovascular disease mortality in older adults: the Rancho Bernardo StudyJ Clin Endocrinol MetabYear: 200489111412010.1210/jc.2003-03096714715837
Conti E,Carrozza C,Capoluongo E,Volpe M,Crea F,Zuppi C,Andreotti F,Insulin-like growth factor-1 as a vascular protective factorCirculationYear: 2004110152260226510.1161/01.CIR.0000144309.87183.FB15477425
Sesti G,Sciacqua A,Cardellini M,Marini MA,Maio R,Vatrano M,Succurro E,Lauro R,Federici M,Perticone F,Plasma concentration of IGF-I is independently associated with insulin sensitivity in subjects with different degrees of glucose toleranceDiabetes CareYear: 200528112012510.2337/diacare.28.1.12015616244
Spallarossa P,Brunelli C,Minuto F,Caruso D,Battistini M,Caponnetto S,Cordera R,Insulin-like growth factor-I and angiographically documented coronary artery diseaseAm J CardiolYear: 199677220020210.1016/S0002-9149(96)90600-18546095
Johnsen SP,Hundborg HH,Sorensen HT,Orskov H,Tjonneland A,Overvad K,Jorgensen JO,Insulin-like growth factor (IGF) I, -II, and IGF binding protein-3 and risk of ischemic strokeJ Clin Endocrinol MetabYear: 200590115937594110.1210/jc.2004-208816131586
Vasan RS,Sullivan LM,D’Agostino RB,Roubenoff R,Harris T,Sawyer DB,Levy D,Wilson PW,Serum insulin-like growth factor I and risk for heart failure in elderly individuals without a previous myocardial infarction: the Framingham Heart StudyAnn Intern MedYear: 2003139864264814568852
Conti E,Andreotti F,Sciahbasi A,Riccardi P,Marra G,Menini E,Ghirlanda G,Maseri A,Markedly reduced insulin-like growth factor-1 in the acute phase of myocardial infarctionJ Am Coll CardiolYear: 2001381263210.1016/S0735-1097(01)01367-511451284
Galderisi M,Caso P,Cicala S,De Simone L,Barbieri M,Vitale G,de Divitiis O,Paolisso G,Positive association between circulating free insulin-like growth factor-1 levels and coronary flow reserve in arterial systemic hypertensionAm J HypertensYear: 200215976677210.1016/S0895-7061(02)02967-912219870
Paolisso G,Ammendola S,Del Buono A,Gambardella A,Riondino M,Tagliamonte MR,Rizzo MR,Carella C,Varricchio M,Serum levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 in healthy centenarians: relationship with plasma leptin and lipid concentrations, insulin action, and cognitive functionJ Clin Endocrinol MetabYear: 19978272204220910.1210/jc.82.7.22049215295
Bailey-Downs LC,Mitschelen M,Sosnowska D,Toth P,Pinto JT,Ballabh P,Valcarcel-Ares MN,Farley J,Koller A,Henthorn JC,et al. Liver-specific knockdown of IGF-1 decreases vascular oxidative stress resistance by impairing the Nrf2-dependent antioxidant response: a novel model of vascular agingThe journals of gerontology Series A, Biological sciences and medical sciencesYear: 2012674313329
Li Q,Ceylan-Isik AF,Li J,Ren J,Deficiency of insulin-like growth factor 1 reduces sensitivity to aging-associated cardiomyocyte dysfunctionRejuvenation ResYear: 200811472573310.1089/rej.2008.071718729805
Li Q,Wu S,Li SY,Lopez FL,Du M,Kajstura J,Anversa P,Ren J,Cardiac-specific overexpression of insulin-like growth factor 1 attenuates aging-associated cardiac diastolic contractile dysfunction and protein damageAm J Physiol Heart Circ PhysiolYear: 20072923H1398H140317085535
Li Q,Ren J,Influence of cardiac-specific overexpression of insulin-like growth factor 1 on lifespan and aging-associated changes in cardiac intracellular Ca2+ homeostasis, protein damage and apoptotic protein expressionAging CellYear: 20076679980610.1111/j.1474-9726.2007.00343.x17973971
Vinciguerra M,Santini MP,Claycomb WC,Ladurner AG,Rosenthal N,Local IGF-1 isoform protects cardiomyocytes from hypertrophic and oxidative stresses via SirT1 activityAgingYear: 201021436220228935
Ungvari Z,Gautam T,Koncz P,Henthorn JC,Pinto JT,Ballabh P,Yan H,Mitschelen M,Farley J,Sonntag WE,et al. Vasoprotective effects of life span-extending peripubertal GH replacement in Lewis dwarf ratsThe journals of gerontology Series A, Biological sciences and medical sciencesYear: 2010651111451156
Urbanek K,Rota M,Cascapera S,Bearzi C,Nascimbene A,De Angelis A,Hosoda T,Chimenti S,Baker M,Limana F,et al. Cardiac stem cells possess growth factor-receptor systems that after activation regenerate the infarcted myocardium, improving ventricular function and long-term survivalCirc ResYear: 200597766367310.1161/01.RES.0000183733.53101.1116141414
Torella D,Rota M,Nurzynska D,Musso E,Monsen A,Shiraishi I,Zias E,Walsh K,Rosenzweig A,Sussman MA,et al. Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpressionCirc ResYear: 200494451452410.1161/01.RES.0000117306.10142.5014726476
Ungvari Z,Kaley G,de Cabo R,Sonntag WE,Csiszar A,Mechanisms of vascular aging: new perspectivesThe journals of gerontology Series A, Biological sciences and medical sciencesYear: 2010651010281041
Li Y,Wu H,Khardori R,Song YH,Lu YW,Geng YJ,Insulin-like growth factor-1 receptor activation prevents high glucose-induced mitochondrial dysfunction, cytochrome-c release and apoptosisBiochem Biophys Res CommunYear: 2009384225926410.1016/j.bbrc.2009.04.11319406106
Rivard A,Fabre JE,Silver M,Chen D,Murohara T,Kearney M,Magner M,Asahara T,Isner JM,Age-dependent impairment of angiogenesisCirculationYear: 199999111112010.1161/01.CIR.99.1.1119884387
Thum T,Hoeber S,Froese S,Klink I,Stichtenoth DO,Galuppo P,Jakob M,Tsikas D,Anker SD,Poole-Wilson PA,et al. Age-dependent impairment of endothelial progenitor cells is corrected by growth-hormone-mediated increase of insulin-like growth-factor-1Circ ResYear: 2007100343444310.1161/01.RES.0000257912.78915.af17234973
Csiszar A,Ungvari Z,Edwards JG,Kaminski P,Wolin MS,Koller A,Kaley G,Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar functionCirc ResYear: 200290111159116610.1161/01.RES.0000020401.61826.EA12065318
Csiszar A,Labinskyy N,Perez V,Recchia FA,Podlutsky A,Mukhopadhyay P,Losonczy G,Pacher P,Austad SN,Bartke A,et al. Endothelial function and vascular oxidative stress in long-lived GH/IGF-deficient Ames dwarf miceAm J Physiol Heart Circ PhysiolYear: 20082955H1882H189410.1152/ajpheart.412.200818757483
Cittadini A,Monti MG,Castiello MC,D’Arco E,Galasso G,Sorriento D,Saldamarco L,De Paulis A,Napoli R,Iaccarino G,et al. Insulin-like growth factor-1 protects from vascular stenosis and accelerates re-endothelialization in a rat model of carotid artery injuryJ Thromb Haemost: JTHYear: 20097111920192810.1111/j.1538-7836.2009.03607.x
Clemmons DR,Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancerNat Rev Drug DiscovYear: 200761082183310.1038/nrd235917906644
Higashi Y,Sukhanov S,Anwar A,Shai SY,Delafontaine P,IGF-1, oxidative stress and atheroprotectionTrends Endocrin Met: TEMYear: 201021424525410.1016/j.tem.2009.12.005
Ross R,Atherosclerosis–an inflammatory diseaseN Eng J MedYear: 1999340211512610.1056/NEJM199901143400207
Jeschke MG,Barrow RE,Herndon DN,Insulinlike growth factor I plus insulinlike growth factor binding protein 3 attenuates the proinflammatory acute phase response in severely burned childrenAnn SurgYear: 2000231224625210.1097/00000658-200002000-0001410674617
National Cholesterol Education Program Expert Panel on Detection E, Treatment of High Blood Cholesterol in AThird report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final reportCirculationYear: 2002106253143342112485966
Akanji AO,Smith RJ,The insulin-like growth factor system, metabolic syndrome, and cardiovascular disease riskMetab Syndr Relat DisordYear: 201210131310.1089/met.2011.008322103319
Bideci A,Camurdan MO,Cinaz P,Dursun H,Demirel F,Serum zinc, insulin-like growth factor-I and insulin-like growth factor binding protein-3 levels in children with type 1 diabetes mellitusJ Pediatr Endocrinol MetabYear: 200518101007101116355814
Simpson HL,Jackson NC,Shojaee-Moradie F,Jones RH,Russell-Jones DL,Sonksen PH,Dunger DB,Umpleby AM,Insulin-like growth factor I has a direct effect on glucose and protein metabolism, but no effect on lipid metabolism in type 1 diabetesJ Clin Endocrinol MetabYear: 200489142543210.1210/jc.2003-03127414715881
Saukkonen T,Shojaee-Moradie F,Williams RM,Amin R,Yuen KC,Watts A,Acerini CL,Umpleby AM,Dunger DB,Effects of recombinant human IGF-I/IGF-binding protein-3 complex on glucose and glycerol metabolism in type 1 diabetesDiabetesYear: 20065582365237010.2337/db05-164616873702
Clemmons DR,Moses AC,McKay MJ,Sommer A,Rosen DM,Ruckle J,The combination of insulin-like growth factor I and insulin-like growth factor-binding protein-3 reduces insulin requirements in insulin-dependent type 1 diabetes: evidence for in vivo biological activityJ Clin Endocrinol MetabYear: 20008541518152410.1210/jc.85.4.151810770191
Kolaczynski JW,Caro JF,Insulin-like growth factor-1 therapy in diabetes: physiologic basis, clinical benefits, and risksAnn Intern MedYear: 1994120147558250456
Paolisso G,Tagliamonte MR,Rizzo MR,Giugliano D,Advancing age and insulin resistance: new facts about an ancient historyEur J Clin InvestYear: 199929975876910.1046/j.1365-2362.1999.00522.x10469164
Schini-Kerth VB,Dual effects of insulin-like growth factor-I on the constitutive and inducible nitric oxide (NO) synthase-dependent formation of NO in vascular cellsJ Endocrinol InvestYear: 1999225 Suppl828810442576
Gomez JM,Maravall FJ,Gomez N,Navarro MA,Casamitjana R,Soler J,Interactions between serum leptin, the insulin-like growth factor-I system, and sex, age, anthropometric and body composition variables in a healthy population randomly selectedClin EndocrinolYear: 200358221321910.1046/j.1365-2265.2003.01698.x
Conti E,Andreotti F,Sestito A,Riccardi P,Menini E,Crea F,Maseri A,Lanza GA,Reduced levels of insulin-like growth factor-1 in patients with angina pectoris, positive exercise stress test, and angiographically normal epicardial coronary arteriesAm J CardiolYear: 200289897397510.1016/S0002-9149(02)02250-611950439
Rasmussen MH,Hvidberg A,Juul A,Main KM,Gotfredsen A,Skakkebaek NE,Hilsted J,Skakkebae NE,Massive weight loss restores 24-hour growth hormone release profiles and serum insulin-like growth factor-I levels in obese subjectsJ Clin Endocrinol MetabYear: 19958041407141510.1210/jc.80.4.14077536210
Twickler MT,Cramer MJ,Koppeschaar HP,Unraveling Reaven’s syndrome X: serum insulin-like growth factor-I and cardiovascular diseaseCirculationYear: 200310720e190e192 author reply e190-192. 12777323
Scheidegger KJ,James RW,Delafontaine P,Differential effects of low density lipoproteins on insulin-like growth factor-1 (IGF-1) and IGF-1 receptor expression in vascular smooth muscle cellsJ Biol ChemYear: 200027535268642686910862615
Malik J,Stulc T,Wichterle D,Melenovsky V,Chytilova E,Lacinova Z,Marek J,Ceska R,Hyperlipidemia is associated with altered levels of insulin-like growth factor-IPhysiological research / Academia Scientiarum BohemoslovacaYear: 200857691992518052685
Sandhu MS,Heald AH,Gibson JM,Cruickshank JK,Dunger DB,Wareham NJ,Circulating concentrations of insulin-like growth factor-I and development of glucose intolerance: a prospective observational studyLancetYear: 200235993191740174510.1016/S0140-6736(02)08655-512049864
Efstratiadis G,Tsiaousis G,Athyros VG,Karagianni D,Pavlitou-Tsiontsi A,Giannakou-Darda A,Manes C,Total serum insulin-like growth factor-1 and C-reactive protein in metabolic syndrome with or without diabetesAngiologyYear: 200657330331110.1177/00033197060570030616703190
Teramukai S,Rohan T,Eguchi H,Oda T,Shinchi K,Kono S,Anthropometric and behavioral correlates of insulin-like growth factor I and insulin-like growth factor binding protein 3 in middle-aged Japanese menAm J EpidemiolYear: 2002156434434810.1093/aje/kwf06912181104
Trejo JL,Carro E,Nunez A,Torres-Aleman I,Sedentary life impairs self-reparative processes in the brain: the role of serum insulin-like growth factor-IRev NeurosciYear: 200213436537412542262
Unden AL,Elofsson S,Knox S,Lewitt MS,Brismar K,IGF-I in a normal population: relation to psychosocial factorsClin EndocrinolYear: 200257679380310.1046/j.1365-2265.2002.01671.x
Dandona P,Aljada A,Dhindsa S,Garg R,Insulin as an anti-inflammatory and antiatherosclerotic hormoneClin CornerstoneYear: 2003Suppl 4S13S20 PMID:14986904. 14986904
Gillespie CM,Merkel AL,Martin AA,Effects of insulin-like growth factor-I and LR3IGF-I on regional blood flow in normal ratsJ EndocrinolYear: 1997155235135810.1677/joe.0.15503519415069
Izhar U,Hasdai D,Richardson DM,Cohen P,Lerman A,Insulin and insulin-like growth factor-I cause vasorelaxation in human vessels in vitroCoron Artery DisYear: 2000111697610.1097/00019501-200002000-0001210715809
Utriainen T,Nuutila P,Takala T,Vicini P,Ruotsalainen U,Ronnemaa T,Tolvanen T,Raitakari M,Haaparanta M,Kirvela O,et al. Intact insulin stimulation of skeletal muscle blood flow, its heterogeneity and redistribution, but not of glucose uptake in non-insulin-dependent diabetes mellitusJ Clin InvestYear: 1997100477778510.1172/JCI1195919259575
Gasperi M,Castellano AE,Growth hormone/insulin-like growth factor I axis in neurodegenerative diseasesJ Endocrinol InvestYear: 201033858759120930497
Torres-Aleman I,Targeting insulin-like growth factor-1 to treat Alzheimer’s diseaseExpert Opin Ther TargetsYear: 200711121535154210.1517/14728222.11.12.153518020976
Carro E,Trejo JL,Gerber A,Loetscher H,Torrado J,Metzger F,Torres-Aleman I,Therapeutic actions of insulin-like growth factor I on APP/PS2 mice with severe brain amyloidosisNeurobiol AgingYear: 20062791250125710.1016/j.neurobiolaging.2005.06.01516183170
Cheng CM,Tseng V,Wang J,Wang D,Matyakhina L,Bondy CA,Tau is hyperphosphorylated in the insulin-like growth factor-I null brainEndocrinologyYear: 2005146125086509110.1210/en.2005-006316123158
Akiyama H,Barger S,Barnum S,Bradt B,Bauer J,Cole GM,Cooper NR,Eikelenboom P,Emmerling M,Fiebich BL,et al. Inflammation and alzheimer’s diseaseNeurobiol AgingYear: 200021338342110.1016/S0197-4580(00)00124-X10858586
Miranda S,Opazo C,Larrondo LF,Munoz FJ,Ruiz F,Leighton F,Inestrosa NC,The role of oxidative stress in the toxicity induced by amyloid beta-peptide in alzheimer’s diseaseProg NeurobiolYear: 200062663364810.1016/S0301-0082(00)00015-010880853
Corbo M,Lunetta C,Magni P,Dozio E,Ruscica M,Adobbati L,Silani V,Free insulin-like growth factor (IGF)-1 and IGF-binding proteins-2 and −3 in serum and cerebrospinal fluid of amyotrophic lateral sclerosis patientsEur J Neurol: the official journal of the European Federation of Neurological SocietiesYear: 201017339840410.1111/j.1468-1331.2009.02815.x
Lunetta C,Serafini M,Prelle A,Magni P,Dozio E,Ruscica M,Sassone J,Colciago C,Moggio M,Corbo M,et al. Impaired expression of insulin-like growth factor-1 system in skeletal muscle of amyotrophic lateral sclerosis patientsMuscle NerveYear: 201245220020810.1002/mus.2228822246875
Kerkhoff H,Hassan SM,Troost D,Van Etten RW,Veldman H,Jennekens FG,Insulin-like and fibroblast growth factors in spinal cords, nerve roots and skeletal muscle of human controls and patients with amyotrophic lateral sclerosisActa NeuropatholYear: 199487441142110.1007/BF003136118017177
Ozdinler PH,Macklis JD,IGF-I specifically enhances axon outgrowth of corticospinal motor neuronsNat NeurosciYear: 20069111371138110.1038/nn178917057708
Xiao Q,Zhao W,Beers DR,Yen AA,Xie W,Henkel JS,Appel SH,Mutant SOD1(G93A) microglia are more neurotoxic relative to wild-type microgliaJ NeurochemYear: 200710262008201910.1111/j.1471-4159.2007.04677.x17555556
Borasio GD,Robberecht W,Leigh PN,Emile J,Guiloff RJ,Jerusalem F,Silani V,Vos PE,Wokke JH,Dobbins T,A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. European ALS/IGF-I study groupNeurologyYear: 199851258358610.1212/WNL.51.2.5839710040
Lai EC,Felice KJ,Festoff BW,Gawel MJ,Gelinas DF,Kratz R,Murphy MF,Natter HM,Norris FH,Rudnicki SA,Effect of recombinant human insulin-like growth factor-I on progression of ALS. A placebo-controlled study. The north america ALS/IGF-I study groupNeurologyYear: 19974961621163010.1212/WNL.49.6.16219409357
Donnan GA,Fisher M,Macleod M,Davis SM,StrokeLancetYear: 200837196241612162310.1016/S0140-6736(08)60694-718468545
Murray CJ,Lopez AD,Mortality by cause for eight regions of the world: global burden of disease studyLancetYear: 199734990611269127610.1016/S0140-6736(96)07493-49142060
De Smedt A,Brouns R,Uyttenboogaart M,De Raedt S,Moens M,Wilczak N,Luijckx GJ,De Keyser J,Insulin-like growth factor I serum levels influence ischemic stroke outcomeStroke; a journal of cerebral circulationYear: 20114282180218510.1161/STROKEAHA.110.600783
Bulow B,Hagmar L,Mikoczy Z,Nordstrom CH,Erfurth EM,Increased cerebrovascular mortality in patients with hypopituitarismClin EndocrinolYear: 1997461758110.1046/j.1365-2265.1997.d01-1749.x
Sonntag WE,Lynch CD,Cooney PT,Hutchins PM,Decreases in cerebral microvasculature with age are associated with the decline in growth hormone and insulin-like growth factor 1EndocrinologyYear: 199713883515352010.1210/en.138.8.35159231806
Sonntag WE,Lynch C,Thornton P,Khan A,Bennett S,Ingram R,The effects of growth hormone and IGF-1 deficiency on cerebrovascular and brain ageingJ AnatYear: 2000197Pt 457558511197531
Lopez-Lopez C,LeRoith D,Torres-Aleman I,Insulin-like growth factor I is required for vessel remodeling in the adult brainProc Natl Acad Sci U S AYear: 2004101269833983810.1073/pnas.040033710115210967
Gonzalez C,Diaz F,Alonso A,Neuroprotective effects of estrogens: cross-talk between estrogen and intracellular insulin signallingInfect Disord Drug TargetsYear: 200881656718473910
Garcia-Segura LM,Arevalo MA,Azcoitia I,Interactions of estradiol and insulin-like growth factor-I signalling in the nervous system: new advancesProg Brain ResYear: 201018125127220478442
Fernandez AM,Torres-Aleman I,The many faces of insulin-like peptide signalling in the brainNat Rev NeurosciYear: 201213422523910.1038/nrn320922430016
Ozdemir D,Baykara B,Aksu I,Kiray M,Sisman AR,Cetin F,Dayi A,Gurpinar T,Uysal N,Arda MN,Relationship between circulating IGF-1 levels and traumatic brain injury-induced hippocampal damage and cognitive dysfunction in immature ratsNeurosci LettYear: 20125071848910.1016/j.neulet.2011.11.05922172933
Muller AP,Fernandez AM,Haas C,Zimmer E,Portela LV,Torres-Aleman I,Reduced brain insulin-like growth factor I function during agingMol Cell NeurosciYear: 201249191210.1016/j.mcn.2011.07.00821807098
Gong X,Ma M,Fan X,Li M,Liu Q,Liu X,Xu G,Down-regulation of IGF-1/IGF-1R in hippocampus of rats with vascular dementiaNeurosci LettYear: 20125131202410.1016/j.neulet.2012.01.07722342912
Zhao J,Harada N,Kurihara H,Nakagata N,Okajima K,Cilostazol improves cognitive function in mice by increasing the production of insulin-like growth factor-I in the hippocampusNeuropharmacologyYear: 2010584–577478320035772
Carmeli E,Coleman R,Reznick AZ,The biochemistry of aging muscleExp GerontolYear: 200237447748910.1016/S0531-5565(01)00220-011830351
Le Roith D,Bondy C,Yakar S,Liu JL,Butler A,The somatomedin hypothesis: 2001Endocr RevYear: 2001221537410.1210/er.22.1.5311159816
Florini JR,Ewton DZ,Coolican SA,Growth hormone and the insulin-like growth factor system in myogenesisEndocr RevYear: 19961754815178897022
Dennis RA,Przybyla B,Gurley C,Kortebein PM,Simpson P,Sullivan DH,Peterson CA,Aging alters gene expression of growth and remodeling factors in human skeletal muscle both at rest and in response to acute resistance exercisePhysiol GenomicsYear: 200832339340018073271
Li M,Li C,Parkhouse WS,Age-related differences in the des IGF-I-mediated activation of Akt-1 and p70 S6K in mouse skeletal muscleMech Ageing DevYear: 2003124777177810.1016/S0047-6374(03)00124-612875741
Berryman DE,Christiansen JS,Johannsson G,Thorner MO,Kopchick JJ,Role of the GH/IGF-1 axis in lifespan and healthspan: lessons from animal modelsGrowth Horm IGF ResYear: 200818645547110.1016/j.ghir.2008.05.00518710818
Bex M,Bouillon R,Growth hormone and bone healthHorm ResYear: 200360Suppl 3808614671403
Giustina A,Mazziotti G,Canalis E,Growth hormone, insulin-like growth factors, and the skeletonEndocr RevYear: 200829553555910.1210/er.2007-003618436706
Sell C,Ptasznik A,Chang CD,Swantek J,Cristofalo VJ,Baserga R,IGF-1 receptor levels and the proliferation of young and senescent human fibroblastsBiochem Biophys Res CommunYear: 1993194125926510.1006/bbrc.1993.18137687431
Pfeilschifter J,Diel I,Pilz U,Brunotte K,Naumann A,Ziegler R,Mitogenic responsiveness of human bone cells in vitro to hormones and growth factors decreases with ageJ Bone Miner Res: the official journal of the American Society for Bone and Mineral ResearchYear: 199386707717
Hirschberg R,Adler S,Insulin-like growth factor system and the kidney: physiology, pathophysiology, and therapeutic implicationsAm J Kidney Dis: the official journal of the National Kidney FoundationYear: 199831690191910.1053/ajkd.1998.v31.pm9631833
Rogers SA,Powell-Braxton L,Hammerman MR,Insulin-like growth factor I regulates renal development in rodentsDev GenetYear: 1999243–429329810322637
Bridgewater DJ,Ho J,Sauro V,Matsell DG,Insulin-like growth factors inhibit podocyte apoptosis through the PI3 kinase pathwayKidney IntYear: 20056741308131410.1111/j.1523-1755.2005.00208.x15780083
Flyvbjerg A,Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney diseaseDiabetologiaYear: 200043101205122310.1007/s00125005151511079738
Wang SN,LaPage J,Hirschberg R,Role of glomerular ultrafiltration of growth factors in progressive interstitial fibrosis in diabetic nephropathyKidney IntYear: 20005731002101410.1046/j.1523-1755.2000.00928.x10720953
Kang BP,Urbonas A,Baddoo A,Baskin S,Malhotra A,Meggs LG,IGF-1 inhibits the mitochondrial apoptosis program in mesangial cells exposed to high glucoseAm J Physiol Renal PhysiolYear: 20032855F1013F102412876069
Skjaerbaek C,Frystyk J,Orskov H,Kissmeyer-Nielsen P,Jensen MB,Laurberg S,Moller N,Flyvbjerg A,Differential changes in free and total insulin-like growth factor I after major, elective abdominal surgery: the possible role of insulin-like growth factor-binding protein-3 proteolysisJ Clin Endocrinol MetabYear: 19988372445244910.1210/jc.83.7.24459661626
Lang CH,Fan J,Frost RA,Gelato MC,Sakurai Y,Herndon DN,Wolfe RR,Regulation of the insulin-like growth factor system by insulin in burn patientsJ Clin Endocrinol MetabYear: 19968172474248010.1210/jc.81.7.24748675563
Sermet-Gaudelus I,Souberbielle JC,Azhar I,Ruiz JC,Magnine P,Colomb V,Le Bihan C,Folio D,Lenoir G,Insulin-like growth factor I correlates with lean body mass in cystic fibrosis patientsArch Dis ChildYear: 2003881195696110.1136/adc.88.11.95614612353
Congote LF,Monitoring insulin-like growth factors in HIV infection and AIDSClin Chim ActaYear: 20053611–2305315970280
Clemmons DR,Clinical utility of measurements of insulin-like growth factor 1Nat Clin Pract Endocrinol MetabYear: 20062843644610.1038/ncpendmet024416932333
Bondy CA,Underwood LE,Clemmons DR,Guler HP,Bach MA,Skarulis M,Clinical uses of insulin-like growth factor IAnn Intern MedYear: 199412075936018116999
Ketelslegers JM,Maiter D,Maes M,Underwood LE,Thissen JP,Nutritional regulation of insulin-like growth factor-IMetab Clin ExpYear: 19954410 Suppl 450577476312
Pascal N,Amouzou EK,Sanni A,Namour F,Abdelmouttaleb I,Vidailhet M,Gueant JL,Serum concentrations of sex hormone binding globulin are elevated in kwashiorkor and anorexia nervosa but not in marasmusAm J Clin NutrYear: 200276123924412081841
Hwa V,Haeusler G,Pratt KL,Little BM,Frisch H,Koller D,Rosenfeld RG,Total absence of functional acid labile subunit, resulting in severe insulin-like growth factor deficiency and moderate growth failureJ Clin Endocrinol MetabYear: 20069151826183110.1210/jc.2005-284216507628
Chernausek SD,Backeljauw PF,Frane J,Kuntze J,Underwood LE,Group GHISC,Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivityJ Clin Endocrinol MetabYear: 200792390291017192294
Backeljauw PF,Underwood LE,Prolonged treatment with recombinant insulin-like growth factor-I in children with growth hormone insensitivity syndrome--a clinical research center study. GHIS Collaborative GroupJ Clin Endocrinol MetabYear: 19968193312331710.1210/jc.81.9.33128784089
Ranke MB,Savage MO,Chatelain PG,Preece MA,Rosenfeld RG,Blum WF,Wilton P,Insulin-like growth factor I improves height in growth hormone insensitivity: two years’ resultsHorm ResYear: 199544625326410.1159/0001846378808010
Guevara-Aguirre J,Vasconez O,Martinez V,Martinez AL,Rosenbloom AL,Diamond FB Jr,Gargosky SE,Nonoshita L,Rosenfeld RG,A randomized, double blind, placebo-controlled trial on safety and efficacy of recombinant human insulin-like growth factor-I in children with growth hormone receptor deficiencyJ Clin Endocrinol MetabYear: 19958041393139810.1210/jc.80.4.13937536209
Laron Z,Anin S,Klipper-Aurbach Y,Klinger B,Effects of insulin-like growth factor on linear growth, head circumference, and body fat in patients with Laron-type dwarfismLancetYear: 199233988041258126110.1016/0140-6736(92)91594-X1349669
Laron Z,Klinger B,Effect of insulin-like growth factor-I treatment on serum androgens and testicular and penile size in males with Laron syndrome (primary growth hormone resistance)Eur J EndocrinolYear: 1998138217618010.1530/eje.0.13801769506862
Rosenbloom AL,Recombinant human insulin-like growth factor I (rhIGF-I) and rhIGF-I/rhIGF-binding-protein-3: new growth treatment options?J PediatrYear: 2007150171110.1016/j.jpeds.2006.09.04017188604
Balhara B,Misra M,Levitsky LL,Recombinant human IGF-1 (insulin-like growth factor) therapy: where do we stand today?Indian J PediatrYear: 201279224424910.1007/s12098-011-0608-522090255
Rosenbloom AL,Mecasermin (recombinant human insulin-like growth factor I)Adv TherYear: 2009261405410.1007/s12325-008-0136-519198769
Ekstrom K,Carlsson-Skwirut C,Ritzen EM,Bang P,Insulin-like growth factor-I and insulin-like growth factor binding protein-3 cotreatment versus insulin-like growth factor-I alone in two brothers with growth hormone insensitivity syndrome: effects on insulin sensitivity, body composition and linear growthHorm Res PaediatrYear: 201176535536610.1159/00033041021968387
Laron Z,Insulin-like growth factor-I treatment of children with Laron syndrome (primary growth hormone insensitivity)Pediatric endocrinology reviews: PERYear: 20085376677118367997
Midyett LK,Rogol AD,Van Meter QL,Frane J,Bright GM,Group MSS,Recombinant insulin-like growth factor (IGF)-I treatment in short children with low IGF-I levels: first-year results from a randomized clinical trialJ Clin Endocrinol MetabYear: 201095261161910.1210/jc.2009-057019880790
Bright GM,Rogers D,Gonzalez-Mendoza LJF,Safety and efficacy of oncedaily rhIGF-1 treatment in prepubertal children with primary IGF-1 deficiency: results from a clinical trial (ICE 2008 meeting: 2008).Year: 2008Rio de Janeiro (Brazil)
Bright GM,Mendoza JR,Rosenfeld RG,Recombinant human insulin-like growth factor-1 treatment: ready for primetimeEndocrinol Metab Clin North AmYear: 200938362563810.1016/j.ecl.2009.06.00319717008
Frystyk J,Freda P,Clemmons DR,The current status of IGF-I assays–a 2009 updateGrowth Horm IGF ResYear: 201020181810.1016/j.ghir.2009.09.00419818658
Belobrajdic DP,Priebe IK,Forbes B,Flyvbjerg A,Chen JW,Cosgrove LJ,Frystyk J,Saunders IW,Assessing the potential usefulness of IGF-related peptides and adiponectin for predicting disease riskGrowth Horm IGF ResYear: 200818319820410.1016/j.ghir.2007.08.00517928251
Brand-Miller JC,Liu V,Petocz P,Baxter RC,The glycemic index of foods influences postprandial insulin-like growth factor-binding protein responses in lean young subjectsAm J Clin NutrYear: 200582235035416087978
Juul A,Serum levels of insulin-like growth factor I and its binding proteins in health and diseaseGrowth Horm IGF ResYear: 200313411317010.1016/S1096-6374(03)00038-812914749
Liao S,Guevara-Aguirre J,Bright G,Validation of a population pharmacokinetic (POP-PK) model for rhIGF-1 in humans (ENDO).Year: 2005San Diego (California)
Wilton P,Ranke MB, Price DA, Reiter EOAdverse events reported in KIGSGrowth hormone therapy in pediatrics: 20 years of KIGSYear: 2007Karger, Basel, Switzerland432441
Maneatis T,Baptista J,Connelly K,Blethen S,Growth hormone safety update from the national cooperative growth studyJ Pediatr Endocrinol MetabYear: 200013Suppl 21035104411086659
Klinger B,Laron Z,Three year IGF-I treatment of children with laron syndromeJ Pediatr Endocrinol MetabYear: 1995831491588521188
Ebeling PR,Jones JD,O’Fallon WM,Janes CH,Riggs BL,Short-term effects of recombinant human insulin-like growth factor I on bone turnover in normal womenJ Clin Endocrinol MetabYear: 19937751384138710.1210/jc.77.5.13848077337
Conchillo M,de Knegt RJ,Payeras M,Quiroga J,Sangro B,Herrero JI,Castilla-Cortazar I,Frystyk J,Flyvbjerg A,Yoshizawa C,et al. Insulin-like growth factor I (IGF-I) replacement therapy increases albumin concentration in liver cirrhosis: results of a pilot randomized controlled clinical trialJ HepatolYear: 200543463063610.1016/j.jhep.2005.03.02516024131
Laron Z,Ginsberg S,Lilos P,Arbiv M,Vaisman N,Long-term IGF-I treatment of children with laron syndrome increases adiposityGrowth Horm IGF ResYear: 2006161616410.1016/j.ghir.2005.12.00116442822
McDonald A,Williams RM,Regan FM,Semple RK,Dunger DB,IGF-I treatment of insulin resistanceEur J EndocrinolYear: 2007157Suppl 1S51S5617785698
Pollak M,The insulin and insulin-like growth factor receptor family in neoplasia: an updateNat Rev CancerYear: 201212315916922337149
Steuerman R,Shevah O,Laron Z,Congenital IGF1 deficiency tends to confer protection against post-natal development of malignanciesEur J EndocrinolYear: 2011164448548910.1530/EJE-10-085921292919
Nakae J,Kato M,Murashita M,Shinohara N,Tajima T,Fujieda K,Long-term effect of recombinant human insulin-like growth factor I on metabolic and growth control in a patient with leprechaunismJ Clin Endocrinol MetabYear: 199883254254910.1210/jc.83.2.5429467572
de la Monte SM,Insulin resistance and alzheimer’s diseaseBMB RepYear: 200942847548110.5483/BMBRep.2009.42.8.47519712582
Lopez-Lopez C,Dietrich MO,Metzger F,Loetscher H,Torres-Aleman I,Disturbed cross talk between insulin-like growth factor I and AMP-activated protein kinase as a possible cause of vascular dysfunction in the amyloid precursor protein/presenilin 2 mouse model of alzheimer’s diseaseJ NeurosciYear: 200727482483110.1523/JNEUROSCI.4345-06.200717251422
Mitchell JD,Wokke JH,Borasio GD,Recombinant human insulin-like growth factor I (rhIGF-I) for amyotrophic lateral sclerosis/motor neuron diseaseCochrane Database Syst RevYear: 20074CD002064 PMID: 17943766. 17943766
Switzer M,Rice J,Rice M,Hardin DS,Insulin-like growth factor-I levels predict weight, height and protein catabolism in children and adolescents with cystic fibrosisJ Pediatr Endocrinol MetabYear: 200922541742419618660
Jacob R,Barrett E,Plewe G,Fagin KD,Sherwin RS,Acute effects of insulin-like growth factor I on glucose and amino acid metabolism in the awake fasted rat. Comparison with insulinJ Clin InvestYear: 19898351717172310.1172/JCI1140722651479
Meyer NA,Barrow RE,Herndon DN,Combined insulin-like growth factor-1 and growth hormone improves weight loss and wound healing in burned ratsJ TraumaYear: 19964161008101210.1097/00005373-199612000-000118970554
Haugaard SB,Andersen O,Hansen BR,Orskov H,Andersen UB,Madsbad S,Iversen J,Flyvbjerg A,Insulin-like growth factors, insulin-like growth factor-binding proteins, insulin-like growth factor-binding protein-3 protease, and growth hormone-binding protein in lipodystrophic human immunodeficiency virus-infected patientsMetab Clin ExpYear: 200453121565157310.1016/j.metabol.2004.06.02515562401
Flynn RS,Murthy KS,Grider JR,Kellum JM,Kuemmerle JF,Endogenous IGF-I and alphaVbeta3 integrin ligands regulate increased smooth muscle hyperplasia in stricturing Crohn’s diseaseGastroenterologyYear: 2010138128529310.1053/j.gastro.2009.09.00319751734
Fletcher L,Kohli S,Sprague SM,Scranton RA,Lipton SA,Parra A,Jimenez DF,Digicaylioglu M,Intranasal delivery of erythropoietin plus insulin-like growth factor-I for acute neuroprotection in stroke. Laboratory investigationJ NeurosurgYear: 2009111116417010.3171/2009.2.JNS08119919284235
Murillo-Cuesta S,Rodriguez-de la Rosa L,Cediel R,Lassaletta L,Varela-Nieto I,The role of insulin-like growth factor-I in the physiopathology of hearingFront Mol NeurosciYear: 201141121845174
Abdulle AM,Gillett MP,Abouchacra S,Sabri SM,Rukhaimi MA,Obineche EN,Singh J,Low IGF-1 levels are associated with cardiovascular risk factors in haemodialysis patientsMol Cell BiochemYear: 20073021–219520117387582
Boonen S,Rosen C,Bouillon R,Sommer A,McKay M,Rosen D,Adams S,Broos P,Lenaerts J,Raus J,et al. Musculoskeletal effects of the recombinant human IGF-I/IGF binding protein-3 complex in osteoporotic patients with proximal femoral fracture: a double-blind, placebo-controlled pilot studyJ Clin Endocrinol MetabYear: 20028741593159910.1210/jc.87.4.159311932288
Rubin CD,Reed B,Sakhaee K,Pak CY,Treating a patient with the Werner syndrome and osteoporosis using recombinant human insulin-like growth factorAnn Intern MedYear: 199412196656687944076
De Ravin SS,Shum E,Zarember KA,Rezvani G,Rosenfeld RG,Stratakis CA,Malech HL,Short stature in partially corrected X-linked severe combined immunodeficiency–suboptimal response to growth hormoneJ Pediatr Endocrinol MetabYear: 200821111057106319189700
Heatwole CR,Eichinger KJ,Friedman DI,Hilbert JE,Jackson CE,Logigian EL,Martens WB,McDermott MP,Pandya SK,Quinn C,et al. Open-label trial of recombinant human insulin-like growth factor 1/recombinant human insulin-like growth factor binding protein 3 in myotonic dystrophy type 1Arch NeurolYear: 2011681374410.1001/archneurol.2010.22720837825
Misra M,McGrane J,Miller KK,Goldstein MA,Ebrahimi S,Weigel T,Klibanski A,Effects of rhIGF-1 administration on surrogate markers of bone turnover in adolescents with anorexia nervosaBoneYear: 200945349349810.1016/j.bone.2009.06.00219523548
Hollis ER II,Lu P,Blesch A,Tuszynski MH,IGF-I gene delivery promotes corticospinal neuronal survival but not regeneration after adult CNS injuryExp NeurolYear: 20092151535910.1016/j.expneurol.2008.09.01418938163
Hansen-Pupp I,Engstrom E,Niklasson A,Berg AC,Fellman V,Lofqvist C,Hellstrom A,Ley D,Fresh-frozen plasma as a source of exogenous insulin-like growth factor-I in the extremely preterm infantJ Clin Endocrinol MetabYear: 200994247748210.1210/jc.2008-129319001522
Katz LE,Ferry RJ Jr,Stanley CA,Collett-Solberg PF,Baker L,Cohen P,Suppression of insulin oversecretion by subcutaneous recombinant human insulin-like growth factor I in children with congenital hyperinsulinism due to defective beta-cell sulfonylurea receptorJ Clin Endocrinol MetabYear: 19998493117312410.1210/jc.84.9.311710487673
Diez-Caballero F,Castilla-Cortazar I,Garcia-Fernandez M,Puche JE,Diaz-Sanchez M,Casares AD,Aliaga-Montilla MA,Rodriguez-Borrajo C,Gonzalez-Baron S,Little effects of insulin-like growth factor-I on testicular atrophy induced by hypoxiaBMC UrolYear: 20066410.1186/1471-2490-6-416504030
Smith LE,Shen W,Perruzzi C,Soker S,Kinose F,Xu X,Robinson G,Driver S,Bischoff J,Zhang B,et al. Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptorNat MedYear: 19995121390139510.1038/7096310581081

Figures

[Figure ID: F1]
Figure 1 

Schematic structures of IGFs and their receptors. Resemblances between Insulin and IGFs allow them to cross-interactions by which IGFs are able to bind to their own receptors (preferently) but also to Insulin receptor (IR) with a lower specificity. The hybrid receptor shares components from both IR and IGF-IR. * IGF-II can also interact with IGF-IR, hybrid receptor and insulin receptor, with a lower affinity.



[Figure ID: F2]
Figure 2 

GH/IGF-I axis and targets. Pituitary GH interacts with GH receptors in hepatocytes increasing IGF-I secretion for endocrinological purposes in different organs, although an autocrine/paracrine IGF-I production by those organs is also present.



[Figure ID: F3]
Figure 3 

Lifelong beneficial properties of IGF-I. Evolution of IGF-I circulating levels and its pluripotent roles along different stages of human development and aging.



[Figure ID: F4]
Figure 4 

IGF-I receptor pathway. Activation of IGF-IR leads to a cascade of related molecules involved in previously described actions of IGF-I (survival, cell growth and differentiation, cytoprotection, glucose metabolism, etc).



Tables
[TableWrap ID: T1] Table 1 

Reported adverse effect during IGF-I treatment


Adverse effect IGF-I doses (μg/Kg/day) References
Tachycardia
150-200
[397]
120-180
[398]
Hypoglycemia
60-120
[377,380]
80-120
[378,387]
Intracrenial pressure increment
80-120
[378,387]
Lipohypertrophy
60-120
[377,387]
Tonsillar/adenoidal hypertrophy
60-120
[377,387]
Headache and vomiting
80-120
[387]
Facial edema
120-180
[398]
120
[373]
Asthenia, orthostatic hypotension
120
[373]
Arthralgia/myalgia 120 [373]

Subcutaneously, daily, for at least 1 year.


[TableWrap ID: T2] Table 2 

Current proposed IGF-I treatments


Pathological condition References
Laron Syndrome
[33-35,200-208,381-389,397]
Liver cirrhosis
[219-234,399]
Aging
[55,56,169,245-248,384]
IUGR
[37-41,182-197]
Neurological disorders
[335,336,405-407]
Stroke
[337,413]
Spinal cord injury
[421]
Cardiovascular protection
[270-277,310,415]
Diabetes
[302-306]
Insulin resistances/hyperinsulinism
[55,404,409,423]
Metabolic syndrome
[301,316]
Osteoporosis
[416,417]
Cystic fibrosis
[408]
Wound healing
[410]
Myotonic dystrophy
[419]
AIDS muscle wasting
[411]
HIV-associated adipose redistribution syndrome
[411]
Burns
[299]
Crohn’s disease
[412]
Werner syndrome
[417]
X-linked severe combined immunodeficiency
[418]
Hearing loss prevention
[414]
Anorexia nervosa
[420]
Retinopathy of prematurity [422]

rhIGF-I replacement therapy may be recommended only to restore IGF-I deficiency conditions. In consequence, despite the number of proposed pathological conditions that may benefit from rhIGF-I treatment, up to date, only those in the white have been well characterized. Conditions in clear grey are supported by a wide body of evidence which render these circunstances prone to be classified as the first group. Dark grey are conditions that may need more research in order to adequately propose the IGF-I treatment as a proper strategy.



Article Categories:
  • Review

Keywords: Laron syndrome, Liver cirrhosis, Aging, Oxidative stress, GH/IGF-I axis, Mitochondrial dysfunction, Cellular protection, Growth, Cancer protection.

Previous Document:  Suicide and Psychiatrist's Liability in Italian Law Cases.
Next Document:  Religiousness/Spirituality, Cardiovascular Disease, and Cancer: Cultural Integration for Health Rese...