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Insulin-like growth factor-1 deficiency and metabolic syndrome

Journal of Translational Medicinevolume 14, Article number: 3 () Cite this article

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Abstract

Consistent evidence associates IGF-1 deficiency and metabolic syndrome. In this review, we will focus on the metabolic effects of IGF-1, the concept of metabolic syndrome and its clinical manifestations (impaired lipid profile, insulin resistance, increased glucose levels, obesity, and cardiovascular disease), discussing whether IGF-1 replacement therapy could be a beneficial strategy for these patients. The search plan was made in Medline for Pubmed with the following mesh terms: IGF-1 and “metabolism, carbohydrate, lipids, proteins, amino acids, metabolic syndrome, cardiovascular disease, diabetes” between the years – The search includes animal and human protocols. In this review we discuss the relevant actions of IGF-1 on metabolism and the implication of IGF-1 deficiency in the establishment of metabolic syndrome. Multiple studies (in vitro and in vivo) demonstrate the association between IGF-1 deficit and deregulated lipid metabolism, cardiovascular disease, diabetes, and an altered metabolic profile of diabetic patients. Based on the available data we propose IGF-1 as a key hormone in the pathophysiology of metabolic syndrome; due to its implications in the metabolism of carbohydrates and lipids. Previous data demonstrates how IGF-1 can be an effective option in the treatment of this worldwide increasing condition. It has to distinguished that the replacement therapy should be only undertaken to restore the physiological levels, never to exceed physiological ranges.

Background

Consistent data from multiple studies (in vitro and in vivo) demonstrate the association between IGF-1 deficit and deregulated lipid metabolism, cardiovascular disease (CVD), diabetes, and altered metabolic profile of diabetic patients. On the other hand, metabolic syndrome (MetS) is a constellation of symptoms that implies a higher risk for CVD and type 2 diabetes (T2D), increasing the morbidity and mortality of these patients. As it is a syndrome clustering different features, the common causative aetiology is yet unknown. Nevertheless, the insulin resistance and abdominal adiposity seems to be essential in the pathophysiological process, and for this reason, based on the information available, we propose IGF-1 as a key hormone in the pathophysiology of metabolic syndrome due to its implications in the metabolism of carbohydrates and lipids. Accumulated evidence shows that IGF-1 can be an effective option in the treatment of this prevalence-increasing condition, as we shall further explain in detail.

Therefore, in this review our aim is to bring all IGF-1 information regarding metabolism together with the objective of offering clear insight into the issue—this way clarifying how miss-regulation of the GH/IGF-1/insulin axis can lead to metabolic disorders such as MetS and diabetes; introducing how obesity and insulin resistance (initiating factors for the onset of MetS and diabetes) may be opposed by recombinant-human-IGF-1 (rhIGF-1) treatment. Firstly, the concept of metabolic syndrome and its different definitions will be reviewed, together with the symptoms or risk factors associated. Secondly, IGF-1’s molecular structure and known actions with emphasis on metabolic actions—which will be discussed in detail. To continue, IGF-1 and IGF-1 binding proteins will be linked to parameters of metabolic syndrome, diabetes, insulin resistance, and obesity. Lastly, IGF-1 will be proposed as valid optional treatment for patients with MetS in which diet and exercise failed due to genetic traits.

Metabolic syndrome

For many decades, the concept of “clustering” metabolic disorder and CVD risk factors has been widely discussed. Table 1 summarises historical definitions and evolution of MetS diagnosis. However, the term “Metabolic Syndrome” has become commonly used since its inception by the “Executive Summary of the Third Report of the National Cholesterol Education Program” (NCEP) in [1]. Since then, many different concepts and definitions have been proposed. Hence, it was not until when a harmonised definition was finally described [2]. According to this definition, a diagnosis of MetS is made when 3 of the following 5 risk factors are present: enlarged waist circumference with population and country-specific criteria; elevated triglycerides (defined as ≥ mg/dL), decreased High Density Lipoprotein (HDL) (ranges below 40 mg/dL in men and 50 mg/dL in women), elevated blood pressure (defined as systolic blood pressure above  mmHg or diastolic blood pressure above 85 mmHg) and elevated fasting glucose (defined as blood glucose above  mg/dL). This definition includes those patients that are taking medication to manage hypertriglyceridemia, low HDL, hypertension and hyperglycemia [2].

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In general MetS continues to be a clustering of symptoms that seem to play a major role as CVD and T2D risk factors, raising the necessity of encouraging these patients to pursue lifestyle changes. Moreover, the harmonised definition criteria was found to be a better predictor of CVD than each of its separate components or the Framinghan Score—this was not applicable for T2D [3].

The prevalence of MetS is difficult to establish since it depends on the definition [1, 2, 4–6] and the composition of the population being studied [7–29]. To dissolve this issue different studies have been undertaken in order to estimate the prevalence of MetS. Nowadays we can understand that sex, age, race and ethnicity, in the context of socioeconomic status and lifestyle (tobacco, alcohol, education, physical exercise, unbalanced diet, etc.) impacts directly in its prevalence [7, 8, 10, 27– 36]. Furthermore, it is well known that it is increasing worldwide [37], this is thought to be related to the westernisation of lifestyle habits [38, 39].

It is well known that MetS represents an assortment of factors that increase the risk of CVD [11] and T2D by different means [11, 40–55]. Obesity and insulin resistance are associated with endothelial dysfunction, sympathetic nervous system hyperactivity, and hyperleptinaemia, all of which can lead to hypertension. Furthermore, insulin resistance can lead to abnormal lipid profiles, like low-HDL and high triglyceride (TG) levels. These two factors can increase the risk for CVD [56–60], nonetheless there is some controversy about the role of TG levels in the CVD development [57]. In summary, the majority of the studies have found that patients with MetS are at increased risk for developing CVD [11, 37, 39–55]. Additionally, as previously mentioned, a recent study has described that MetS -taking the harmonised definition criteria for diagnosis—is a better predictor for CVD than the sum of each of its separate components or the Framingham Score. Other studies have found that the more components of the MetS are present, the greater the risk of developing CVD [42, 53, 61].

Moreover, MetS is also a good predictor for the development of T2D [62–64]. Insulin resistance, hyperinsulinemia, dyslipidaemia, and obesity precede the progression to T2D in 75–85 % of patients [65], and the presence of MetS increases up to fivefold the risk for T2D compared to individuals without MetS [66, 67]. This risk is increased up to fold, if insulin resistance is present [54].

Other conditions that have been associated with MetS are strongly related with insulin resistance and adiposity, namely, non-alcoholic fatty liver disease (NAFLD), polycystic ovarian syndrome, obstructive sleep apnoea (OSA), hypogonadism, lipodystrophy, and microvascular disease. Moreover, the presence of NAFLD is a robust predictor of MetS [68]. Liver fat also correlates to each of the components of MetS [69]. In the case of OSA, there is evidence—adjusting for obesity—that individuals with this alteration are more likely to develop MetS than those without OSA [70–72]. Also, sleep disorders have been associated with weight gain and insulin resistance [73–77]. In the case of microvascular disease, some studies relate it to MetS, independent to the presence of T2D [78–86], but further studies are needed to ensure these results.

Insulin-like growth factor-1

Insulin-like growth factor 1 (IGF-1) is a aminoacid polypeptide hormone with endocrine, paracrine, and autocrine effects, which shares structural homology (>60 %) with IGF-2 and proinsulin [87, 88]. It is mainly produced by the liver (accounting for ≈75 % of circulating IGF-1) secondary to growth hormone (GH) and insulin endocrine stimulation in the liver. Conversely, IGF-1 acts to provide an inhibitory feedback signal on GH secretion in the hypothalamus by stimulating somatostatin production in the pituitary [89–91]. IGF-1 is also produced locally in all bodily tissues [92]. IGF-1 availability is tightly regulated by the so-called insulin-like growth factor binding proteins (IGFBPs), which may act by increasing IGF-1 half-life, from minutes to hours (most commonly by forming a tertiary complex with Acid-Labile Subunit and IGFBP3), however blocking its binding to the insulin-like growth factor 1 receptor (IGF-1R) [93–95]. IGFBPs can also act to guide IGF-1 to specific tissues, or even to inhibit or potentiate IGF-1 actions by acting as an independent substrate for the IGF-1R and/or other specific membrane, intracellular or nuclear receptors [93–95]. To date there have been described 6 high affinity IGFBPs [93–95]. Moreover, insulin-like growth factor binding protein related proteins (IGFBPrPs) have been recently characterised, which aid the metabolic effects of the hormone but their role remains unclear [96, 97]. Relevant roles of each specific IGFBPs will be further discussed when applicable to metabolism since there is a huge emerging world of IGFBPs independent actions.

IGF-1 can act over its putative receptor (IGF-1R) or it can also bind to the insulin receptor (IR), albeit with less affinity [98–]. In addition, there is a hybrid receptor with components of the IR (one α and one β-chain) and the IGF-1R (one α and one β-chain), to which both insulin and IGF-1 can bind to, but with less affinity than that of their putative receptors [98–]. All of these receptors have tyrosine kinase activity, hence are natural and potent activators of the Akt pathway [98–].

IGF-2 actions have been poorly characterised, however relevant roles have been determined for foetus development and cerebral protection [, ]. IGF-2 can act over its own receptor (IGF-2 receptor—IGF-2R), which is a manosephosphate transmembrane protein with undetermined actions—it is thought that it acts as a scavenger receptor by sequestering IGF-2 and IGF-1 from the extracellular medium and targeting them for destruction []. Nonetheless, it seems that it could have intracellular targets instead of only being proteolysed. As of recent discovery IGF-2R shows to activate Gαq proteins within cardiomyocites []. Additionally, IGF-2 can also act over IGF-1R, IR and hybrid receptors but with reduced affinity [].

In the last decades, IGF-1 has been implicated in many physiological actions, among others: tissue growth and development, proliferative, lipid metabolism, pro-survival/anti-aging, anti-inflammatory, anabolic, and antioxidant with neuro- and hepatoprotective properties [–]. IGF-1 exerts protective effects over mitochondria by preserving it from the oxidative damage generated by augmented metabolism, and increasing ATP synthesis and reducing intramitochondrial production of free radicals [–].

Insulin receptor, insulin-like growth factor-1 receptor and insulin resistance signalling

As a brief review of insulin signalling and its resistance molecular basis: insulin and IGF-1 receptors (IR and IGF-1R) are tyrosine kinases. As such they attract molecules containing a Src-homolgy 2 (SH2) domain (several docking sites for phosphorylated tyrosines). The most often and potent ones attracted are the insulin receptor substrates 1/2 (IRS1/2)—although there are 6 found to date- (not to forget that Shc proteins, p60dok, Cbl, APS, and Gab-1 are also recruited to activated IRs). These provide additional tyrosine residues to be phosphorylated by the tyrosine kinase domain of the activated receptor that will attract further molecules containing SH2 domains or plekstrin homoly (PH) domains, these last will anchor IRS to phosphoinositides on the cell membrane. When PI3K and its regulatory proteins, p85 and p, are recruited by IRS, they will further recruit and activate PDK1 (PIP3-dependent kinase 1), Akt (PKB), mTORC2, S6 kinases and PKC; all leading to augmented glucose transport, glycogen and protein synthesis. Zick and colleagues [] have elegantly summarised recent evidence that show how IRS also possess serine residues that can be phosphorylated. When this happens tyrosine phosphorylation becomes less likely to happen. This is, in a certain way, a termination pathway to uncouple the insulin signalling. There are other mechanisms to terminate the insulin signalling that include lipid and protein phosphatases along the cascade and controlling mechanisms; long-term regulation includes transcription inhibition of the IR and proteolysis by ubiquitination. One convergent pathway activated by IGF-1R and IR is the mTORC1 and mTORC2 signalling. It is widely known they both posses serine and threonine phosphorylation capability. However, it has been recently described that mTORC2 also possesses tyrosine phosphorylation capacity [], and that it phosphorylates tyrosines on IRS and tyrosine kinases in both receptors, IGF-1 and IR, thus reinstituting the signal of the activated receptors []. Whilst mTORC1 activates S6 kinase, which phosphorylates serine residues on IRS which in turn uncouples IRS from the receptor and its substrates, mTORC2 can reactivate this signalling.

Complementary to the above, it has been thought for a long time that only supraphysiological concentrations of IGF-1 are able to activate the IR, as will be further discussed in this manuscript. However, the exact mechanism by which IGF-1 improves insulin signalling has not yet be explained (other than indirect actions through lipid clearance from the bloodstream by inhibiting GH (lipolysis on adipocytes) and FFA uptake by muscles; all these mechanisms are collected below). We now propose a feasible mechanism: Denley and colleagues [] have beautifully designed a study where they demonstrate how IR has a splice variant lacking exon 11 which confers the receptor affinity for IGF-1 and IGF In this way, IGF-1 gains the ability to stimulate the IR, and without activating the tyrosine kinase domain, recruits IRS Complementarily, IGF-1R preferentially activates IRS-2 [] as it was found that IRS-2 contains a KLRB domain that functions to block the tyrosine kinase domain in the cytoplasmic region of the IR, and that such does not happen in the IGF-1R. Thus suggesting a specificity for IGF-1R. It has been found, using specific knock out (KO) mice and cultures, different specific activities for IRS-1 and IRS-2, additional further complexity comes with tissue-specific roles. For example, in muscle, IRS-1 is more related to glucose uptake whereas IRS-2 stimulates the MAPK pathway []. In the liver, they both have metabolic regulation actions, but IRS-2 has a more profound role in lipid metabolism []. Additional complexity, and in accordance with IGF-1 secretion patterns, appeared when researchers found that IRS-1 was found more active in post-prandial states contrary to IRS-2 in fasting states []. Even more interesting is the fact that Shc and PLC were found to only interact with IRS-2 []. Recall that Shc ultimately activates the MAPK pathway, while PLC has more metabolic effects including GLUT4 translocation. IGF-1 displays more binding sites for SHP2 (a phosphatase related to growth) and seems more prone to recruit Cbl [] (an E3 ligase that targets the receptor for ubiquitination and destruction) and thus may explain a different regulatory mechanism not mediated by serine phosphorylation, and thus not so sensitive to metabolic derangements. Intriguingly, another interesting research lead to the discovery of a differential role for IRSs in apoptosis, suggesting an antiapoptotic effect for IRS-2 [] which is consistent with known differential roles of IGF-1 and insulin.

Taking all this data together it seems logical or appropriate to conclude that, because IGF1-R has a different signalling pathway that can maintain lipid oxidation in the liver, FFA uptake in muscle, and activates mTORC1 could reactivate IR through tyrosine kinase activity on IRS, thus displacing serine phosphorylation, reinstituting insulin signalling. Also since most of serine inhibiting phosphorylation occurs in IRS-1, it renders IGF-1R a rescue pathway to reinstitute insulin sensitivity. Because IGF-1 is normally found at low levels in MetS and T2D, maybe because of insulin cessation to inhibit IGFBP-1 production by the liver and because of decreased liver IGF-1 secretion by insulin stimulation, as insulin resistance prevails in the liver. Consistent with the evidence presented we suggest a positive effect towards re-establishing IGF-1 levels by substitutive therapy only to physiological levels, never above them.

Insulin-like growth factor-1 metabolic effects

At a first glance, IGF-1 has historical fame for being a growth and differentiation factor, however, a number of growth-unrelated actions have been recently unravelled []. From our perspective IGF-1, GH, and insulin conform a finely regulated axis that inform cells about the nutritional status of the organism so that they can either undergo apoptosis/senescence/quiescence or, to the contrary, grow and differentiate. Parallel to this signal, potent protective effects have been attributed to this hormone, thus, besides signalling abundance and growth, it provides the protection against the possible deleterious effects of augmented metabolism. Likewise, anti-inflammatory actions of IGF-1 [] can be regarded as a crucial factor protecting tissues from the deleterious effects of pro-inflammatory mediators in chronic disorders such as obesity. It has been well established that pro-inflammatory cytokines produced by the adipose tissue in obesity affect normal nutrition-related signalling, establishing the progression to MetS and ultimately to T2D []. Additionally, it is now known that pro-inflammatory cytokines also hijack IGF-1 intracellular signalling by phosphorylating serine residues on insulin related substrate (IRS) molecules and hence impeding their binding to IGF-1R []. This results in a blockade of IGF-1 beneficial actions [, , ]. Under this scenario, a correlation between IGF-1 and MetS can be established.

When caloric restriction is present, mammals synthesise less IGF-1 and its synthesis in the liver is refractory to GH stimulation [–]. This process functions to limit growth and protein synthesis when nutrient availability is compromised. After a meal, GH responsiveness and IGF-1 synthesis is reinstituted [, ]. When inadequate carbohydrates are ingested, the decrease in portal vein insulin concentration leads to a reduction in IGF-1 synthesis by the liver [, ]. In pathophysiological states, including increased insulin resistance, the hybrid receptor number is changed significantly, thus potentially abrogating the chance for IGF-1 to alter glucose metabolism [, , ]. It is important to mentions that IGF-1 receptors are expressed ubiquitously [99]. This means that their actions can occur in all cell types, stimulating fat, carbohydrate, and protein metabolic coordination, as we shall explain in detail herein. IGF-1 possesses both, GH-like actions and insulin-like actions, whose effects in vivo depend on the dosage, length of treatment, and even route of administration [, ]. However, GH can also exert metabolic actions independent from IGF-1 generation in the liver via activation of the phosphoinositide 3-kinase (PI3 K) and IRS pathways [98]. In this way, GH and insulin act in symphony with IGF-1 to produce a coordinated response. Supported by an increasing number of studies these effects suggest the involvement of IGF-1 in metabolism coordination [].

Insulin-like growth factor-1 and carbohydrate metabolism

IGF-1 can promote glucose uptake in certain peripheral tissues [–] in the magnitude of 4–7 % from that of insulin [, ]. In addition, exogenous IGF-1 administration has been shown to reduce serum glucose levels [95, , ], not only in healthy individuals [, –], but also in those with insulin resistance [, ], type I [–], and T2D [–]. An interesting experiment shows how, in the presence of insulin resistance, there is up-regulation of the insulin/IGF-1 hybrid receptor expression in both, muscle and fat [, ]. It is important to bear in mind that IGF-1 serum concentration is fold greater than insulin, however when bound to IGFBPs its biological activity is modulated and in its free-unbound form presents different effects [99, ]. High doses of IGF-1 administration typically results in hypoglycaemia despite the potent suppression of circulating insulin concentrations it triggers [, , ]. Even though this effect may be mediated by the insulin receptor, experimental KO mice for the insulin receptor gene show a potent glucose lowering effect of IGF-1, indicative that the hypoglycaemic effect is also mediated, in part, by its own IGF-1R. However, this study was undertaken in 1–3 day old mice, as without IR they were not viable, and thus, results are not conclusive [].

Berryman and colleagues revised IGF-1 actions on obesity, and concluded that this molecule possesses direct effects on muscle glucose uptake []. Moreover, KO mice for liver IGF-1 gene developed muscle insulin resistance (it is important to mention that skeletal muscle myocytes express high number of IGF-1R), showing an increase in insulin concentrations and a substantial decrease in the insulin-induced autophosphorylation of the insulin receptor and IRS in skeletal muscle (being normal in liver and white adipose tissue). This effect was efficiently reverted by IGF-1 administration []. Such results could indicate that hepatic derived IGF-1 plays a crucial role in skeletal muscle insulin signalling and glucose uptake. In murine studies, deletion of the IGF-1R in skeletal muscle resulted in glucose intolerance issues ultimately leading to T2D at an early age, because, although they express insulin receptors, they cannot form hybrid or IGF-1 receptors []. When these mice where administered IGF-1 they showed lowered fasting glucose, and because no functional IGF-1R is present in muscle, such effect is believed to be due to renal gluconeogenesis suppression [, ]. Our group, working with partially deficient IGF-1 mice, has demonstrated that the liver is capable of expressing IGF-1R (which under physiological conditions it does not [99]) as a “defence” mechanism (peer review). If the abovementioned is occurring, it could mean that IGF-1 administration could also lower glucose levels by suppressing hepatic gluconeogenesis, as well as improving insulin signalling in this organ, leading to IGFBP-1 suppression and overall improvement of the IGF-1/GH/insulin axis. Furthermore, additional performed studies suggested [] that genetic expression of enzymes involved in glucose and lipid homeostasis together with cholesterol transport are altered (as we shall further explain in detail later on).

IGF-1 reduces serum GH levels (via somatostatin negative feedback in the pituitary) which in turn suppresses GH actions in the liver, thus enhancing insulin actions in this organ []. In both, fat and liver, GH stimulates the synthesis of p85 subunit of PI3K [] leading to the suppression of p subunit activity and, thus, antagonising insulin’s actions []. Therefore, IGF-1 may indirectly modulate carbohydrate metabolism through GH suppression and enhancement of insulin action.

During postprandial periods there is an increase in free circulating IGF-1 via insulin-induced suppression of IGFBP-1 secretion [–], which sequesters free IGF-1 making it unavailable. IGFBP-1 gene is transcriptionally regulated by insulin in the liver []. This change in available IGF-1 may be (it is difficult to extrapolate data from altered IGF-1/GH concentrations from animal models, as each author measures IGF-1 levels using different methods) adequate for fatty acid (FA) oxidation in muscle, suppression of GH, stimulation of glucose transport into muscle [, ], and lastly for the suppression of renal gluconeogenesis in mice [].

Besides the already discussed actions of IGF-1 on glucose, it also has an indirect glucose-lowering effect secondary to its ability in increasing FA oxidation in muscle (will be further discussed in detail within the IGF-1 and lipid metabolism section). Such ability produces a decreased FFA flux in the liver and hence insulin signalling is improved, being now able, such signalling to suppress hepatic glucose output [].

IGFBPs are also hypothesised to play a role in glucose metabolism. IGFBP-1 regulates glucose levels through its effect on free IGF IGFBP-2 actions are linked to insulin, although only in cases of hyperinsulinemia [] where it seems to play a role on adipocyte autocrine control []. It has been reported that IGFBP-3 binds to a nuclear receptor, 9-cis retinoic acid receptor-alpha (RXR-α), which interacts with peroxisome proliferator activated receptor-gamma (PPAR-γ), a nuclear protein involved in the regulation of glucose and lipid metabolism [, ]. A transgenic mice study stated that the overexpression of IGFBP-3 is associated with impaired glucose tolerance [, ]. Also, IGFBPrPs have been associated with insulin resistance and fasting glucose levels [, ].

In a recent investigation undertaken by our group, adult mice with partial IGF-1 showed a decrease in the expression of genes involved in glucose metabolism (phosphoenolpyruvate carboxylase-1, glucosephosphatase, pyruvate dehydrogenase kinase isoenzyme-4, and ATP-citrate lyase), resulting serious hyperglycaemia []. Such genetic alterations were all reverted by low doses if IGF-1 replacement therapy for only 10 days. Interestingly, it is well accepted that insulin increases the expression of glucosephosphatase and phosphoenolpyruvate carboxylase Results in the study demonstrate that IGF-1 induces the opposite effects since the IGF-1 deficit reduces the expression of glucosephosphatase and phosphoenolpyruvate carboxylase Thus, these activities of IGF-1 are not “insulin-like” but rather antagonistic. These findings reinforce the role of IGF-1 in glucose homeostasis. Also, pyruvate dehydrogenase kinase isoenzyme-4 encodes pyruvate dehydrogenase complex (PDK). PDK is an emerging target for the treatment of MetS which may allow the maintenance of the steady-state concentration of adenosine triphosphate during the feed-fast cycle. For that, cells require efficient utilization of fatty acids and glucose, and such is controlled by PDK. Particularly the pyruvate dehydrogenase kinase isoenzyme-4 gene encodes PDK that converts pyruvate, CoA and oxidized nicotinamide adenine dinucleotide (NAD+) into acetyl-CoA, the reduced form of nicotinamide adenine dinucleotide (NADH) and carbon dioxide.

Insulin-like growth factor-1 and lipid metabolism

IGF-1 promotes preadipocyte differentiation [], however, as preadipocytes differentiate, they stop expressing IGF-1Rs, delegating such functions now to insulin receptors, which increase in number significantly. Thus, in the adipose tissue, physiological IGF-1 concentrations are not effective in stimulating changes in lipid synthesis or lipolysis, only at high concentrations is capable of stimulating glucose transport via the insulin receptor []. Contrarily, a study with 8 GH-deficient subjects found that IGF-1 administration increased lipid oxidation (being this effect more potent when co-administered with GH), energy expenditure, and insulin resistance [, ]. This effect is believed to be due to IGF-1 suppression of insulin secretion, which leads to augmented lipolysis in adipose tissue and promotion of FFA use by muscle.

Although mature adipocytes are not a target for IGF-1, they secrete it. In fact, cultured adipocytes secrete more IGF-2 than IGF-1, and predominantly IGFBP Growth hormone, interleukin-β (IL-1β), and TNF-α affect secretion of IGF-1—whereas IGF-2 is affected by TNF-α only. Hence, cytokines may control adipocytes homeostasis by affecting local IGF-1 synthesis [].

Growth hormone has direct effects on mature adipocytes that result in the release of FFAs following TG breakdown and in increased FFA oxidation in the liver []. GH can enhance the lipolytic effect of catecholamines by increasing the number of adrenergic receptors in adipocytes. GH also increases hepatic glucose production [, ] and leads to increased lipolysis in adipocytes through the β-3 adrenergic receptor [, ]. Such receptor activates the protein kinase A (PKA) cascade, eventually activating lipases [, , ]. Additional effects include uncoupling of the electron transport chain to produce heat [, ]. In skeletal muscle, GH increases lipoprotein lipase activity via the β-3 adrenergic receptor, as a result facilitating FFA use [].

On the other hand, insulin is a potent stimulant of lipid synthesis, antagonising TG breakdown. An increase in FFA efflux from adipose tissue to liver can result in insulin resistance in the liver and GH is known to antagonise insulin action by this mean []. Definitive evidence of the role of FFAs in GH-mediated insulin resistance was obtained in clinical studies in which the effects of exogenously administered GH on insulin resistance were abrogated by Acipimox™—an inhibitor of lipolysis [, , ]. The increased efflux of FFAs from adipose tissue to lipid-sensitive tissues (such as liver and skeletal and cardiac muscle) increases serine phosphorylation of IRSs. Such phosphorylation leads to the blockade of the tyrosine residues in IRSs, to which the insulin and IGF-1 receptors phosphorylate to activate IRSs and consequently commence the signalling cascade [, ], as comprehensively discussed above.

IGF-1 promotes fatty acid transport in muscle [, , ] and its inhibition causes severe consequences like insulin resistance and eventual diabetes []. This is due to the liver taking up all the circulating FFAs, which then interfere with insulin and IGF-1 signalling (as described above) and eventually leading to hepatic steatosis. Therefore, the two major effects that are enhanced by IGF-1 are FFA use by muscle and GH suppression. These two actions result in a decreased FFA flux in the liver, improving insulin and IGF-1 signalling. Such improvement promotes lipogenesis in fat (recall that IGF-1 could maintain cytokine homeostasis—anti-inflammatory effects-, and thus protection from mild inflammation as a consequence of obesity). This fact, linked to the augmented FFA use by muscle and insulin signal reinstitution by IGF-1, results in a marked reduction in total FFA flux.

Moreover, IGF-1 could be implicated in nutrient absorption as our group demonstrated more than a decade ago. We showed that cirrhotic (an IGF-1 deficiency condition) rats had diminished amino acid and glucose intestinal absorption [, , ] and that IGF-1 replacement therapy was able to restore both alterations, suggesting a role of IGF-1 in the position of transporters []. Such findings suggest that IGF-1 implications on metabolism may not only affect energy use and balance, but as well act regulating transport and nutrient absorption. Therefore, this finding could be indicating that IGF-1 deficiency could be altering nutritional balance. However, more profound studies in the matter are necessary.

In the aforementioned study from our group, adult mice with partial IGF-1 also displayed decreased expression of genes involved in lipid metabolism (ATP-citrate lyase, acetyl-CoA acyltransferase 1B, acetyl-CoA acetyltransferase 1) and cholesterol synthesis and transport (Both HMG-CoA reductase and synthase, LDL-related protein 1, proprotein convertase subtilisin/Kesin type 9), resulting in dyslipidaemia. Such genetic alterations were reverted by IGF-1 replacement therapy and may seriously contribute to the establishment of MetS [].

Figure 1 and Table 2 have been included to represent schematically IGF-1 actions in metabolism with target organs.

Metabolic effects of IGF-1, GH, and insulin under physiological conditions on their target organs. The figure summarises schematically some of the metabolic effects that IGF-1 (blue continuous line), GH (red discontinuous line), and insulin (green dotted line) exert on kidney (upper left), brain (upper centre), skeletal muscle (left), liver (centre), adipose tissue (right), and pancreas (bottom). GH growth hormone, GHRH growth hormone releasing hormone, FFA free fatty acid, IRS insulin receptor substrate, IGF-1 insulin-like growth factor 1, IGBBP-1 insulin-like growth factor binding protein 1

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Can insulin-like growth factor-1 deficiency be involved in metabolic syndrome establishment?

An assortment of epidemiological and clinical studies have stated glucose and lipid metabolism alterations, insulin resistance, and central obesity as predominant factors for the development of MetS [38, ].

Similarities between insulin and IGF-1 suggest the possible role of IGF-1 in the pathological process of this syndrome, therefore several studies have attempted to correlate IGF-1 plasma levels with MetS. Figure 2 represents the pathophysiology of an altered IGF-1/GH/insulin axis, and potential beneficial actions of IGF-1 therapy.

Metabolic effects of IGF-1 and GH under pathological conditions. The figure summarises schematically some of the metabolic mechanisms altered in obesity and the role that IGF-1 and GH exert on them

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A general finding is that obese patients fulfilling criteria for MetS together with low IGF-1 plasma levels tend to develop a worse cardiovascular disease outcome than those with mid-normal to high-normal IGF-1 levels []. Nevertheless, many of them also present insulin resistance and inflammatory cytokine secretion, so it is difficult to determine the exact role of each component in the cardiovascular outcome.

Nonetheless, low IGF-1 circulating levels are also associated with reduced insulin sensitivity [], glucose intolerance, and T2D [, , ]. Moreover, some inflammatory cytokines are known to reduce IGF-1 levels in animal models []. Additionally, the IGF-1/IGFBP-3 ratio, a common rough of free IGF-1 levels, is significantly decreased in obesity [], however no IGF-1 bioactivity was estimated. This parameter has been further studied, showing that those men and women in the lowest quartile of the IGF-1/IGFBP3 ratio are threefold more likely to meet the Adult Treatment Panel III (ATP-III) definition for MetS, and twice as likely to be insulin resistant—that IGF-1/IGFBP-3 ratio decreases notably as the number of MetS components increases []. Furthermore, visceral adipose tissue mass has been inversely correlated with circulating IGF-1 levels []. Nevertheless, the mechanism of this possible inverse relationship between MetS and free IGF-1 levels remains unclear.

A very interesting epidemiological study that supports this idea showed that in normal subjects, IGF-1 contributes to glucose homeostasis. This study analysed a group of Dutch Caucasians with a polymorphism in the promoter of the IGF-1 gene [, ]. Results within this group showed a reduced IGF-1 secretion—40 % lower than those without the polymorphism. These subjects are  cm shorter and have fold increase in T2D prevalence after the age of 60 [, ]. A different study [] tested IGF-1 in response to energy intake in the Gujarati migrant community in Sandwell (UK) and data was compared with people still resident in their village of origin in India. Total energy and total fat intake were higher in UK migrants, as were IGFBP-3 and IGF-1, but IGFBP-1 was lower in UK migrants. At both sites, IGF-1 and IGFBP-3 correlated positively with total energy and fat. Conversely, in Indian Gujaratis, IGFBP-1 fell with increasing total energy and fat intake but not in UK Gujaratis.

Several other studies (one of them being a large scale community-based Framingham Heart Study []) have suggested a role for IGF-1 in the prevalence of insulin resistance and MetS [–]. Biomarkers correlating the lower IGF-1 concentration to increased waist-to-hip ratio or to impaired glucose tolerance are also being studied [, ].

Insulin-like growth factor-1, as discussed earlier, has implications on lipid and glucose metabolism [87, 88], and its exogenous administration enhances insulin sensitivity in healthy adults [, ] as well as those with T2D [].

A fascinating study including over patients revealed that IGF-1 concentrations were independently associated with insulin sensitivity accounting for  % of its variation. The results were assessed by HOMA-S together with anthropometric measurements, HDL, TG and blood pressure, and found correlations between these parameters and IGF-1 plasma levels. Additionally, they established that according to the WHO definition for MetS, each unit increase in log-transformed IGF-1 concentrations, was associated with a  % reduction in the risk of MetS [].

Salmon et al. [] showed that transgenic mice with reduced levels of IGF-1 can induce female insulin resistance []. Moreover, global deletion of IGF-1 gene expression in mice does not result in glucose intolerance. It has to be mentioned that KO mice for IGF-1 gene are not viable and studies in such mice have to be done in the first days of life, and thus results are not very conclusive as metabolism is not properly established at this stage [, ]. However, if a partial deletion is present, the mice will develop glucose intolerance if starved. Additional studies found that elimination of hepatic IGF-1 gene expression results in a compensatory threefold increase in GH secretion—recall that IGF-1 is secreted by GH stimulation in hepatocytes. This combination of lowered serum IGF-1 and increased GH secretion leads to increased insulin resistance—as in the systemic deletion but also developed glucose intolerance [, ]. Interestingly, glucose intolerance could be improved when IGF-1 was systemically administered. This response was caused primarily by GH hypersecretion, as expression of a GH antagonist resulted in improvement of glucose homeostasis [, ]. Additionally, administration of IGF-1 in the presence of this antagonist results in a further improvement in insulin sensitivity; suggesting that, at high concentrations, IGF-1 has effects not simply mediated by suppressing the effect of GH on hepatic insulin sensitivity [, ]. In a similar study, the pivotal role for the IGF-1 in insulin sensitivity has received further support from liver-specific IGF-1 KO mice which exhibited overt insulin resistance and hyperinsulinaemia that was reversed by the administration of IGF-1 [].

Moreover, results from the aforementioned Framingham heart study also demonstrated the correlation between low IGF-1 and the increasing metabolic syndrome markers []. A good example is the finding that low circulating levels of IGF-1 are independently associated with hyperglycaemia and insulin resistance in adults [, –]. To the contrary, high to normal levels of circulating IGF-1 correlate with a rise in adiponectin levels and a reduced prevalence of MetS is found [].

Since the liver is the major site of IGF-1 production, when steatosis develops lowering insulin sensitivity, the severity of steatosis at different stages of insulin resistance and metabolic syndrome seems to be correlated with worsened circulating IGF-1 levels []. In addition, low IGF-1 subjects in a study were found to possess up-regulated fatty acid metabolism along with down-regulated GLUT-1 gene (in charge of glucose uptake in erythrocytes, brain endothelial cells, eye, peripheral nerve and also responsible for materno-placental glucose transfer) [].

In summary, reconciling all discussed aspects relevant to insulin, IGF-1 improves insulin sensitivity by suppressing insulin and GH secretion and by improving insulin signalling indirectly reducing FFA flux.

When we look to IGF-1 levels in sera from T2D patients, the results found are very wide []. It must be considered that multiple factors interact to control IGF-1 levels, many of which are disturbed in T2D, namely: increased inflammatory cytokines, decreased hepatic insulin action due to resistance, concomitant changes in IGFBPs, and the effects of obesity. In addition, T2D is the result of a complex interaction of environmental and genetic factors, being difficult to establish the role of each one in the pathogenesis of diabetes and in the levels of IGF In an experimental model, transgenic mice expressing a kinase-deficient IGF-1R β-subunit (thus displaying reduced signal transduction in both IGF-1R and hybrid receptors) developed diabetes early on life [, ]. Also, mice carrying a genetic mutation that lack one of the igf1r alleles (igf1r+/−) show a 10 % reduction in post-natal growth, insulin resistance and glucose intolerance []. Additionally, infants born small for gestational age who exhibit low IGF-1 levels presented a higher risk for the onset and development of T2D in adult life than those born with normal weight [, ]. Nevertheless, it is noteworthy that the inverse correlation between IGF-1 and diabetes only prevails in younger individuals (<65 years) [], establishing that this deficiency can lead to MetS—as aging can be considered an IGF-1 deficiency condition [].

Abnormal IGF-1 and GH levels have been proposed to play a key role in obesity [, ,

Sours: https://translational-medicine.biomedcentral.com/articles//sz

IGF-1 (Insulin-like Growth Factor 1) Test

What is an IGF-1 test?

This test measures the amount of IGF-1 (insulin-like growth factor 1) in your blood. IGF-1 is a hormone that manages the effects of growth hormone (GH) in your body. Together, IGF-1 and GH promote normal growth of bones and tissues. GH levels in the blood fluctuate throughout the day depending on your diet and activity levels. But IGF-1 levels remain stable. So, an IGF-1 test is a useful way to find out if your body is making a normal amount of GH.

Other names: somatomedin C test

What is it used for?

An IGF-1 test is used to diagnose growth hormone disorders, including:

  • GH deficiency. In children, GH is essential for normal growth and development. A GH deficiency can cause a child to grow more slowly and be much shorter than children of the same age. In adults, GH deficiency can lead to low bone density and reduced muscle mass.
  • GH insensitivity, also known as Laron syndrome. This is a rare genetic disorder in which the body is unable to use the growth hormone it produces. It also causes slowed growth rate and shorter than normal height in children.
  • Gigantism. This is a rare childhood disorder that causes the body to produce too much growth hormone. Children with gigantism are very tall for their age and have large hands and feet.
  • Acromegaly. This disorder, which affects adults, causes the body to produce too much growth hormone. Adults with acromegaly have thicker than normal bones and enlarged hands, feet, and facial features.

Why do I need an IGF-1 test?

Your provider may order an IGF-1 test if you or your child has symptoms of a GH disorder.

Symptoms of GH deficiency or GH insensitivity in children include:

  • Slowed growth rate compared with children of the same age
  • Shorter height, arms, and legs, and lower weight than children of the same age
  • Small penis in males
  • Thin hair
  • Poor nail growth

Adults with GH deficiency may have symptoms such as fatigue and decreased bone density and muscle mass. But IGF-1 testing isn't common for adults, as other disorders are much more likely to cause these symptoms.

Symptoms of GH excess (gigantism) in children include:

  • Excessive growth compared with children of the same age
  • Overly large head
  • Larger than normal hands and feet
  • Mild to moderate obesity

Symptoms of GH excess (acromegaly) in adults include:

What happens during an IGF-1 test?

A health care professional will take a blood sample from a vein in your arm, using a small needle. After the needle is inserted, a small amount of blood will be collected into a test tube or vial. You may feel a little sting when the needle goes in or out. This usually takes less than five minutes.

Will I need to do anything to prepare for this test?

You don't need any special preparations for an IGF-1 test.

Are there any risks to this test?

There is very little risk to you or your child in having a blood test. There may be slight pain or bruising at the spot where the needle was put in, but most symptoms go away quickly.

What do the results mean?

If your child's results show lower than normal levels of IGF-1, it probably means he or she has a GH deficiency or insensitivity to GH. In a child, this may be caused by a genetic disorder or brain disease. Your child may benefit from treatment with GH supplementation. GH supplementation is an injected medicine that contains manufactured human growth hormone. When GH deficiency is diagnosed and treated early, some children can grow several inches in the first year of treatment. Others grow less, and more slowly, but still benefit from treatment.

If your results show lower than normal IGF-1, it may be due to a normal age-related decrease in the hormone or other condition. Your provider may order more tests to help make a diagnosis.

Higher than normal levels of IGF-1 may mean gigantism in children or acromegaly in adults. Gigantism and acromegaly are most often caused by a tumor in the pituitary gland, a small organ in the base of the brain that controls many functions, including growth. Treatment for the tumor may include radiation therapy, surgery, and/or medicine. If the disorder was not caused by a tumor, you or your child may need more tests.

Learn more about laboratory tests, references ranges, understanding results.

Is there anything else I need to know about an IGF-1 test?

Your provider may order other blood tests to help diagnose a GH disorder. These include:

  • A GH stimulation test, which helps diagnose a GH deficiency or insensitivit
  • A GH suppression test, which helps diagnose a GH excess
  • IGBP-3 test. IGBP-3 is a protein that is the main carrier of IGF This test can help diagnose a GH deficiency, GH insensitivity, or GH excess.

References

  1. Hormone Health Network [Internet]. Endocrine Society; c Acromegaly; [updated Apr; cited Apr 5]; [about 3 screens]. Available from: https://www.hormone.org/diseases-and-conditions/acromegaly
  2. Hormone Health Network [Internet]. Endocrine Society; c Growth Hormone Deficiency; [updated Nov; cited Apr 5]; [about 3 screens]. Available from: https://www.hormone.org/diseases-and-conditions/growth-hormone-deficiency
  3. Kids Health from Nemours [Internet]. Jacksonville (FL): The Nemours Foundation; c– Blood Test: IGF Binding Protein-3 (IGFBP-3); [cited Apr 5]; [about 2 screens]. Available from: https://kidshealth.org/en/parents/test-igfbp3.html
  4. Kids Health from Nemours [Internet]. Jacksonville (FL): The Nemours Foundation; c– Blood Test: Somatomedin C (IGF-1); [cited Apr 5]; [about 2 screens]. Available from: https://kidshealth.org/en/parents/somatomedin-test.html
  5. Lab Tests Online [Internet]. Seattle (WA): LabTestsOnline.org; c Insulin-like Growth Factor-1 (IGF-1); [updated Mar 24; cited Apr 5]; [about 2 screens]. Available from: https://labtestsonline.org/tests/insulin-growth-factorigf-1
  6. Mayo Clinic [Internet]. Mayo Foundation for Medical Education and Research; c– Acromegaly: Diagnosis and treatment; Feb 16 [cited Apr 5]; [about 4 screens]. Available from: https://www.mayoclinic.org/diseases-conditions/acromegaly/diagnosis-treatment/drc
  7. Mayo Clinic [Internet]. Mayo Foundation for Medical Education and Research; c– Acromegaly: Symptoms and causes; Feb 16 [cited Apr 5]; [about 3 screens]. Available from: https://www.mayoclinic.org/diseases-conditions/acromegaly/symptoms-causes/syc
  8. Mayo Clinic Laboratories [Internet]. Mayo Foundation for Medical Education and Research; c– Test ID: IGFMS: Insulin-Like Growth Factor-1, LC-MS, Serum: Clinical and Interpretive; [cited Apr 5]; [about 3 screens]. Available from: https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/
  9. National Center for Advancing Translational Sciences [Internet]. Gaithersburg (MD): U.S. Department of Health and Human Services; Gigantism; [updated Feb 10; cited Apr 5]; [about 3 screens]. Available from: https://rarediseases.info.nih.gov/diseases//gigantism
  10. National Center for Advancing Translational Sciences [Internet]. Gaithersburg (MD): U.S. Department of Health and Human Services; Laron syndrome; [updated Sep 30; cited Apr 5]; [about 3 screens]. Available from: https://rarediseases.info.nih.gov/diseases//laron-syndrome
  11. National Heart, Lung, and Blood Institute [Internet]. Bethesda (MD): U.S. Department of Health and Human Services; Blood Tests; [cited Apr 5]; [about 3 screens]. Available from: https://www.nhlbi.nih.gov/health-topics/blood-tests
  12. NORD: National Organization for Rare Disorders [Internet]. Danbury (CT): NORD: National Organization for Rare Disorders; c Growth Hormone Deficiency; [cited Apr 5]; [about 3 screens]. Available from: https://rarediseases.org/rare-diseases/growth-hormone-deficiency
  13. The Magic Foundation [Internet]. Warrenville (IL): Magic Foundation; c– Insulin-like Growth Factor Deficiency; [cited Apr 5]; [about 3 screens]. Available from: https://www.magicfoundation.org/Growth-Disorders/Insulin-Like-Growth-Factor-Deficiency
  14. University of Rochester Medical Center [Internet]. Rochester (NY): University of Rochester Medical Center; c Health Encyclopedia: Insulin-Like Growth Factor; [cited Apr 5]; [about 2 screens]. Available from: https://www.urmc.rochester.edu/encyclopedia/content.aspx?ContentTypeID=&ContentID=insulin_like_growth_factor

The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.

Sours: https://medlineplus.gov/lab-tests/igfinsulin-like-growth-factortest/
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Role of IGF-1 in the Growth Hormone/IGF Axis

The Growth Hormone/IGF axis consists of IGF-1, IGF-2 and several high and low affinity IGF Binding Proteins (IGFBP). The whole system is tightly regulated by a feedback loop involving Growth Hormone (GH) secreted by the pituitary, and GH production and secretion controlled by Growth Hormone Releasing Hormone (GHRH) at the hypothalamus.

A process map outlining the role of IGF-1 in the Growth Hormone/IGF Axis

 

Insulin-like Growth Factors & Binding Proteins

Insulin-like growth factors (IGF) are involved in the proliferation and function of nearly every cell, tissue and organ in the human body. The IGF protein family consists of signaling proteins (IGF-1, IGF-2), cell membrane receptor proteins (IGF-1R, IGF-2R) with tyrosine kinase activity and a series of IGF binding proteins (IGFBP1 &#; IGFBP6). The IGFs’ mechanism of action is mediated through IGF/IGFR binding, kinase activation and the initiation of intracellular signaling via the AKT signaling pathway.1,2

The IGFBPs may modulate the action of IGFs in several different ways:

  • Inhibitory Model &#; IGFBPs prevent IGF/receptor association
  • Enhancing Model &#; IGFBPs transport IGFs and facilitate binding with IGF receptors
  • IGF Receptor-Independent Model &#; Product of direct IGFBPs/IGFBP receptor interaction
  • Proteolytic Cleavage of IGFBP &#; Cleaved into lower affinity fragments which increases freely circulating, bioavailable IGF

IGF-1

IGF-1 (Somatomedin C) is one of several growth factors necessary for normal human development. IGF-1 is synthesized mainly by the liver but also locally in many tissues. In contrast to many other peptide hormones, IGFs are avidly bound to specific IGFBPs, which significantly increases the half-life of IGF-1 in circulation.The seven classes of IGFBPs which are known at present1,3,4 either bind IGF-1 and IGF-2 with similar affinities or show a preference for IGF5,6 The predominant IGFBP is IGFBP-3, which binds not only IGF-1 but also the Acid-labile Subunit (ALS). Thus, most of the IGF-1 in circulation is bound within this ternary complex.

Study Significance of IGF-1

A deregulation or imbalance in the IGF system could have implications in a number of different disorders including perturbations with normal growth, cancer and diabetes. As such, the IGF protein family continues to be a viable target for new therapeutic agents.

Growth and Development

In newborns, basal IGF-1 levels are low, but as humans develop, the GH feedback loop and the regulation of IGF-1 become more pronounced.7 Circulating IGF-1 stimulates growth in all cells, from skeletal muscle and bone to organ tissue and vessel linings.2 Circulating levels of IGF-1 vary greatly depending on a number of intrinsic and extrinsic factors, including age, gender, genetics, nutritional status, physical activity and stress.7 Due to the tightly controlled relationship between IGF-1 and GH, a deficiency or excess in either hormone can result in physiological errors in metabolism such as dwarfism, pituitary gigantism and acromegaly.2,3

Dwarfism can result from a mutation in the hepatic GH receptor which yields insensitivity to secreted GH. As a consequence, IGF-1 is synthesized and secreted at suboptimal levels. With outright GH deficiency, the pituitary does not produce enough GH, which negatively impacts IGF-1 levels.2,3

Pituitary gigantism arises from excessive GH and IGF-1 prior to growth plate fusion. Should hormone excess present after epiphyseal plate fusion, the condition is referred to as acromegaly. Both disorders are extremely rare and symptoms can be intermittent, often confounded by coexisting conditions. The common therapeutic approach for these disorders is aimed at regulating circulating GH and IGF-1 levels using recombinant hormone therapy,8 but ongoing in vitro and in vivo studies are employing newer methods of treatment. To date, treatments have the greatest impact when started prior to puberty.

Cancer

IGF-1 is a significant signaling molecule with regards to cancer cell transformation and proliferation, and IGF-1/IGF-1R binding and activation is the key step in downstream events including mitogenesis and apoptosis inhibition.1

When IGF-1 binds to IGF-1R, the tyrosine kinase activates the phosphoinositide 3-kinase (PI3K)-AKT pathway and many integral proteins involved in cellular metabolism, apoptosis, cell adhesion, and angiogenesis are regulated within this pathway. Numerous in vitro and in vivo studies have been performed that focused on the modulation of total and free IGF-1 levels and relative impact on tumor growth, invasiveness and response to therapeutics.6,9 These treatments range from siRNA knockdowns in mammalian tissue culture to targeted antibodies (biologics) specific for the IGF-1R.1,3,9 Inhibition of IGF-1R activation via small molecule inhibitors or a biologics could be a large step towards identifying viable cancer therapies.

Diabetes

IGF-1 is highly homologous with insulin and can readily bind to the insulin receptor (IR). However, the IGF-1R exhibits a significantly higher affinity for IGF-1 binding than for the IR. Due to this relationship, scientists have theorized that IGF-1 can be used to treat diabetes, especially if started prior to puberty.2,3 Preliminary studies have demonstrated positive results in this approach, yet the mechanism by which IGF-1 treatments might correct for insulin resistance clinically remains unclear.2

References

1. Baserga R et al. The IGF-1 Receptor in Cancer Biology. Int. J. Cancer. ;
2. Le Roith D. Insulin-Like Growth Factors. N Engl J Med. ;
3. Bonday C et al. Clinical Uses of Insulin-like Growth Factor I. Ann Int Med ; (7)
4. Clemmons DR & Van Wyk JJ. Factors controlling blood concentration of somatomedin C. Clin Endocrinol Metab. ;
5. Daughaday WH & Rotwein P. Insulin like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr Rev ;
6. Guevara-Aguirre J et al. Growth Hormone Receptor Deficiency is Associated with a Major Reduction in Pro-Ageing Signaling, Cancer, and Diabetes in Humans. Sci Transl Med ; ra
7. Scarth J. Modulation of the growth hormone-insulin-like growth factor (GH-IGF) axis by pharmaceutical, nutraceutical and environmental xenobiotics: an emerging role for xenobiotic-metabolizing enzymes and the transcription factors regulating their expression. A review. Xenobiotica. ; 36 (2–3)–
8. Rosenbloom AL. The role of recombinant insulin-like growth factor I in the treatment of the short child. Curr Opin Pediatr ; 19(4)–
9. Kalebic T et al. In Vivo Treatment with Antibody against IGF-1 Receptor Suppresses Growth of Human Rhabdomyosarcoma and Down-Regulates p34cdc2. Cancer Res ;
Daughday WH et al. Serum somatomedin binding proteins: physiological significance and interference in radioligand assay. J Lab Clin Med. ;

Additional References

Click here for a complete pdf listing of IGF references.

Sours: https://www.alpco.com/role-igfgrowth-hormoneigf-axis
The IGF-1 Trade-Off: Performance vs. Longevity

Insulin-Like Growth Factor 1: At the Crossroads of Brain Development and Aging

Insulin-like growth factor 1 (IGF1) signaling is an essential factor for early brain development, but its role in the aging brain remains unclear. In fact, while reduced IGF1 signaling with age has been historically observed as a causative factor in the aging process, correlation does not imply causation, and falling IGF1 signaling with age may in fact attenuate the effects of aging. Further work must be done in order to truly discern the role and effects of IGF1 signaling in the aging brain.

Insulin-Like Growth Factor Downstream Signaling Cascades and Cellular Effects

IGF-1 is synthesized primarily in the liver, where its synthesis is regulated by pituitary secretion of growth hormone (GH). It is central to the somatrotropic axis, acting downstream of GH to promote anabolic processes and tissue growth throughout life. IGF1 is also synthesized locally in many organs, including the brain. Both in circulation and in tissues, IGF1 is bound to high affinity IGF1-binding proteins (IGFBPs), which modulate interactions between IGF1 and its receptor.

The biological actions of IGF1 are mediated through IGF1R, a membrane-bound receptor tyrosine kinase (RTK). Binding of IGF1 to its receptor causes autophosphorylation of the intracellular component, leading to enzymatic activation and subsequent phopshorylation of the insulin receptor substrate-1 (IRS1) protein on multiple tyrosine sites. These phosphotyrosine sites then serve as docking sites for numerous intracellular signaling proteins. By bringing these interacting proteins together, complex signaling pathways are begun, including the canonical PI3-kinase and mitogen-activated protein (MAP) kinase pathways.

IGF-1R activation triggers the PI3kinase-Akt signaling pathway, which promotes cell growth and maturation. IRS1 binds PI3kinase which phosphorylates PIP2 to PIP3. PIP3 binds two protein kinases; Akt and PDK1, leading to activation of Akt, which acts on numerous proteins throughout the cell to promote cell growth and survival. Downstream substrates of Akt include mammalian target of rapamycin (mTOR), which stimulates ribosome production and protein synthesis, and Bad, a pro-apoptopic protein that is inhibited by Akt phosphorylation. Another effect of IGF1R activation through PI3kinase-Akt signaling is inhibitory phosphorylation of pro-apoptopic glycogen synthase 3² (GSK3²), which is associated with increased glycogen storage in projection neurons in the post-natal brain, as well as reduced tau hyperphosphorylation which causes neuronal death (Bondy and Cheng, ). IGF1-induced PI3K-Akt signaling is also linked to production of GLUT4 glucose transporters and translocation to neuronal cell membranes, promoting glucose uptake into neurons (Bondy and Cheng, ). This corresponds to studies demonstrating increased glucose utilization in areas of higher IGF1 and IGF1R expression in the developing brain, and reduced glucose utilization in IGF1 null brains (Cheng et al., ). This pathway also leads to inactivation of FOXO1, preventing FOXO-driven transcription of pro-apoptopic genes (Yin et al., ). Hence, PI3K signaling directly inhibits the pro-apoptopic machinery via multiple pathways.

IGF1R also phosphorylates the Sch protein, which recruits the GDP2/SOS complex, leading to activation of Ras, thereby triggering the MAP kinase pathway central to growth-related gene transcription and mitogenesis (Figure 1).

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Figure 1. A schematic of Insulin-like growth factor 1 (IGF1) molecular pathways activated in brain maturation and aging. Black rows indicate inhibition, red rows indicate activation. The underlined proteins have been identified to be genetically associated to aging.

IGF1-Signaling, Aging and Lifespan in Model Organisms

IGF1 signaling is central to pathways that promote cell growth and survival, maturation and proliferation, allowing for tissue growth and renewal. Furthermore, the activity of the GH-IGF1 somatotrophic axis decreases with age, and is almost undetectable in people over 60 years (Junnila et al., ). This has led to many theories that upregulation of the GH/IGF1 pathway may delay aging. However, studies of IGF1 signaling on nematodes and many other species have suggested that, on the contrary, downregulation of IGF1 signaling delays aging and increases lifespan.

The IGF1 signaling pathway is an evolutionarily ancient pathway, conserved from C. elegans through to modern humans. The C. elegans IR-IGF1 receptor homolog is Daf Mutations that lower the level of Daf-2 double the lifespan of the C. elegans model (Kenyon et al., ). Exactly how Daf-2 mutations increase C. elegans lifespan in unclear. Some daf-2 mutants adopt a quiescent state of reduced movement and fertility known as the dauer state, whereas other mutants are shown to have a lower metabolic rate, and other mutants again demonstrate a metabolic shift to fat production. However, these findings are not consistent among all daf-2 mutants, and can therefore not be coupled to lifespan extension (Kenyon, ). Another theory is that daf-2 mutants are better able to withstand oxidative stress (Holzenberger et al., ). Reduced Daf-2 activity downregulates Akt-mediated inhibition of Daf (FOXO homolog), allowing Daf translocation to the nucleus for target gene activation. The transcriptional targets of Daf/FOXO may be at least in part responsible for the stress resistance and longevity associated with Daf-2 mutants (Lin et al., ; Gami and Wolkow, ).

The impact of altered Daf-2 activity on lifespan varies between different cell lineages. While present in ectodermal, mesodermal and endodermal lineages, it is reduction in ectodermal (neuronal, skin tissue) daf-2 activity that induces a dauer state (Guarente and Kenyon, ). Restoration of insulin-like signaling alone in Daf-2 mutants reverts these mutants back to a wild-type lifespan, whereas restoration of insulin-like signaling in muscle or adipose tissue had no effect on lifespan (Wolkow et al., ). This study provides persuasive evidence that insulin/IGF1 signaling in neurons regulates lifespan. Interestingly, reduction in sensory input to the olfactory system by mutations in sensory cilia or olfactory support cell ablation can increase lifespan by up to 50% without affecting development or reproduction. This suggests that sensory neurons influence lifespan and this is at least partly mediated through Daf-2 signaling (Apfeld and Kenyon, ). Downstream of Daf-2 (IGF1R), mutations in age-1 (PI3K homolog) also increase lifespan, suggesting that reduction in factors downstream of IGF1 signaling are sufficient to extend lifespan (Morris et al., ).

The effect on lifespan by inhibition of insulin/IGF1 signaling observed in the C. elegans model is conserved in other species, including the Drosophila fly, whereby inhibiting IGF1 signaling or increasing the activity of FOXO (the Daf homolog) in adipose tissue increases lifespan (Kenyon, ). Heterozygous mutation of the insulin receptor (IR) in Drosophila extends lifespan by up to 85% (Tatar et al., ). Furthermore, mutation of CHICO, the IRS homolog, extends lifespan by 48% in homozygotes and 36% in heterozygotes (Clancy et al., ). A striking inverse correlation between IGF1 levels and lifespan is also observed in mice (Kenyon, ). While IGF1R null mice die shortly after birth (Liu et al., ), heterozygous knockout (KO) of IGF1R extends lifespan by 26% compared to wild-type littermates (Holzenberger et al., ). This mouse model of reduced IGF1 signaling were normal in size, and displayed normal energy metabolism, but showed greater resistance to oxidative stress (Holzenberger et al., ).

Interestingly, this is in contrast to mice with IR or IRS KO, which show severe insulin resistance and die earlier due to hyperglycemia. From invertebrates to mammals, IGF1 signaling and insulin signaling became distinct cellular pathways with different downstream effects. Therefore, IGF1 signaling in mammals can be manipulated without interfering with systemic glucose metabolism.

In humans, lowered IGF signaling is also shown to improve longevity. Mutations known to impair IGFR function are observed in Ashkenazi Jewish centenarians (Suh et al., ). Additionally, Akt, FOXO3A and FOXO1A mutations are linked to longevity in numerous patient cohorts (Willcox et al., ; Flachsbart et al., ; Kenyon, ).

The findings that reductions in Daf-2/IGF1R signaling can radically increase lifespan would suggest that IGF1 signaling is directly linked to the aging of organisms, which is in contradiction to the theory that a fall in the activity of GH-IGF1 somatotropic axis underlies the mechanism of aging.

Although in the whole organism a general decrease of IGF signaling delays aging, this review will focus on the role of IGF1 signaling in the developing and aging brain, where IGF1 signaling in the brain promotes development and, in some cases, appears to attenuate age-related changes. Numerous studies outlined below demonstrate the neurotrophic effects of IGF1 signaling, giving evidence for promotion of neurogenesis, development and maturation, myelination, prolonged survival and resistance to injury.

IGF1 and the Developing Brain: Expression Patterns of IGF1 and IGF1R in the Developing Brain

IGF1 is produced by all major cell types in the CNS. IGF1 expression peaks perinatally and falls throughout life, though it persists in discrete brain regions associated with continual renewal and remodeling. This is in contrast to the IGF1 receptor, which is shown to be widely expressed throughout the brain, and concentrated in neuron-rich areas including the granule cell layers of olfactory bulb, dentate gyrus and cerebellar cortex, with little hybridization in white matter regions (Bondy et al., a). IGF1R is expressed in all neuroepithelial cell types, and shows a relatively stable pattern of expression from early development to maturity (Bondy et al., b). There is, however, a period of increased IGF1R expression coinciding with increased IGF1 expression in specific sensory and cerebellar projecting neurons during late post-natal development (Bondy et al., b). Early post-natal IGF1 expression was identified in brain regions where neurogenesis persisted after birth, including the cerebellum, olfactory bulb and hippocampus, and was shown to fall after this period of neuronal proliferation (Bach et al., ; Bartlett et al., ).

IGF1 expression persists in these areas in adult brains, but at levels much lower than that of early neonatal animals (García-Segura et al., ). These expression patterns highlight the association between regions of increased neurogenesis and local IGF1 and IGF1R expression during early development.

While local IGF1 expression falls shortly after birth, there exists throughout life an active transport mechanism that allows peripheral circulating IGF1 to cross the blood brain barrier (Fernandez and Torres-Alemán, ). This finding, combined with the fact that IGF1 receptor expression in the brain persists throughout life, suggests a role for peripherally produced IGF1 in adult brain function. Therefore, while locally produced IGF1 appears to play a role in brain function during prenatal and early post-natal development, peripherally produced IGF1 may have a continued role in the adult brain.

IGF1 and the Developing Brain: Evidence from In Vitro and In Vivo Studies on the Effect of IGF1 on Brain Size, Neuronal Cell Number, Axonal Growth and Myelination during Early Development

IGF1 has been shown to have pleiotropic actions in all neural cells, including neurons, oligodendrocytes and astrocytes, by increasing cell number and promoting maturation and myelination. This has been proven through in vitro culture studies, and through both overexpression and under-expression studies in transgenic mice.

IGF1 and the Developing Brain: Effects of IGF1 on Neural Stem Cells

In vitro studies examining the effect of IGF1 in neural stem cells report increased neural progenitor cell proliferation and maintenance in cell culture following treatment with IGF1 (Drago et al., ; Supeno et al., ). IGF1 was found to be more potent than insulin in stimulating mitosis of sympathetic neuroblasts (DiCicco-Bloom and Black, ). Furthermore, numbers of neurons produced from neural stem cell clones was increased following administration of IGF1 or heparin or withdrawal of FGF2 from cell culture, the effects of which were negated by administration of IGF1 and IGF1BP antibodies (Brooker et al., ). Examination of adult rat hippocampal progenitor cells showed uniform IGF1R expression, and the combined addition of IGF1 and FGF2 to these cells in culture increased DNA synthesis and cell division, without significant changes in the rate of cell death (Åberg et al., ).

IGF1 and the Developing Brain: Evidence from Prenatal Overexpression and Underexpression Studies

Popken et al. () demonstrated through nestin-driven overexpression of IGF1 early in the embryonic development of transgenic mice a 6% increase in brain weight by embryonic day 16, associated with a cortical plate volume 42% greater and a total cell number 54% greater in the transgenic mice compared to controls. This increase in total cell number was attributed to a 15% increase in proliferating cells in the ventricular and subventricular zones of the embryonic cerebral cortex, which give rise to the neuronal and glial cell types respectively. At post-natal day 12, a 27% increase in overall brain weight was observed, with significant increases in volume and total cell number in certain brain regions including the cerebral cortex, subcortical white matter, caudate-putamen, hippocampus, dentate gyrus and habernacular complex (Popken et al., ). This enhancement in neuroepithelial cell proliferation by IGF1 during embryonic neurogenesis has been shown to result from acceleration through the cell cycle (Hodge et al., ). Further studies in the same mouse model reported that, in ddition to enhanced proliferation of neural progenitors, there are reduced numbers of apoptopic cells throughout the cerebral cortex both prenatally and post-natally in the mice showing IGF1 overexpression, correlating with overall increased brain weight 9 months post-natally (Hodge et al., ).

Conversely, examination of homozygous IGF&#x;/&#x; KO mice at 2 months demonstrates a grossly structurally normal brain, but a 38% reduction in brain weight. A reduction in parvalbumin-containing neurons in the hippocampus and striatum was shown, as well as a significant reduction in the thickness of the dentate gyrus granule cell layer (Beck et al., ). IGF1&#x;/&#x; mice also show reduced dendritic length and complexity, and a 16% reduction in synaptotagmin levels, suggesting a reduction in the number of synapses, in the frontoparietal cortex (Cheng et al., ). A study by Liu et al. () showed that brain-specific IGF1R heterozygous KO mice had brain weights 56% lower than controls at birth and 60% lower at post-natal day The hippocampus was particularly affected, where the rate of growth post-natally was much lower in IGF1R heterozygous KOs compared to wild-type controls, with a greater fall in the numbers of neurons in the CA1&#x;3 region and a smaller rise in the neuronal cell number in the dentate gyrus post-natally. This was attributed to a higher rate of cell death in IGF1R heterozygous KO mice. In all experiments performed, the phenotype was more severe in the two IGF1R homozygous KO mice that survived to adulthood, suggesting that degree of brain growth retardation was related to the level of IGF1R expression (Liu et al., ).

IGF1 and the Developing Brain: Evidence from Post-Natal Overexpression and Underexpression Studies

While the above studies examined the downstream effect of prenatal IGF1 over-and under-expression on subsequent brain development, other studies had focused on the role of IGF1 in the post-natal period, given that IGF1 mRNA expression in the developing rodent brain peaks in the first two post-natal weeks of life. Using a line of transgenic mice that begin to express the transgene at birth, causing brain-restricted overexpression of IGF1, studies have shown that IGF1 overexpression causes increases in brain weight after day 10, with enlargement of the brainstem, cerebellum, cerebral cortex and hippocampus (Ye et al., ; Dentremont et al., ; O&#x;Kusky et al., ). Cerebellar weight was increased by 90%, with concomitant increases in granule and Purkinje cell numbers by 82% and 20% respectively (Ye et al., ).

Specifically, given the persistence of IGF1 expression in the hippocampal subventricular zone and dentate gyrus post-natally, the in vivo actions of IGF1 on growth and development of the hippocampal dentate gyrus up to post-natal days have been investigated. Transgenic IGF1 overexpression was shown to increase granule cell layer and molecular cell layer by 27%&#x;69%, total number of neurons by 29%&#x;61%, and total number of synapses in the molecular layer by 42%&#x;% compared to control littermates (O&#x;Kusky et al., ). Increased neuronal numbers in the dentate gyrus in the post-natal period is thought to be due not only to increased neurogenesis but also reduced neuronal death.

Numerous studies have reported that IGF1 promotes cell survival in the post-natal brain. Transgenic mice overexpressing IGF1 have significantly fewer apoptopic cerebellar neurons at post-natal day 7 compared to wild-type controls, with increased expression of anti-apoptopic proteins and reduced expression of pro-apoptopic proteins (Chrysis et al., ). Similarly, in the dentate gyrus of post-natal brains, IGF1 null mice had higher rates of granule cell proliferation but lower numbers of mature granule cells, suggesting the IGF1 promotes survival of granule cells in the post-natal period (Cheng et al., ). For a focused review on the function of IGF1 in brain development and plasticity see Dyer et al. (). The role of IGF1 in improving neuronal survival and reorganization following injury in both the developing and aging brain are outlined further on in this article.

IGF1 and the Developing Brain: Oligodendrocyte Development and Myelination

In addition to the effect of IGF1 on neuronal proliferation and survival in the developing brain, the effect on glial cells, especially oligodendrocytes, has been investigated through in vitro and in vivo studies.

In vitro studies show that administration of IGF1 to oligodendrocyte cells in culture promotes oligodendrocyte proliferation, differentiation, myelin production and survival (McMorris and Dubois-Dalcq, ; Mozell and McMorris, ; Barres et al., ; Ye and D&#x;Ercole, ).

In vivo studies comparing transgenic mice with increased IGF-1 expression to those with IGFBP-1 expression (an inhibitor of IGF1) have shown that the mice with increased IGF-1 expression demonstrate higher numbers of oligodendrocytes, increased percentage of myelinated axons and increased thickness of myelin sheath compared to the transgenic mice with increased IGFBP-1 expression (Ye et al., ). In another study, prenatal overexpression of IGF1 in transgenic mice produced a mouse brain 55% larger, owing to an overall increase in total cell number, and a total myelin brain content % higher than that found in their non-transgenic littermates, which was not associated with a higher percentage increase in oligodendrocyte number, suggesting that increased meylin content was due to increased myelin production per oligodendrocyte (Carson et al., ).

Conversely, examination of IGF1 KO mice reported reduced cerebral and spinal cord white matter volume due to fewer myelinated axons and oligodendrocytes at post-natal day 55 (Beck et al., ). Further detailed study of IGF-1 KO mice showed consistently reduced overall brain weight 1 week post-natally compared to wild-type littermates, affecting all brain regions, as well as reduced myelination in all brain regions during the first 3 weeks of life, though this normalized and became similar to that of wild-type mice thereafter. Ths coincided with reduced levels of myelin-binding protein (MPB) and proteolipid protein (PLP) in IGF-1 KO mice during the first 3 weeks, which also normalized and became similar to controls by 10 weeks, while percentage oligodendrocyte number was persistently reduced in IGF-1 KO mice at weeks 1, 3 and Additionally, reduced levels of the median subunit of neurofilament (a neuron-specific intermediate filament which acts a s a marker of axon growth) was reduced in IGF-1 KO mice and did not recover as the brain matured (Ye et al., ).

These studies suggest the importance of prenatal IGF1 expression in the developing brain for axon growth and CNS myelination in the early post-natal brain.

IGF1 and the Developing Brain: Evidence from Studies of External Stimuli Known to Promote Past-Natal Cortical Maturation

Certain external stimuli have been shown to promote neurodevelopment, and in many cases these studies show that the effect is mediated by IGF1 signaling. In particular, the visual cortex is studied in the context of how brain development is affected by external sensory input. For instance, environmental enrichment (EE), defined as a complex of inanimate and social stimulation, is known to promote hippocampal neurogenesis and increase dendritic branching and synaptogenesis. It accelerates development of the visual cortex, causing enhanced visual acuity and increased expression of BDNF, which is known to act through the GABAergic system to promote neuroplasticity (Cancedda et al., ). A further study showed that this effect of EE on post-natal visual cortical development is inhibited by treatment of enriched pups with IGF1 antagonists and mimicked by treatment of non-EE pups with IGF1 infusion (Ciucci et al., ). Similarly, maturation of the visual system in preterm infants was accelerated by massage therapy, as evidenced both through electrophysoiogical studies and through visual acuity testing performed 3 months later. This correlated with higher serum levels of IGF1 and IGFBP3 in massaged infants. This was similarly shown in rat pups undergoing tactile stimulation, who showed faster maturation of electrophysiological tracings and higher levels of IGF1 in the brain compared to controls (Guzzetta et al., ).

While the above studies use the EE model to investigate the role of IGF1 in post-natal cortical maturation, other studies have used the model of monocular deprivation (MD) to assess the role of IGF1 in neuroplasticity and reorganization, whereby blocking visual input from one eye leads to structural organization of the visual cortex, allowing for ocular dominance of the intact eye. Expression of regulatory IGFBP5 gene is highly upregulated after MD, and the effects of MD on ocular dominance plasticity are negated by exogenous application of IGF1 (Tropea et al., ). Given that the capacity of ocular dominance plasticity in response to short deprivation is a marker of circuit immaturity, this study further supports the theory that IGF1 signaling promotes brain maturation in juvenile animals.

IGF1 and the Adult Brain: Adult Neurogenesis

As well as the role of IGF1 in early brain development, much research has been done into the role of IGF1 in ongoing neurogenesis and CNS plasticity in the adult brain. In most regions of the brain, neurogenesis ceases after birth. IGF1 mRNA expression correlates both temporally and spatially with these periods of rapid neurogenesis in the perinatal brain. Similarly, there are certain brain regions, namely the dentate gyrus and subventricular zone of the hippocampus, where neurogenesis persists into adulthood, and this correlates with the finding that IGF1 expression in the brain is diffuse during antenatal development, but persists only in the subventricular zone and dentate gyrus of the hippocampus after birth (Anderson et al., ). IGF1 expression levels decrease again later in life, again at a time that corresponds with a decrease in hippocampal neurogenesis. Therefore, much research has been done to investigate how manipulation of IGF1 signaling affects adult hippocampal neurogenesis.

It has already been noted in in vitro studies that adult hippocampal neural progenitor cells express IGF1R, and that administration of IGF1 with FGF2 increased progenitor cell proliferation (Åberg et al., ). This group further suggested that low-dose IGF1 treatment triggered a small increase in the differentiation of neuronal progenitors into neurons. A further in vivo study used hypophysectomied rats, as this model would have low levels of circulating IGF1. Six days of peripheral subcutaneous IGF1 administration increased proliferation of neuronal progenitors in the hippocampal dentate gyrus, as evidenced by BrdU uptake. After 20 days of subcutaneous IGF1 administration, these new cells expressed neuronal-specific proteins, suggesting stimulation of neurogenesis (Aberg et al., ). This suggests that, while local IGF1 mRNA expression levels fall after birth, peripheral IGF1 plays a role in adult hippocampal neurogenesis.

Another study looked at the effect of local IGF1 administration on neuronal cell numbers in the dentate gyrus. Mice aged 5, 18 and 28 months were examined. The dentate gyrus was divided for analysis into the proliferative subgranular zone (PZ), the granular cell layer (GCL) and the hilus, and the numbers of new cells were quantified using BrdU labeling. This study showed that the number of BrdU labeled cells decreases with age, with 80% fewer BrdU labeled cells in the PZ of the 18 month old rats than the 5 month old rats, with a much smaller but significant decrease in BrdU labeled cells in the hilus, though no age-related changes were observed in the GCL. Intracerebroventricular infusion of IGF-I maintained an approximately three-fold increase in the number of BrdU-labeled cells in the PZ, GCL and hilus in old rats examined 31 days after BrdU injection. IGF-I did not, however, selectively induce a neuronal fate since the percentage of BrdU-labeled cells in IGF-I-treated animals that colocalized NeuN was identical to that observed in age-matched controls (Lichtenwalder et al., ). Transgenic overexpression of IGF1 was similarly shown to increase the proliferation of neural stem cells in the subgranular and subventricular zones of adult mice brains (Yuan et al., ). In this study, however, IGF1 overexpression also led to an increase in the differentiation of neuronal stem cells into neurons, in contrast to the previous study (Yuan et al., ).

A recent study has looked in detail at the effects of both global and brain-specific KO of IGF1 in adult hippocampal neurogenesis. Global IGF1 KO mice had both low brain IGF1 expression and low serum IGF1 levels, and showed a fold reduction in hippocampal volume compared to controls. Using extensive immunohistochemisty studies, this group demonstrated higher staining for markers of immature differentiation from neural progenitor cells to neurons in IGF&#x;/&#x; mice compared to controls, reduced staining for markers of the later stages of differentiation, and disorganized staining for markers of differentiated granule cells in the GCL of the dentate gyrus compared to controls (Nieto-Estévez et al., b). IGF1&#x;/&#x; cells in the GCL showed greater proliferative capacity but more immature morphology compared to controls (Nieto-Estévez et al., b). The group then studied the effects of brain-specific IGF1 KO on adult hippocampal neurogenesis. These mice had normal body size and total brain volume compared to controls, but reduced volume of the GCL of the dentate gyrus. As with the global IGF1 KO mice, these mice demonstrated greater immunostaining for immature differentiation markers and more disorganized distribution of mature differentiation markers in the GCL of the dentate gyrus (Nieto-Estévez et al., b). In all, this study of two IGF1&#x;/&#x; mouse models demonstrates that a lack of IGF1 in the brain is associated with accumulation of neuronal progenitor cells, impaired transition from neural progenitor to mature granule cell neurons, a reduction in mature morphology of granule cells and disorganization of the GCL (Nieto-Estévez et al., b), all of which supports the idea that IGF1 signaling is key in promoting organized adult hippocampal neurogenesis. Thus, IGF1 not only promotes adult neurogenesis through increased stem cell proliferation, but also through organized cell migration. This is similarly demonstrated in the study of IGF1 KO mice who showed reduced neuroblast migration from the subventricular zone to the olfactory bulb and poor organization of immature neurons in the olfactory bulb compared to normal mice (Hurtado-Chong et al., ).

Multiple processes are thought to stimulate adult neurogenesis, the best studied of which is exercise, and recent studies show that this effect is mediated through IGF1 signaling. This was shown through administration of an antibody that blocked systemic IGF1 uptake into the brain parenchyma, which reversed the exercise-induced effects on hippocampal neurogenesis (Trejo et al., ). Blocking IGF1R reverses exercise-induced increases in BDNF, suggesting that the downstream effects of IGF1 signaling are at least in part medicated though upregulation of brain-derived neurotrophic factor (Ding et al., ).

Exercise promotes functional recovery of spatial memory acquisition in rats who have undergone hippocampal injury, and attenuated the loss of motor coordination in rats following brainstem injury or Purkinje cell degeneration (Carro et al., ). The neuroprotective effects of exercise demonstrated in this study were reduced in rats who received subcutaneous IGF1 antibody treatment (Carro et al., ). Memory deficits are frequently reported in depression, and imaging studies have shown decreased hippocampal volume in patients with depression. Antidepressant therapy, including SSRIs and ECT, is known to cause upregulation of BDNF, and this has recently been shown to be IGF1-dependent (Chen and Russo-Neustadt, ). For a focused review on IGF1 and neurogenesis please see Nieto-Estévez et al. (a).

IGF1 and the Adult Brain: Prolonged Survival, Reduced Cell Death, Resistance to Injury, Reparation and Neuroplasticity in Response to Environmental Cues

In addition to its role in neurogenesis in the adult brain, IGF1 has been studied for its effect on CNS reparation and plasticity using injury and sensory deprivation models. These studies may indicate that falling levels of IGF1 in the aging brain may indirectly lead to aging through reduced reparation, remodeling and resistance to stress.

One model of injury is the cerebellar deafferentiation model, whereby the olivocerebellar pathway is transected. The remaining olivocerebellar fibers reinnervate the hemicerebellum, but only in the early post-natal period (days 7&#x;10). However, injection of IGF1 into the cerebellum of rats aged 11&#x;30 days allowed for reinnervation of this pathway, indicating that this period of neuroplasticity is extended with use of IGF1 (Sherrard and Bower, ). IGF1-mediated reinnervation of the olivocerebellar pathway caused full motor recovery in rats rendered ataxic after 3-acetylpyridine-induced cerebellar injury (Fernandez et al., ).

More evidence for its role in reparative neuroplasticity is shown through the use of excitotoxicity models. Chronic intracerebral administration of IGF1 following an excitotoxic lesion in the dentate gyrus caused increased dendritic formation in young neurons in the dentate gyrus compared to untreated controls, and recovery of contextual fear memory, which is a dentate gyrus-dependent function (Liquitaya-Montiel et al., ). Another model of dentate gyrus injury is injection of trimethyltin, which is shown to cause elevated IGF1 mRNA levels in the hippocampus. Mice deficient in IGF1 had a significant level of CA1 hippocampal cell death, implying a role for IGF1 in CA1 hippocampal cell survival (Wine et al., ).

IGF1 is also thought to be protective in hypoxic-ischemic injury. Intracerebroventricular infusion of IGF1 during perinatal asphyxia in near-term foetal sheep was linked to reduced loss of striatal cholinergic and GABAergic neurons compared to controls on post-mortem examination (Guan et al., ). A single dose of intracerebroventricular IGF1 2 h hypoxic-ischemic injury reduced somatosensory deficits for up to 20 days after the initial insult (Guan et al., ). The effects of malnourishment in the post-natal period are also attenuated by IGF1 administration. Malnourished mice treated with IGF1 comparable brain weights and cell numbers compared to nourished controls, and higher numbers of oligodendrocytes and expression of myelin markers MPB and PLP, suggesting that this protective effect is through increased myelination (Ye et al., ).

The effects of IGF1 signaling following traumatic brain injury (TBI) have also been studied. Overexpression of IGF1 was shown to increase the density of hippocampal immature neurons following TBI. This was shown to be the result of post-traumatic proliferation and differentiation of neural stem cells into immature neurons, rather than through protection against initial insult. IGF1 overexpression also enhanced dendritic arborization of immature neurons compared to normal controls (Carlson et al., ). Thus, through enhanced neurogenesis and maturation, IGF1 overexpression accelerated recovery.

The role of IGF1 in activity-dependent neuroplasticity is also demonstrated through the use of sensory deprivation models. MD is a model of reduced activity-dependent activity, whereby one eye is deprived of visual stimuli, which leads to neuronal network reorganization with subsequent ocular dominance of the normal eye. IGFBP-5 is highly upregulated after MD, and administration of IGF1 promotes recovery of normal visual function in these models (Tropea et al., ) through upregulation of BDNF (Landi et al., ). Based on these findings, studies were performed to investigate whether administration of IGF1 in adult brains restores neuroplasticity. Adult rats underwent MD by eyelid suturing, and were then treated with IGF1. This was shown to trigger ocular dominance plasticity compared to MD rats untreated with IGF1 (Maya-Vetencourt et al., ). Furthermore, in rats rendered amblyopic by long-term sensory deprivation, those treated with IGF1 prior to restoration of sensory input showed full recovery of visual acuity compared to rats untreated with IGF1 (Maya-Vetencourt et al., ). Downregulation of intracortical inhibitory GABA activity, increased utilization of glucose, and interaction with 5-HT were offered as potential mechanisms through which IGF1 mediates this restoration of plasticity. An alternative sensory deprivation model is that of hindlimb unloading (HU). In adult rats, 14 days of HU decreases IGF1 levels in the somatosensory cortex (Mysoet et al., ) and shrinks the somatotopic representation of the hindpaw. Administration of IGF1 prevents this change in somatotopic representation (Papadakis et al., ; Mysoet et al., ). These interventional studies have demonstrated that IGF1 administration alters neuronal plasticity in response to sensory deprivation in adult animals.

The above studies outline the role of IGF1 in adult neurogenesis, reparation and reorganization in response to stressors. It is therefore possible that loss of these IGF1-driven mechanisms with age leads to age-related cognitive changes. However, numerous studies outlined later in this article report the contrary theory that it is a reduction IGF1 signaling that is neuroprotective following CNS insult.

IGF1 and the Aging Brain: Evidence from Molecular Biology

The GH-IGF1 signaling pathway is the best characterized hormonal pathway in the process of aging. Pulsatile pituitary secretion of GH in response to stimuli such as induced hypoglycemia or arginine administration declines with age (Laron et al., ). This is associated with concomitant declines of circulating IGF1 levels (Johanson and Blizzard, ). Numerous age-related changes in the brain have been identified that suggest changes in IGF1 signaling. The density of GH receptors decreases with age, while reports are conflicting regarding age-related changes in IGF1 receptor density, with one group reporting increased density of IGF1R expression in the CA3 region of the hippocampus (Chung et al., ) and others reporting reduced decreased hippocampal and cortical IGF1R density in aging rats (D&#x;Costa et al., ; Sonntag et al., ). Expression of IGF1 mRNA was reported to be reduced in the cerebellum of aging rats (Pañeda et al., ). These findings would suggest that IGF1 signaling is reduced in the aging brain. How this is linked to functional changes in the aging brain is unclear.

IGF1 and the Aging Brain: Evidence from Cognitive Testing

Therefore, studies have been done to examine whether reduced IGF1 signaling is linked to cognitive dysfunction. Studies in humans found a significant correlation between better perceptual motor performance, information processing speed and fluid intelligence and higher circulating IGF1 levels (Aleman et al., , ). Others have found a correlation between higher IGF1 levels and higher MMSE scores (Paolisso et al., ; Rollero et al., ). The MMSE is a well-validated test in terms of repeat-test reliability and tracking of cognitive function over time. In a 2 year prospective study, higher levels of circulating IGF1 levels were associated with reduced cognitive decline over the study period. However, these findings are inconsistent, with many studies also reporting no correlation between IGF1 and attention, fluid intelligence, memory or cognitive decline (Papadakis et al., ; Aleman et al., , ).

IGF1 and the Aging Brain: Evidence from Interventional Studies

In any case, correlation does not imply causation. Therefore interventional studies in human were performed to assess if GH or IGF1 levels improved cognitive function, but the results were conflicting and ultimately inconclusive (Papadakis et al., ; Friedlander et al., ). In mice, intracerebroventricular infusion of IGF1 attenuated age-related deficits in working and reference memory as assessed by Morris water maze and object recognition tasks (Markowska et al., ).

Further work has been done in mice studies to assess the downstream molecular effects of IGF1 administration in an aging brain. Intracerebroventricular infusion of IGF1 has been shown to increase microvascular density in aged animals (Sonntag et al., b). Furthermore, it increases hippocampal NMDAR2A/B subunit expression (Sonntag et al., a), which is relevant because NMDAR2B subunit ablation has been shown to impair spatial learning (Clayton et al., ). Local IGF1 increases local glucose utilization in the anterior cingulate cortex of aged rats (Lynch et al., ). Finally administration of IGF1 attenuates the age-related decline in neurogenesis in aged rats (Lichtenwalder et al., ).

IGF1 and Disease: Evidence from Disorders of Neurodevelopment and Neurodegeneration

IGF1 and Disorders of Impaired Neurodevelopment

In order to better understand the physiological roles of IGF1 in normal neurodevelopment and aging, one can look at IGF1 activity in the context of known disorders of neurodevelopment and neurodegeneration. For instance, Rett Syndrome is an X-linked neurological disorder characterized by seemingly normal post-natal development initially, followed by a sudden deterioration in function, with loss of acquired functional and motor skills at 12&#x;18 months of age. Rather than being a neurodegenerative process, the underlying pathology is thought to be a stagnation in neuronal maturation. It is caused by a mutation in the MECP2 gene, which codes a transcriptional modulator. It is abundant in neuronal tissue and its expression correlates with that of synaptic maturation. A downstream factor of MECP2 is BDNF, which activates the same PI3K and MAPK pathways that are activated by IGF1 signaling. Therefore, subcutaneous injections if IGF1 have been administered to both mouse models and human subjects to assess if this intervention can reverse the Rett Syndrome phenotype. IGF1 has been shown to increase brain weight, dendritic spine density and levels of PSD, a post-synaptic scaffold protein that promotes synaptic maturation, in MECP2 null mice, as well as partially reverse the reduction in amplitude of excitatory post-synaptic current in MECP2 mice (Tropea et al., ). Interestingly, persistence of ocular dominance plasticity following MD, a marker of neuronal immaturity, is a feature of MECP2 mouse models of Rett syndrome. It is prevented by pre-treatment with IGF1, giving further evidence for the role of IGF1 in neuronal circuit maturation and reduction in neuroplasticity (Tropea et al., ; Castro et al., ). These studies indicate the role of IGF1 signaling in neuronal circuit maturation. Similarly, work in SHANK3 deficient models of autism have showed that treatment with IGF1 promotes maturation of excitatory synapses (Shcheglovitov et al., ), and reverses deficits in LTP, AMPA signaling and motor function (Bozdagi et al., ). Therefore, through the study of IGF1 in the context of disorders caused by poor brain development, it appears that IGF1 promotes neuronal development and brain maturation. For a review focused on IGF1 function in neurodevelopmental disorders, see Vahdatpour et al. ().

IGF1 and Disorders Associated with Brain Aging

Findings through the study of IGF1 in age-related neurodegenerative disorders, however, have been contradictory, with some studies reporting that reduced IGF1 signaling is neuroprotective, while others claim that reduced IGF1 signaling with age contributes to brain aging. For instance, Alzheimer&#x;s disease (AD) is a neurodegenerative disease associated with aging, and one group have shown that a reduction in IGF1 signaling rescues mice from AD-like pathology. An AD mouse model with reduced IGF1 signaling was created, and was reported as having reduced neuronal loss and behavioral deficits compared to the control AD mouse model with normal levels of IGF1 signaling (Cohen et al., ). This was attributed to tighter aggregation of A² plaques leading to reduced proteotoxicity. These mice also show greater resistance to oxidative stress than mice with intact IGF1 signaling (Holzenberger et al., ), suggesting that these findings may be due to an enhanced capacity to protect against the inflammatory effects of A² plaques. Similarly, another group demonstrated protection of the aging brain from amyloid pathology by knocking out neuronal IGF1R activity in the brains of adult rats (Gontier et al., ). In this study, IGF1R KO in adult neurons led to reduced A² pathology and neuroinflammation, along with preservation of spatial memory. Another study reported reduction in A² plaques and improved learning and memory following IRS2 KO compared to controls in APP transgenic mice (Killick et al., ).

This is in contrast to the prevailing theory that AD is a disorder of insulin and IGF1 resistance. AD has recently been termed Type 3 Diabetes, given the observation that the spectrum of Mild Cognitive Impairment&#x;AD is associated with global reductions in glucose uptake and utilization occurring early in the course of the disease (Steen et al., ; Mosconi et al., ). In particular, hippocampal hypometabolism has been observed to correlate with faster progression to dementia (Mosconi et al., ). AD could therefore represent a form of CNS insulin resistance. Expression patterns of IR, IGF1 receptor (IGF1R), the intracellular substrate proteins IRS1 and IRS2, and the regulatory IGFBP-2, have been studied in brains affected by AD. One study reported increased IGF1R and decreased IGFBP-2 expression in AD brains, with higher IGF1R expression levels concentrated around amyloid plaques and in neurons with neurofibrillary tangles. These AD neurons showed decreased intracellular levels of IRS1 and IRS2, in association with greater levels of the phosphorylated inactivated forms of these proteins. These findings would suggest that AD neurons show resistance to IGF1 signaling (Moloney et al., ). Similarly, another study showed that cerebral neurons in AD brains demonstrate reduced responses to insulin and IGF1 signaling, mainly through phosphorylation and subsequent inactivation of IRS1 (Talbot et al., ). Another group that found that mutant rats with lower circulating levels of IGF1 have higher levels of A² plaques in the brain, and that levels of A² can be reduced in aging rats to levels similar to that in young rats by increasing serum levels of IGF1 (Carro et al., ). This is thought to be due to increased clearance of A² by albumin and transthyretin carrier proteins due to increased choroid plexus permeability to these proteins (Carro et al., ). Furthermore, IGF1R blockade in the choroid plexus worsens AD like pathology, causing amyloidosis, tau hyperphosphorylation and cognitive disturbance (Carro et al., ). These studies would therefore suggest that decreased insulin-IGF1 signaling in the brain at least correlates with the development of AD.

The effect of IGF1 signaling in the pathogenesis of Huntington&#x;s disease (HD) has also been investigated. This is a triple repeat disorder caused by mutation of the HTT protein, whereby elongation of the CAG triple repeat leads to a resultant HTT protein with a prolonged polyglutamine tract. This prolongated protein is cut into toxic fragments that aggregate, causing neurotoxicity and degeneration. Reduced IGF1 signaling is linked to pathological and symptomalogical improvements in mouse models of HD. The R6/2 mouse model of HD showed more rapid neurodegeneration following increased expression of IRS2, while decreasing IRS2 expression is associated with a longer lifespan in this model (Sadagurski et al., ). This is attributed to fewer polyQ-HTT aggregates in the brain. Conversely, another study showed that treatment of neurons transfected with the HTT mutation with IGF1 reduced polyQ-htt aggregation through Akt-mediated huntingtin phosphorylation (Humbert et al., ).

IGF1 and Metabolism: Targeting IGF1

IGF1 signaling has many effects on metabolism, at the tissue and cellular levels. This signaling is not limited to glucose and lipid homeostasis but also influences protein turnover (Sharples et al., ).

Manipulating IGF1 depends on our understanding of the metabolic trade-offs, especially in the brain, adipose tissue and skeletal muscle, that are associated with it. IGF and its related molecules are important in protein metabolism and the regulation of skeletal muscle mass. KO of IGFI, IGFII or the IGFI receptor causes neonatal lethality and decreases in skeletal muscle mass in rodents (Sharples et al., ). The role of IGF1 and its related molecules in the maintenance of skeletal muscle mass in humans is especially important for elderly individuals whose IGF1 levels decrease with age and are at risk of frailty (Maggio et al., ) and sarcopenia (Sharples et al., ). Manipulating metabolism by using dietary restriction offers a similar mechanism to reduced IGF1 signaling in that it results in the inhibition of mTOR and it has also been linked to reduced IGF1 levels. It has the potential to be used in combination with an increase in protein or amino acid intake to counteract the losses in skeletal muscle that accompany a reduction in IGF1 (Sharples et al., ).

Choosing which pathway to target poses an obstacle to the modification of IGF1 signaling. mTOR, which functions through complexes mTORC1 and mTORC2, might be a promising target. mTORC1 is responsive to nutrients, energy and growth factors and its inhibition has been shown to decrease aging rate and age-related weight gain in mice (Hu and Liu, ). KO of RAPTOR, an mTORC1-specific accessory protein, in adipose tissue preserves the lifespan extension seen in other models reducing Insulin/IGF1 signaling while also improving metabolic markers such as glucose tolerance and insulin sensitivity (Hu and Liu, ). This, taken with the detrimental effects of KO on tissues such as skeletal muscle and the importance of IGF1 in metabolism in the developing brain, suggests that tissue-specific reductions in signaling may be one way of overcoming this obstacle. In addition to approaches which take into account specific pathways and tissues, it may also be beneficial to investigate the differences in the effects of IGF1 reductions at different time points. Human population studies point to a positive impact of IGF1 reductions at a young age and elevations at an old age (Sharples et al., ).

It has been questioned whether the extended longevity afforded by reduced IGF-1 signaling and its effects on metabolism are mediated in the same way. In fact, it has recently been suggested that extended lifespan in the Ames and Snell dwarf mice is not due to IGF1 levels but rather the decrease in GH (Brown-Borg and Bartke, ). Furthermore, it is thought that distinct sets of neurons mediate the functions of insulin/IGF1 in the brain. KO of IRS2 in the entire brain in mice does result in lifespan extension but at 22 months these mice are also overweight, hyperinsulinemic and glucose-intolerant, demonstrating the centrality of this pathway in metabolic homeostasis. Nutrient-sensing which is central to the regulation of glucose and lipid homeostasis is carried out by the leptin-sensitive neurons of the arcuate nucleus which contain IRS2 and the IR. While it is in these neurons that insulin/IGF1 exert profound effects on metabolism, IRS2 is not required for leptin action. So then, IRS2 in these neurons mediates the functions of insulin/IGF1 ad not those of leptin, once again highlighting the importance of insulin-like signaling in metabolism. Interestingly, the decrease of IRS2 on leptin receptor-expressing neurons did not result in the increase in lifespan seen with overall IRS2 decrease. These results indicate that the neurons which act as the metabolic mediators of insulin/IGF1 signaling in the CNS are distinct from those which underlie mammalian lifespan extension due to a reduction in insulin/IGF1 signaling (Sadagurski and White, ; White, ). This provides a powerful starting point for the potential development of strategies to manipulate IGF1 function without causing metabolic dysfunction.

There is a paradox presented by the Insulin/IGF1 signaling pathway in metabolism which warrants further research. In the CNS, this paradox could well be due to the existence of neuronal subsets which mediate the effects of IGF1/Insulin and in the periphery could be owed to the differing actions of IGF1 on various tissues. The importance of IGF1 and its related molecules on metabolism is undeniable and if manipulated correctly could prove to be viable therapeutically.

The Debate Continues

In conclusion, the above studies largely support a role for IGF1 signaling in brain development, and adult neuroplasticity and neurogenesis. However, while numerous studies report that IGF1 signaling serves to delay brain aging, and that the known fall in IGF1 signaling with age acts as a causative factor in age-related brain changes, there remain as many studies that stand in contradiction, and suggest that a reduction in IGF1 signaling delays age-related changes and diseases.

IGF1 levels are higher in the developing brain, and this is shown, through the studies outlined above, to promote neuronal development. It activates the PI3K pathway, which promotes survival by directly inactivating pro-apoptopic machinery (van der Heide et al., ), and increases glucose uptake by neurons (Bondy and Cheng, ). Post-natally, IGF1 promotes neuronal maturation, and has been shown to partially correct the phenotype of certain neurodevelopmental disorders. IGF1 is associated, in the adult brain, with regions of continued neurogenesis. These findings would suggest that IGF1 signaling exerts an overall neuroprotective effect, and that falling IGF1 levels with age contribute to the effects of aging in the brain.

However, there also exists a body of evidence suggesting that reduced IGF1 signaling attenuates the effects of aging, both in the brain and in the whole organism. A reduction in IGF1 signaling increases the life span of C. elegans, as DAF-2 mutants with a lower level of DAF-2 signaling have a lifespan double that of normal controls (Kenyon et al., ). With regards to brain function, age-related decline in axonal regeneration in C.elegans was shown to be regulated by DAF-2 signaling. While the rate of axonal regeneration following injury was 65% in day1 C.elegans worms and 28% in day 5 worms, the same experiment in DAF2&#x;/&#x; worms had no reduction in axonal degeneration. Reduced DAF-2 signaling allowed for increased DAF activity, stimulating neuronal regeneration in response to injury (Byrne et al., ). However, in the C. elegans, the insulin and IGF1 pathways are not diverged, and therefore the effects of IGF1 on aging cannot be studied in isolation. Studies of IGF1 signaling and lifespan in mammals have also been done, and an IGF1R+/&#x; transgenic mouse model with a reduced level of IGF1 signaling activity has been created that has a longer lifespan than control mice, and demonstrated greater resistance to oxidative stress (Holzenberger et al., ). These findings would therefore suggest that the fall in IGF1 signaling with age is not in fact the cause of aging, but is perhaps a protective mechanism that occurs as to attenuate the effects of aging.

These contradictions may arise partly because of the differential activity of IGF1 signaling in the brain compared to the whole body in different experimental models. One particular study characterizes the distinction in Ames mice, which have a primary deficiency in GH, leading to low levels of circulating IGF1. These mice demonstrate a longer lifespan, which has been attributed to absence of GH-IGF1 signaling, thereby affording evidence that IGF1 signaling contributes to aging. However, Sun et al. () demonstrated that while these Ames mice show lower levels of GH and IGF1 peripherally, they have elevated levels of IGF1 in the hippocampus compared to normal mice. Furthermore, this correlated with higher levels of neurogenesis in the dentate gyrus, compared to the controls (Sun et al., ). This elevated level of neurogenesis in the Ames mice may underlie the observation that these mice showed less age-related cognitive deficits. Therefore, while globally reduced IGF1 signaling appears to extend the lifespan of these organisms, one should not assume that brain-specific IGF1 signaling is also reduced, or that the effect of IGF1 activity in the brain compared to the rest of the organism on the process of aging is necessarily the same.

Contradictions again arise when studying the neuroprotective effect of IGF1 signaling in hypoxic-ischemic injury. While above studies describe reduced neuronal loss following intracerebroventricular infusion of IGF1 (see above), other studies report that following Cre-LoxP-mediated inactivation of IGF1R in forebrain neurons, there was reduced neuronal damage, inflammation and edema in response to hypoxic-ischemic insult (De Maghalaes Filho et al., ).

These contradictions between different studies may be due to the different approaches taken: decreasing IGF1 or the receptor, or the IRS receptor, or the targeting of the modulators IGFBPs. In fact, the systems are highly regulated and the changes in each factor may have a different effect. For example, a moderate decrease in IGF1R increases life span, contrary to what happens to decreases in IGF1. Another factor to take into account is the integration insulin-IGF1 in the brain. In neurons, IRSBPs proteins and IGF1R form a complex which also binds insulin and may activate different intracellular signals. This interaction should be taken into account in therapies which use IGF1 to improve brain function, because the variability of the results may be due to different levels of insulin in the body. This theory is in line with the homeostatic function of IGF1 as a connector between body and brain. In addition, as demonstrated by Sun et al. (), inconsistencies also arise when the differential activity and effect of IGF1 in different organ systems is not taken into account, for it may be the case that peripheral and brain IGF1 signaling have opposing effects, with the former leading to overall acceleration of aging in the body while the latter continues to promote renewal and reparation. Furthermore, it is possible that while IGF1 signaling continues to promote neuronal development and plasticity throughout life, through its effects on cellular apoptotic machinery, glucose utilization and other neurotrophic factors, such anabolic process may simultaneously contribute to aging through accumulation of reactive oxygen species and resultant prolonged oxidative stress over time.

In all, there remains much to be done in elucidating the role of IGF1 signaling in the brain as it develops, matures and ages. IGF1 appears to act in concert with BDNF and other neurotrophic factors to promote neurogenesis and remodeling in the brain. However, its overall effects on energy metabolism and cellular oxidation may contribute to aging in all organs. What is obvious is that it is not simply a matter of high IGF1 signaling early in life promoting development and falling levels thereafter underlying the process of aging. An evolutionarily ancient pathway, IGF1 signaling has likely taken on numerous differential roles in different body tissues in health and disease (Forbes, ), and its complex effects on cellular maturation, tissue development and energy metabolism may contribute to organismal development and aging simultaneously.

Author Contributions

SW wrote a consistent part of the manuscript. DA wrote part of the manuscript and contributed to the figures. DT designed the structure of the review, wrote part of the manuscript and contributed to the figures.

Conflict of Interest Statement

DT has a patent for the potential use of IGF1 in neurodevelopmental disorders.

The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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1 igf

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The Dreadful Duo: Uncontrolled GH and IGF-1

Insulin-like growth factor 1

IGF1
Protein IGF1 PDB 1bqt.png
Available structures
PDBOrtholog search: PDBeRCSB
List of PDB id codes

1B9G, 1GZR, 1GZY, 1GZZ, 1H02, 1H59, 1IMX, 1PMX, 1TGR, 1WQJ, 2DSR, 2GF1, 3GF1, 3LRI, 1BQT, 4XSS

Identifiers
AliasesIGF1, IGF-I, IGF1A, IGFI, MGF, insulin like growth factor 1, IGF
External IDsOMIM: MGI: HomoloGene: GeneCards: IGF1
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)Chr – MbChr – Mb
PubMed search[3][4]
Wikidata

Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults.

IGF-1 is a protein that in humans is encoded by the IGF1gene.[5][6] IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges. IGF-1 has a molecular weight of 7, Daltons.[7]

IGF-1 is produced primarily by the liver. Production is stimulated by growth hormone (GH). Most of IGF-1 is bound to one of 6 binding proteins (IGF-BP). IGFBP-1 is regulated by insulin. IGF-1 is produced throughout life; the highest rates of IGF-1 production occur during the pubertal growth spurt.[8] The lowest levels occur in infancy and old age.[medical citation needed]

A synthetic analog of IGF-1, mecasermin, is used in children for the treatment of growth failure.[9]

Synthesis and circulation[edit]

See also: Neurobiological effects of physical exercise §&#;IGF-1 signaling

IGF-1 is produced primarily by the liver as an endocrine hormone as well as in target tissues in a paracrine/autocrine fashion. Production is stimulated by growth hormone (GH) and can be retarded by undernutrition,[8]growth hormone insensitivity, lack of growth hormone receptors, or failures of the downstream signaling pathway post GH receptor including SHP2 and STAT5B. Approximately 98% of IGF-1 is always bound to one of 6 binding proteins (IGF-BP). IGFBP-3, the most abundant protein, accounts for 80% of all IGF binding. IGF-1 binds to IGFBP-3 in a molar ratio. IGFBP-1 is regulated by insulin.[10]

IGF-1 is produced throughout life. The highest rates of IGF-1 production occur during the pubertal growth spurt. The lowest levels occur in infancy and old age.[medical citation needed]

Protein intake increases IGF-1 levels in humans, independent of total calorie consumption.[11] Factors that are known to cause variation in the levels of growth hormone (GH) and IGF-1 in the circulation include: insulin levels, genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, ethnicity, estrogen status and xenobiotic intake.[12]

Mechanism of action[edit]

See also: Hypothalamic–pituitary–somatic axis

IGF-1 is a primary mediator of the effects of growth hormone (GH). Growth hormone is made in the anterior pituitary gland, is released into the blood stream, and then stimulates the liver to produce IGF IGF-1 then stimulates systemic body growth, and has growth-promoting effects on almost every cell in the body, especially skeletal muscle, cartilage, bone, liver, kidney, nerve, skin, hematopoietic, and lung cells. In addition to the insulin-like effects, IGF-1 can also regulate cellular DNA synthesis.[13]

IGF-1 binds to at least two cell surface receptor tyrosine kinases: the IGF-1 receptor (IGF1R), and the insulin receptor. Its primary action is mediated by binding to its specific receptor, IGF1R, which is present on the surface of many cell types in many tissues. Binding to the IGF1R initiates intracellular signaling. IGF-1 is one of the most potent natural activators of the AKTsignaling pathway, a stimulator of cell growth and proliferation, and a potent inhibitor of programmed cell death .[14][15] The IGF-1 receptor seems to be the "physiologic" receptor because it binds IGF-1 with significantly higher affinity than insulin receptor does. IGF-1 activates the insulin receptor at approximately times the potency of insulin. Part of this signaling may be via IGF1R/Insulin Receptor heterodimers (the reason for the confusion is that binding studies show that IGF1 binds the insulin receptor fold less well than insulin, yet that does not correlate with the actual potency of IGF1 in vivo at inducing phosphorylation of the insulin receptor, and hypoglycemia).[medical citation needed]

IGF-1 binds and activates its own receptor, IGF-1R, through the cell surface expression of Receptor Tyrosine Kinase's (RTK's)[16] and further signal through multiple intracellular transduction cascades. IGF-1R is the critical role-playing inducer in modulating the metabolic effects of IGF-1 for cellular senescence and survival. At a localized target cell, IGF-1R elicits the mediation of paracrine activity. After its activation the initiation of intracellular signaling occurs inducing a magnitude of signaling pathways. An important mechanistic pathway involved in mediating a cascade affect a key pathway regulated by phosphatidylinositol-3 kinase (PI3K) and its downstream partner, mTOR (mammalian Target of Rapamycin).[16] Rapamycin binds with the enzyme FKBPP12 to inhibit the mTORC1 complex. mTORC2 remains unaffected and responds by up-regulating AKT, driving signals through the inhibited mTORC1. Phosphorylation of Eukaryotic translation initiation factor 4E (EIF4E) by mTOR suppresses the capacity of Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) to inhibit EIF4E and slow metabolism.[17] A mutation in the signaling pathway PI3K-AKT-mTOR is a big factor in the formation of tumors found predominantly on skin, internal organs, and secondary lymph nodes (Kaposi sarcoma).[18] IGF-1R allows the activation of these signaling pathways and subsequently regulates the cellular longevity and metabolic re-uptake of biogenic substances. A therapeutic approach targeting towards the reduction of such tumor collections could be induced by ganitumab. Ganitumab is a monoclonal antibody (mAb) directed antagonistically against IGF-1R. Ganitumab binds to IGF-1R, preventing binding of IGF-1 and the subsequent triggering of the PI3K-mTOR signaling pathway; inhibition of this pro-survival pathway may result in the inhibition of tumor cell expansion and the induction of tumor cell apoptosis.[citation needed]

Insulin-like growth factor 1 has been shown to bind and interact with all seven IGF-1 binding proteins (IGFBPs): IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, and IGFBP7.[medical citation needed] Some IGFBPs are inhibitory. For example, both IGFBP-2 and IGFBP-5 bind IGF-1 at a higher affinity than it binds its receptor. Therefore, increases in serum levels of these two IGFBPs result in a decrease in IGF-1 activity.[medical citation needed]

Metabolic effects[edit]

As a major growth factor, IGF-1 is responsible for stimulating growth of all cell types and causing significant metabolic effects.[19] One important metabolic effect of IGF-1 is its ability to signal cells that sufficient nutrients are available for cells to undergo hypertrophy and cell division.[20] These signals also enable IGF-1 to inhibit cell apoptosis and increase the production of cellular proteins.[20] IGF-1 receptors are ubiquitous, which allows for metabolic changes caused by IGF-1 to occur in all cell types.[19] IGF-1's metabolic effects are far-reaching and can coordinate protein, carbohydrate, and fat metabolism in a variety of different cell types.[19] The regulation of IGF-1's metabolic effects on target tissues is also coordinated with other hormones such as growth hormone and insulin.[21]

Related growth factors[edit]

IGF-1 is closely related to a second protein called "IGF-2". IGF-2 also binds the IGF-1 receptor. However, IGF-2 alone binds a receptor called the "IGF-2 receptor" (also called the mannose-6 phosphate receptor). The insulin-like growth factor-II receptor (IGF2R) lacks signal transduction capacity, and its main role is to act as a sink for IGF-2 and make less IGF-2 available for binding with IGF-1R. As the name "insulin-like growth factor 1" implies, IGF-1 is structurally related to insulin, and is even capable of binding the insulin receptor, albeit at lower affinity than insulin.

A splice variant of IGF-1 sharing an identical mature region, but with a different E domain is known as mechano-growth factor (MGF).[22]

Disorders[edit]

Laron dwarfism[edit]

Rare diseases characterized by inability to make or respond to IGF-1 produce a distinctive type of growth failure. One such disorder, termed Laron dwarfism does not respond at all to growth hormone treatment due to a lack of GH receptors. The FDA has grouped these diseases into a disorder called severe primary IGF deficiency. Patients with severe primary IGFD typically present with normal to high GH levels, height below&#;3 standard deviations (SD), and IGF-1 levels below 3&#;SD. Severe primary IGFD includes patients with mutations in the GH receptor, post-receptor mutations or IGF mutations, as previously described. As a result, these patients cannot be expected to respond to GH treatment.

People with Laron syndrome have very low rates of cancer and diabetes.[23] Notably people with untreated Laron syndrome also never develop acne.[24]

Acromegaly[edit]

Acromegaly is a syndrome that results when the anterior pituitary gland produces excess growth hormone (GH). A number of disorders may increase the pituitary's GH output, although most commonly it involves a tumor called pituitary adenoma, derived from a distinct type of cell (somatotrophs). It leads to anatomical changes and metabolic dysfunction caused by both an elevated GH and elevated IGF-1 levels.[25] High level of IGF-1 in acromegaly is related to an increased risk of some cancers, particularly colon cancer and thyroid cancer.[26]

Cancer[edit]

A mutation in the signaling pathway PI3K-AKT-mTOR is a factor in the formation of tumors found predominantly on skin, internal organs, and secondary lymph nodes (Kaposi sarcoma).[18]

IGF-1R allows the activation of these signaling pathways and subsequently regulates the cellular longevity and metabolic re-uptake of biogenic substances. A therapeutic approach targeting towards the reduction of such tumor collections could be induced by ganitumab. Ganitumab is a monoclonal antibody (mAb) directed antagonistically against IGF-1R. Ganitumab binds to IGF-1R, preventing binding of IGF-1 and the subsequent triggering of the PI3K-mTOR signaling pathway; inhibition of this pro-survival pathway may result in the inhibition of tumor cell expansion and the induction of tumor cell apoptosis.[citation needed]

Use as a diagnostic test[edit]

IGF-1 levels can be measured in the blood in &#;ng/ml amounts. As levels do not fluctuate greatly throughout the day for an individual person, IGF-1 is used by physicians as a screening test for growth hormone deficiency and excess in acromegaly and gigantism.

Interpretation of IGF-1 levels is complicated by the wide normal ranges, and marked variations by age, sex, and pubertal stage. Clinically significant conditions and changes may be masked by the wide normal ranges. Sequential measurement over time is often useful for the management of several types of pituitary disease, undernutrition, and growth problems.

Causes of elevated IGF-1 levels[edit]

Use as a therapeutic agent[edit]

Patients with severe primary insulin-like growth factor-1 deficiency (IGFD), called Laron syndrome, may be treated with either IGF-1 alone or in combination with IGFBP[33]Mecasermin (brand name Increlex) is a synthetic analog of IGF-1 which is approved for the treatment of growth failure.[33] IGF-1 has been manufactured recombinantly on a large scale using both yeast and E. coli.

IGF-1 may have a beneficial effect on atherosclerosis and cardiovascular disease.[34] IGF-1 has also been shown to have an antidepressant effect in mouse models.[35]

Clinical trials[edit]

Recombinant protein[edit]

Several companies have evaluated administering recombinant IGF-1 in clinical trials for type 1 diabetes, type 2 diabetes, amyotrophic lateral sclerosis,[36] severe burn injury and myotonic muscular dystrophy.

Results of clinical trials evaluating the efficacy of IGF-1 in type 1 diabetes and type 2 diabetes showed reduction in hemoglobin A1C levels and daily insulin consumption.[medical citation needed] However the sponsor discontinued the program due to an exacerbation of diabetic retinopathy,[37] coupled with a shift in corporate focus towards oncology.

Two clinical studies of IGF-1 for ALS were conducted and although one study demonstrated efficacy the second was equivocal,[medical citation needed] and the product was not submitted for approval to the FDA.

Society and culture[edit]

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History of name[edit]

In the s IGF-1 was called "sulfation factor" because it stimulated sulfation of cartilage in vitro,[38] and in the s due to its effects it was termed "nonsuppressible insulin-like activity" (NSILA).

See also[edit]

References[edit]

  1. ^ abcGRCh Ensembl release ENSG - Ensembl, May
  2. ^ abcGRCm Ensembl release ENSMUSG - Ensembl, May
  3. ^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^Höppener JW, de Pagter-Holthuizen P, Geurts van Kessel AH, Jansen M, Kittur SD, Antonarakis SE, Lips CJ, Sussenbach JS (). "The human gene encoding insulin-like growth factor I is located on chromosome 12". Hum. Genet. 69 (2): – doi/BF PMID&#; S2CID&#;
  6. ^Jansen M, van Schaik FM, Ricker AT, Bullock B, Woods DE, Gabbay KH, Nussbaum AL, Sussenbach JS, Van den Brande JL (). "Sequence of cDNA encoding human insulin-like growth factor I precursor". Nature. (): – BibcodeNaturJ. doi/a0. PMID&#; S2CID&#;
  7. ^Rinderknecht E, Humbel RE (). "The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin". J Biol Chem. (8): – doi/S(17) PMID&#;
  8. ^ abDecourtye L, Mire E, Clemessy M, Heurtier V, Ledent T, Robinson IC, Mollard P, Epelbaum J, Meaney MJ, Garel S, Le Bouc Y, Kappeler L (). "IGF-1 Induces GHRH Neuronal Axon Elongation during Early Postnatal Life in Mice". PLOS ONE. 12 (1): e BibcodePLoSOD. doi/journal.pone PMC&#; PMID&#;
  9. ^Keating GM (). "Mecasermin". BioDrugs. 22 (3): – doi/ PMID&#;
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  11. ^Levine ME, Suarez JA, Brandhorst S, Balasubramanian P, Cheng CW, Madia F, et&#;al. (March ). "Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population". Cell Metabolism. 19 (3): – doi/j.cmet PMC&#; PMID&#;
  12. ^Scarth JP (). "Modulation of the growth hormone-insulin-like growth factor (GH-IGF) axis by pharmaceutical, nutraceutical and environmental xenobiotics: an emerging role for xenobiotic-metabolizing enzymes and the transcription factors regulating their expression. A review". Xenobiotica. 36 (2–3): – doi/ PMID&#; S2CID&#;
  13. ^Yakar S, Rosen CJ, Beamer WG, Ackert-Bicknell CL, Wu Y, Liu JL, et&#;al. (September ). "Circulating levels of IGF-1 directly regulate bone growth and density". The Journal of Clinical Investigation. (6): – doi/JCI PMC&#; PMID&#;
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  15. ^Juin P, Hueber AO, Littlewood T, Evan G (June ). "c-Myc-induced sensitization to apoptosis is mediated through cytochrome c release". Genes & Development. 13 (11): – doi/gad PMC&#; PMID&#;
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  17. ^Martin D, Nguyen Q, Molinolo A, Gutkind JS (May ). "Accumulation of dephosphorylated 4EBP after mTOR inhibition with rapamycin is sufficient to disrupt paracrine transformation by the KSHV vGPCR oncogene". Oncogene. 33 (18): – doi/onc PMID&#;
  18. ^ abWang Z, Feng X, Molinolo AA, Martin D, Vitale-Cross L, Nohata N, et&#;al. (April ). "4E-BP1 Is a Tumor Suppressor Protein Reactivated by mTOR Inhibition in Head and Neck Cancer". Cancer Research. 79 (7): – doi/CAN PMC&#; PMID&#;
  19. ^ abcClemmons DR (June ). "Metabolic actions of insulin-like growth factor-I in normal physiology and diabetes". Endocrinology and Metabolism Clinics of North America. 41 (2): –43, vii–viii. doi/j.ecl PMC&#; PMID&#;
  20. ^ abBikle DD, Tahimic C, Chang W, Wang Y, Philippou A, Barton ER (November ). "Role of IGF-I signaling in muscle bone interactions". Bone. 80: 79– doi/j.bone PMC&#; PMID&#;
  21. ^Clemmons DR (January ). "The relative roles of growth hormone and IGF-1 in controlling insulin sensitivity". The Journal of Clinical Investigation. (1): 25–7. doi/JCI PMC&#; PMID&#;
  22. ^Carpenter V, Matthews K, Devlin G, Stuart S, Jensen J, Conaglen J, Jeanplong F, Goldspink P, Yang SY, Goldspink G, Bass J, McMahon C (February ). "Mechano-growth factor reduces loss of cardiac function in acute myocardial infarction". Heart Lung Circ. 17 (1): 33–9. doi/j.hlc PMID&#;
  23. ^Wade N (17 February ). "Ecuadorean Villagers May Hold Secret to Longevity". The New York Times.
  24. ^Khanna N, Kubba R (28 February ). World Clinics: Dermatology - Acne. JP Medical Ltd. ISBN&#;.
  25. ^Giustina A, Chanson P, Kleinberg D, Bronstein MD, Clemmons DR, Klibanski A, van der Lely AJ, Strasburger CJ, Lamberts SW, Ho KK, Casanueva FF, Melmed S (). "Expert consensus document: A consensus on the medical treatment of acromegaly". Nat Rev Endocrinol. 10 (4): –8. doi/nrendo PMID&#;
  26. ^AlDallal S (August ). "Acromegaly: a challenging condition to diagnose". review. International Journal of General Medicine. 11: – doi/IJGM.S PMC&#; PMID&#;
  27. ^Levine ME, Suarez JA, Brandhorst S, Balasubramanian P, Cheng CW, Madia F, et&#;al. (March ). "Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population". primary. Cell Metabolism. 19 (3): – doi/j.cmet PMC&#; PMID&#;
  28. ^ abSakuma TH, Maibach HI (). "Oily skin: an overview". review. Skin Pharmacology and Physiology. 25 (5): – doi/ PMID&#; S2CID&#;
  29. ^Melnik BC, John SM, Schmitz G (June ). "Over-stimulation of insulin/IGF-1 signaling by western diet may promote diseases of civilization: lessons learnt from laron syndrome". primary. Nutrition & Metabolism. 8: doi/ PMC&#; PMID&#;
  30. ^Imran SA, Pelkey M, Clarke DB, Clayton D, Trainer P, Ezzat S (). "Spuriously Elevated Serum IGF-1 in Adult Individuals with Delayed Puberty: A Diagnostic Pitfall". primary. International Journal of Endocrinology. : 1–4. doi// PMC&#; PMID&#;
  31. ^ abcFreda PU (August ). "Monitoring of acromegaly: what should be performed when GH and IGF-1 levels are discrepant?". review. Clinical Endocrinology. 71 (2): – doi/jx. PMC&#; PMID&#;
  32. ^Phillips JD, Yeldandi A, Blum M, de Hoyos A (October ). "Bronchial carcinoid secreting insulin-like growth factor-1 with acromegalic features". primary. The Annals of Thoracic Surgery. 88 (4): –2. doi/j.athoracsur PMID&#;
  33. ^ abRosenbloom AL (). "The role of recombinant insulin-like growth factor I in the treatment of the short child". Curr. Opin. Pediatr. 19 (4): – doi/MOP.0be PMID&#; S2CID&#;
  34. ^Higashi Y, Gautam S, Delafontaine P, Sukhanov S (April ). "IGF-1 and cardiovascular disease". Growth Hormone & IGF Research. 45: 6– doi/j.ghir PMC&#; PMID&#;
  35. ^Mueller PL, Pritchett CE, Wiechman TN, Zharikov A, Hajnal A (October ). "Antidepressant-like effects of insulin and IGF-1 are mediated by IGF-1 receptors in the brain". Brain Research Bulletin. : 27– doi/j.brainresbull PMID&#; S2CID&#;
  36. ^Vaught JL, Contreras PC, Glicksman MA, Neff NT (). "Potential utility of rhIGF-1 in neuromuscular and/or degenerative disease". Ciba Found. Symp. Novartis Foundation Symposia. : 18–27, discussion 27– doi/ch3. ISBN&#;. PMID&#;
  37. ^"Genentech Discontinues IGF-I Drug Development Effort in Diabetes" (Press release). Genentech. 5 September Retrieved 15 March
  38. ^Salmon WD, Daughaday WH (). "A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro". J Lab Clin Med. 49 (6): – PMID&#;

External links[edit]

PDB gallery

  • 1bqt: THREE-DIMENSIONAL STRUCTURE OF HUMAN INSULIN-LIKE GROWTH FACTOR-I (IGF-I) DETERMINED BY 1H-NMR AND DISTANCE GEOMETRY, 6 STRUCTURES

  • 1gzr: HUMAN INSULIN-LIKE GROWTH FACTOR; ESRF DATA

  • 1gzy: HUMAN INSULIN-LIKE GROWTH FACTOR; IN-HOUSE DATA

  • 1gzz: HUMAN INSULIN-LIKE GROWTH FACTOR; HAMBURG DATA

  • 1h02: HUMAN INSULIN-LIKE GROWTH FACTOR; SRS DARESBURY DATA

  • 1h59: COMPLEX OF IGFBP-5 WITH IGF-I

  • 1imx: Angstrom crystal structure of IGF-1

  • 1pmx: INSULIN-LIKE GROWTH FACTOR-I BOUND TO A PHAGE-DERIVED PEPTIDE

  • 1wqj: Structural Basis for the Regulation of Insulin-Like Growth Factors (IGFs) by IGF Binding Proteins (IGFBPs)

  • 2dsp: Structural Basis for the Inhibition of Insulin-like Growth Factors by IGF Binding Proteins

  • 2dsq: Structural Basis for the Inhibition of Insulin-like Growth Factors by IGF Binding Proteins

  • 2dsr: Structural Basis for the Inhibition of Insulin-like Growth Factors by IGF Binding Proteins

  • 2gf1: SOLUTION STRUCTURE OF HUMAN INSULIN-LIKE GROWTH FACTOR 1: A NUCLEAR MAGNETIC RESONANCE AND RESTRAINED MOLECULAR DYNAMICS STUDY

  • 3gf1: SOLUTION STRUCTURE OF HUMAN INSULIN-LIKE GROWTH FACTOR 1: A NUCLEAR MAGNETIC RESONANCE AND RESTRAINED MOLECULAR DYNAMICS STUDY

  • 3lri: Solution structure and backbone dynamics of long-[Arg(3)]insulin-like growth factor-I

Sours: https://en.wikipedia.org/wiki/Insulin-like_growth_factor_1

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