Insulin-like Growth Factors in Pediatric Health and Disease

Derek Le Roith and Andrew A. Butler

Clinical Endocrinology Branch, National Institute of Diabetes Digestive and Kidney Diseases, Bethesda, Maryland 20892-1758

Address correspondence and requests for reprints to: Derek Le Roith, M.D., Ph.D., Chief, Clinical Endocrinology Branch, National Institute of Diabetes Digestive and Kidney Diseases, Room 8D12, Building 10, Bethesda, Maryland 20892-1758. E-mail derek{at}helix.nih.gov


    Introduction
 Top
 Introduction
 The IGF System (Fig....
 Complications/Diseases
 Conclusions
 References
 
SINCE THE introduction of the somatomedin hypothesis by Daughaday et al. (1) almost a half-century ago, our understanding of the insulin-like growth factor (IGF) system has evolved considerably. This evolution, from one of a simple pituitary-dependent growth factor secreted from liver to a ubiquitous and complex family of ligands, receptors, and binding proteins, has been spurred by advances in both protein biochemistry and, more recently, with the advent of the powerful tools of molecular biology. IGF-I and IGF-II are essential for normal growth and development. In tissue and organ systems that have fully differentiated, on the other hand, they play important roles in the homeostatic mechanisms associated with the normal function and maintenance of those tissues (2). Both IGF-I and IGF-II have been implicated in disease progression, either secondarily as the result of altered expression inducing abnormal growth and/or physiology (e.g. renal hypertrophy and deteriorating retinopathy during diabetes) or as one of the primary causative factors of the disease (e.g. overexpression in certain cancers and pediatric overgrowth disorders). This review discusses the normal physiology of the IGF system and describes some examples of pediatric diseases associated with alterations in this system and the possible therapeutic implications due to the availability of recombinant human IGF-I (rhIGF-I).


    The IGF System (Fig. 1Go)
 Top
 Introduction
 The IGF System (Fig....
 Complications/Diseases
 Conclusions
 References
 
The IGF family of growth factors consists of the three ligands insulin, IGF-I, and IGF-II. Each share peptide sequence identity to the other, as well as a similar tertiary structure. Insulin is generally regarded as being primarily involved in metabolic homeostasis. The IGF are also believed to act as hormones regulating metabolism, but also function as regulators of cellular proliferation (mitogenesis) and other tissue-specific functions. The cellular functions of insulin are mediated by the insulin receptor (IR). The biological functions of IGF-I and IGF-II are currently believed to be mediated by the IGF-I receptor (IGF-IR) (3). The insulin and IGF-IR are cell surface glycoproteins and are part of a family of tyrosine kinase receptors that includes the orphan IR-related receptor. A third receptor that binds IGF-II with high affinity does not belong to this family. The IGF-II/mannose-6-phosphate receptor has no apparent signaling capabilities, but is believed to play an essential role in regulating IGF-II function by internalizing and degrading cell surface IGF-II. Each ligand binds to its cognate receptor with very high affinity (~10-10 M), however, IGF-II also binds the IR with a higher affinity compared with IGF-I while binding the IGF-IR with an affinity comparable with that shown for IGF-I. Insulin binds the IGF-IR with low affinity. Recent genetic data indicate a role for the IR in mediating the effects of IGF-II on fetal growth in the mouse (4). A recently described modified form of the IR has been shown to have a high affinity for IGF-II. IR isoform A (IR-A) and IR-B differ by 12 amino acids due to the alternate splicing of exon 11. IR-A is preferentially expressed in fetal cells such as fetal fibroblasts, muscle, liver, and kidney, as well as in certain breast and colon cancers. IR-B has a high affinity for insulin, whereas IR-A binds both insulin and IGF-II with high affinity. Although the exact physiological function of the IR-A form is unclear, it has been implicated in fetal development and cancer (5).



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Figure 1. IGF system. IGF-I and IGF-II are ligands that stimulate cellular function by activating the IGF-IR, a receptor tyrosine kinase. The IGFBPs also bind IGF with high affinity. This interaction may be reduced by proteolytic cleavage of the IGFBPs. The IGFBPs also play a role in targeting the IGF to the cell surface receptors and modulating the function of IGF at these sites. Also shown are IGF/IGF receptor-independent actions by interacting with integrins and the type V TGF-ß receptor.

 
Another mechanism exists in most vertebrates to separate the insulin and IGF into discrete systems. Six IGF-binding proteins (IGFBP-1 to -6) that demonstrate high-affinity binding to the IGFs and extremely low affinity for insulin have been well-characterized (6). Found in both the circulation and in the local tissue, the IGFBPs modulate the activity of IGF-I and IGF-II, but have no role in the control of insulin and its biological functions, at least directly. In the circulation, the IGFs are bound to IGFBP-1 through -6. The acid labile subunit (ALS), which with IGFBP-3 and the ligands forms a highly stable ternary complex, resulting in ~99% of the ligands being bound and presumably unable to interact with receptors. Interestingly, as is the case with IGF-I, the hepatocyte is the principle site of ALS synthesis because ALS messenger RNA (mRNA) expression is primarily located in the liver (7). ALS and IGF-I genes have been found to be coexpressed in hepatocytes, along with GH receptor and binding protein (GHR/GHBP) mRNA, whereas IGFBP-3 is expressed in the sinusoidal endothelium (7). It has been hypothesized that the ternary complex of IGF-I, IGFBP-3, and ALS forms coincident with the passage of IGF-I and the other ternary complex components from the liver to the circulation. The formation of the high-affinity IGF/IGFBP-3/ALS complex, along with the less stable lower molecular weight complexes, is the primary reason for the most obvious difference between the IGF system and insulin. By prolonging the half-life of the IGF to several hours, compared with insulin, which circulates unbound and has a half-life measured in minutes, the IGFBP-3/ALS complex leads to the formation of a sizeable and stable pool of IGF in the circulation. Dissociation of this complex presumably allows the IGF to bind smaller complexes, leave the circulation and reach the target tissues.

In the local tissue environment, the IGFBPs modulate the interaction of the IGF with their receptors. IGFBPs with high affinity for the IGF have been shown to inhibit their interaction with the receptors. However, regulatory mechanisms exist that cause the slow release of the IGF, thus enabling prolonged interaction with the receptors and resulting in enhanced biological responses. The affinity of the IGFBP is regulated by protease activity, with proteolytic cleavage being one mechanism potentially involved in releasing IGF from an inactive complex. Other mechanisms allowing the release of the IGF from the complex include the state of phosphorylation of the IGFBPs and the partitioning of the IGFBPs from extracellular matrix to cell surface association that decreases the affinity of the IGFBP for the ligands. Finally, there is increasing evidence that certain IGFBPs may affect cellular responses in an IGF-I/IGF-IR-independent manner. The exact mechanism for this latter response is yet to be defined, although interactions with cell surface receptors such as integrins and transforming growth factor-ß (TGF-ß) type 5 receptor have been reported (figure 1Go).

Regulation of the IGF system

Determining the distribution and ontogeny of the expression of the various ligands, binding proteins, and receptors has been the basis for a large number of studies over the past 2 decades. The advent of modern molecular biology and the characterization of the genes for most of the components of the IGF system stimulated this process. Most interesting, in terms of growth regulation, has been the identification and evaluation of the interaction between GH and the IGF-I system. In the 1970s, Daughaday et al. (1) coined the phrase "somatomedin hypothesis." The hypothesis emerged from the seminal findings that, for GH to stimulate 35S-sulphate incorporation into the cartilage of growing bones, a circulating factor was required that virtually disappeared from the circulation following hypophysectomy and returned after GH treatment to these rats (8). The production of "somatomedin," or IGF-I as it later became known, by the liver was enhanced by GH and entered the circulation whereby it reached its target tissue (i.e. the "endocrine form" of IGF-I). Isaksson et al. (9) modified this hypothesis in the 1980s after the discovery by D’Ercole et al. (10) that IGF-I was produced by most, if not all, nonhepatic tissues. Furthermore, GHR were also detected in multiple nonhepatic tissues, indicating that the actions of GH was not confined to the liver. The modified somatomedin hypothesis suggested that GH affects postnatal longitudinal growth by two mechanisms: 1) by stimulating hepatic IGF-I production, which produced IGF-I acting as an endocrine hormone; and 2) stimulating GHR present in the growth plate, thereby increasing IGF-I synthesis that acted locally in an autocrine/paracrine manner.

Proof of the modified hypothesis has awaited more modern technology, which has now become available (vida infra). The hypothesis stating the liver as the primary source of circulating IGF-I was based on calculations of hepatic production rate and by the observation that liver IGF-I expression far exceeds that in most nonhepatic tissues. Verification of this hypothesis was, however, technically difficult, and it is only with recent advances in molecular biology that experiments testing this hypothesis have become feasible. In particular, the discovery and validation of the Cre-LoxP system for engineering tissue- or inducible-gene knockouts has allowed, for the first time, scientists to examine tissue-specific functions of a given gene. To determine the relative contribution of the circulating hepatic "endocrine" form of IGF-I and the autocrine/paracrine form of IGF-I in postnatal growth and development, liver IGF-I gene was deleted in mice using the bacteriophage Cre-Lox/P system of tissue-specific tissue gene deletion. Mice with lox/P sequences flanking exon 4 of the IGF-I gene were created by homologous recombination and then mated with mice that express the recombinase enzyme Cre in the liver. Successful matings resulted in Cre recombining the region between the lox/P sequences only the liver, resulting in a marked reduction of IGF-I expression in the liver (11).

Mice in which exon 4 of the IGF-I gene was deleted in liver had an approximately 80% reduction in circulating IGF-I levels. A several-fold increase in serum GH levels was also observed, most likely due to the loss of negative feedback from circulating IGF-I on pituitary GH synthesis and release. Interestingly, the levels of IGFBP-1 and IGFBP-3 were also markedly reduced. However, despite the loss of liver IGF-I and the marked reduction in circulating IGF-I, postnatal and peripubertal growth was normal. Therefore, it would seem that although pubertal growth spurts induced by GH are entirely IGF-I dependent (J. L. Liu, unpublished data), it is not dependent on liver IGF-I production. Rather, autocrine/paracrine IGF-I expressed at the sites of GH action maybe sufficient for this function (Fig. 2Go). The role for circulating IGF-I, in addition to controlling GH secretion, still remains to be established. Thus, yet again, the somatomedin hypothesis has been revisited, found to be incomplete, and, therefore, is in need of revision.



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Figure 2. Left, The original somatomedin hypothesis suggested that GH controls body growth by stimulating somatomedin (IGF-I) production by the liver. IGF-I reaches the target tissues via the circulation. Middle, The modified hypothesis suggested that GH stimulates body growth by enhanced production of IGF-I both in the liver and at the peripheral nonhepatic tissue level. Right, The results of recent knockout experiments suggest that liver IGF-I may not be essential for GH-stimulated, IGF-I-mediated effects.

 
It should be noted that although GH induces IGF-I gene expression in many tissues, it is not the unique regulator of this process. For example, nutritional status and insulin levels in the blood perfusing the liver also modulate liver IGF-I and IGFBP gene expression. Furthermore, sex steroids and pituitary factors affect IGF-I expression by the reproductive organs, such as the testes, ovary, and uterus, and bone IGF-I gene expression is also regulated by estrogen and PTH.

IGF in fetal and postnatal development

Fetal tissues produce both IGF-I and IGF-II. In rodents IGF-II synthesis declines rapidly postnatally and is virtually undetectable in most adult tissues and serum. IGF-I, on the other hand, increases in the circulation during the peripubertal stages under the direct influence of circulating GH. The importance of both growth factors in fetal growth and development has been convincingly demonstrated by gene-deletion experiments. Using homologous recombination, the genes for IGF-I and IGF-II were deleted in mice (12, 13). In both instances, fetal development was affected. At birth the animals with the IGF-I gene deleted were smaller and often died immediately after birth due to underdevelopment of their respiratory muscles. Those that survived this period grew more slowly postnatally than their normal littermates, and both males and females were infertile. At birth they were ~60% of the normal weight, and throughout the pubertal growth spurt showed minimal growth, becoming ~30% of the weight of wild-type adult animals.

Mice with the IGF-II gene deleted were ~50% normal birth weight, but grew at a normal rate postnatally, in parallel with their normal littermates, and, thus, did not show catch-up growth. Their development was otherwise normal. These results can be interpreted to have shown that although both IGF-I and IGF-II are important for fetal growth, IGF-I is essential for normal postnatal growth and development in the mouse. Additionally, when GH was administered to the IGF-I knockout mice there was no change in growth measured as body weight and femoral length. Thus, the effects of GH on these parameters in the peripubertal stage of development is totally dependent on IGF-I. This result is in stark contrast to the ability of IGF-I overexpression to correct the dwarfism associated with GH deficiency.

The function of IGF-II is less clear, although at a paracrine level it is presumably able to emulate the mitogenic functions of IGF-I by activation the IGF-IR. The absence of IGF-II in juvenile mice and rats has meant that experiments examining its functions are difficult, relying on larger experimental animals, such as sheep and pigs. However, quantitative trait loci affecting skeletal and cardiac muscle mass and fat deposition have been mapped to the IGF-2 gene locus in pigs, suggesting an important role for IGF-2 in postnatal development in some mammals.

In vivo metabolic effects of IGF-I and IGF-II

Whereas the IGF are primarily growth factors, when administered either by acute bolus injection or chronic infusion many insulin-like effects on metabolic functions have been reported. These responses can differ depending on whether IGF-I is given acutely or chronically. However, it should be noted that these effects are pharmacological. Acute or chronic administration of rhIGF-I to animals and humans results in a lowering of blood glucose (14). The exact mechanism whereby this effect is brought about is still incompletely understood. IGF-I inhibits insulin and C-peptide release from the ß-cell of the pancreas, acting through IGF-IR expressed on these cells. IGF-I, in contrast to insulin, inhibits glucagon secretion by the {alpha}-cells of the pancreatic islets, and the lowered circulating glucagon levels reduce hepatic glucose output. On the other hand, the effect of IGF-I on inhibiting hepatic glucose output is less than that for insulin because hepatocytes express IR but not the IGF-IR. IGF-I may stimulate glucose uptake by the muscle either via the IR or via the IGF-IR, both of which are expressed in skeletal muscle. In regard to protein metabolism, although insulin prevents proteolysis in muscle, IGF-I both inhibits proteolysis and enhances protein synthesis.

IGF-I administered chronically by sc injection causes circulating FFA to rise, probably due to inhibition of insulin that is antilipolytic. As noted earlier, IGF-II seems to activate the IR. The significance of this result is unclear, although it is interesting to note that in the human circulating IGF-II levels are actually higher than that of IGF-I (~500–700 ng/mL compared with 200–300 ng/mL for IGF-II and IGF-I, respectively). The possibility that IGFs in the circulation may contribute to the regulation of glucose homeostasis by insulin, perhaps by regulating the availability of IGF-I through regulating IGFBP levels in the circulation, has been discussed. For example, insulin is a potent inhibitor of hepatic IGFBP-1 production (15). IGFBP-1 inhibits IGF metabolic activities, whereas transgenic mice expressing high levels of IGFBP-1 have been reported to have defects in glucose homeostasis.


    Complications/Diseases
 Top
 Introduction
 The IGF System (Fig....
 Complications/Diseases
 Conclusions
 References
 
IGF-I gene deletion in humans

A single case of IGF-I gene deletion in a young boy has been described recently (16). Homozygous partial deletion of the coding region of the IGF-I gene abrogated IGF-I gene expression, and the patient demonstrated absent circulating IGF-I. Similar to the murine model described above, the young boy was growth retarded. He had a number of dysmorphic facial features, a small brain, and mild mental retardation. As expected, serum GH levels were markedly elevated, and this was associated with increased ALS levels. Both were normalized on rhIGF-I therapy that also increased IGFBP-3 levels. Other causes of IGF-I deficiency in children include primary and secondary GH deficiencies, GHR mutations, malnutrition, and many severe disease states. These will be discussed in other reviews in this volume.

IGF-I in type 1 diabetes

The GH/IGF-I axis is often abnormal in patients with poorly controlled type 1 diabetes. With inadequate insulin therapy and the resultant hyperglycemia, the patients develop a resistance to GH, as evidenced by reduced circulating IGF-I levels and elevated serum GH levels. The lack of insulin causes an elevation of IGFBP-1, and the lowered IGF-I levels cause a fall in IGFBP-3 in the circulation. If this situation occurs during the period of the pubertal growth spurt, patients will exhibit reductions in growth velocity, reversible with adequate insulin therapy and normalization of the GH/IGF-I axis. Normalization of the axis will also lower the GH levels, which might play a role in the deterioration of glycemic control by exercising an anti-insulin effect (17).

IGF-I has insulin-like effects when given acutely, particularly on blood glucose levels. Thus, rhIGF-I has been tested as a possible therapeutic agent in type 1 diabetes (as well as in type 2 diabetes). When administered sc at bedtime, rhIGF-I decreased GH secretion (18). Long-term administration resulted in an improvement in glycemic control and a reduction in insulin requirements (19). These effects are apparently due to inhibition of GH secretion and the effect of GH on antagonizing insulin, thereby improving insulin sensitivity in these cases. Although these results were initially very promising, in one study the effect was seen at 3 months of therapy and absent at 6 months after initiation of therapy. Furthermore, the results are tempered by the side effects experienced by the patients (usually at higher doses than required for adequate therapy), and the concern that long-term therapy may be associated with mitogenic responses, including retinopathy and tumor progression, although no long-term clinical trials have been carried out.

Use of rhIGF-I in patients with extreme severe insulin resistance was a particularly exciting idea because these patients fail to respond even to extremely high doses of insulin. The patients tested included those with the type A insulin resistance syndrome, the Rabson-Mendenhall syndrome, leprechaunism, and lipodystrophy, all due to a genetic mutation in the IR. Many of the patients treated with rhIGF-I demonstrated increased insulin sensitivity and a lowering of the blood glucose. Because many of these patients had mutations in the IR, it was concluded that the effects of the administered rhIGF-I were mediated through the IGF-IR. Proof of this hypothesis needs further investigation because some studies have shown no response in the most severe cases, such as, for example, in a case of leprechaunism due to a compound heterozygous mutation with a deletion of the IR from one allele (20, 21).

The role of the IGF system in the complications of type 1 diabetes

Multiple factors play a role in the development of microvascular complications of type 1 diabetes. Hyperglycemia is one of the most important factors since improvements in glycemic control has been shown unequivocally by the Diabetes Control and Complications Trial to delay or prevent microvascular events, such as diabetic retinopathy and nephropathy. In addition to hyperglycemia, growth factors, including the IGF system, have been invoked as being causative in the microvascular changes. Neovascularization seen in diabetic retinopathy may lead to blindness. GH therapy has resulted in deterioration of retinopathy in a few cases, and IGF-I has been invoked as the mediator of this effect. In a model of ischemia-induced retinopathy in mice, GH antagonists reduced this effect in parallel with a decrease in GH and IGF-I levels (22, 23). Similar results were obtained with a somatostatin analog that potently inhibits GH levels. When either GH or IGF-I were coadministered with the somatostatin analog, the neovascularization was restored. Whereas IGF-I is not a very powerful mitogen for endothelial cells by itself, it enhances the expression of other growth factors, such as fibroblast growth factor and vascular endothelial growth factor, which are powerful mitogens and have been shown to cause pathological changes in the vasculature (24). Thus, local retinal production of IGF-I in diabetics has been invoked as a causative agent in retinopathy. Similarly, the deterioration of the retinopathy seen in the early stages of insulin therapy and correction of hyperglycemia maybe due to an increase (normalization) of circulating IGF-I levels. These findings have led many investigators to send a message of caution in the use of rhIGF-I in patients with type 1 diabetes.

Studies in various animal models of diabetes have suggested a role for the IGF system in the renal complications of diabetes. In these animal models, IGF-I protein levels may be elevated in the kidney, causing hemodynamic changes including increased glomerular filtration rates, increased renal plasma flow, and an enlargement of the kidney typically seen in poorly controlled type 1 diabetes in humans. The effect on the vasculature is via the kallikrein and angiotensin systems (25). Persistent elevations in IGF-I levels may lead to changes in the microvasculature and basement membrane changes, which could explain the long-term nephropathic complication seen in patients with diabetes. The elevated IGF-I levels are apparently not associated with detectable elevations in IGF-I gene expression, but are apparently due to increased expression of IGFBPs, which trap circulating IGF-I and deliver it to the IGF-IR (26).

Cancer

Numerous studies have demonstrated a significant role for the IGF system in controlling tumor growth (27, 28, 29). Many tumors overexpress IGF-II, IGF-IR, and certain IGFBPs. IGF-II expression leads to an autocrine feedback loop stimulating the IGF-IR to stimulate cancer cell proliferation. The production of IGFBPs by the tumor cells often enhances the effect of the IGFs, thereby increasing cancer cell proliferation (30). Conversely, IGFBPs might also potentially act as tumor suppressors. For example, IGFBP-3 has been reported to stimulate apoptosis in an IGF-I-independent manner, possibly by binding to and activating the type V TGF-ß receptor (31).

IGF-II overexpression is found consistently in pediatric cancers, such as Wilms’ tumor (WT) and rhabdomyosarcoma (32, 33). In most normal human tissues, IGF-II is actively transcribed from the paternal allele, which is highly methylated in its promoter region. The maternal allele is silenced by a mechanism known as genomic imprinting. Loss of imprinting can lead to carcinogenesis. In the case of rhabdomyosarcomas and WT, for example, the silenced maternal IGF-II allele is activated. Furthermore, in cases of the Beckman-Wiedeman syndrome, there is evidence for unbalanced translocations with paternal duplication of chromosome 11, and other chromosomal abnormalities affecting the region of chromosome 11p, which contains the IGF-II gene locus (34, 35). The increased IGF-II gene expression may explain this overgrowth syndrome with increased incidence of WT. The WT gene product is a transcription factor that suppresses the expression of many growth factors and their receptors by direct binding to the promoter regions, thereby modulating their expression (36). When mutated in the DNA-binding domain, WT allows the overexpression of IGF-II and the IGF-IR. Mutations in WT are often found in cases of WT. The role of the IGF-IR in cancer has been studied extensively by a number of investigators. Overexpression of IGF-IR is a general phenomenon in cancer, and although not by itself an initiator of cancer development this receptor may enhance tumor proliferation and metastases. Reductions in IGF-IR levels using antisense technologies inhibit tumor growth (37, 38).

On rare occasions, the production of IGF-II by tumors may result in hypoglycemia (Fig. 3Go). These tumors express an incompletely processed form of IGF-II, called "big IGF-II" (39). Big IGF-II cannot complex with IGFBP-3 and ALS in the circulation and is shifted to a complex with IGFBP-2, allowing it to reach the target tissues and interact with the IR. Big IGF-II retains biological activity and stimulates skeletal muscle glucose uptake and inhibits hepatic glucose output, resulting in hypoglycemia (40). Big IGF-II inhibits GH hormone secretion, which in turn reduces circulating IGF-I, IGFBP-3, and ALS levels. Removal of the tumor reverses these effects, and the hypoglycemia is ameliorated (41).



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Figure 3. IGF-II and tumor hypoglycemia. Nonislet cell tumors secrete a large amount of the precursor form of IGF-II, namely "big IGF-II". Because big IGF-II is incompletely complexed with IGFBP-3/ALS, it readily interacts with tissue insulin and IGF-IR, enhancing peripheral tissue glucose uptake and inhibiting hepatic glucose output. Negative feedback regulation at the level of the pituitary inhibits GH release, which in turn decreases IGF-I, IGFBP-3, and ALS levels in the circulation. IGF-II also inhibits pancreatic insulin secretion.

 
Use of IGF-I and IGFBP levels as diagnostic indicators

In the diagnosis of growth retardation, GH levels after provocative stimuli are the standard test used. Because these measurements often fail to discriminate between normal and GH-deficient children, measurements of circulating total or free IGF-I were considered as an alternative. Although a number of studies have shown a good correlation between GH levels, IGF-I levels, and growth retardation, too many variables, such as nutritional status, complicate the use of IGF-I as an alternative (42). The addition of IGFBP-3 measurements increased the sensitivity, as did the increased levels of IGFBP-2 in GH-deficient children (43). Thus, a single parameter seems to be inadequate, and multiple parameters improve the sensitivity but still fail to improve specificity. In serum IGF-I, levels are increased in acromegaly and are used to monitor the effectiveness of therapy. In children with GH deficiency, however, growth rate is used to monitor response to GH rather than the levels of IGF-I in the circulation.


    Conclusions
 Top
 Introduction
 The IGF System (Fig....
 Complications/Diseases
 Conclusions
 References
 
The IGF system of ligands, binding proteins, and receptors is a ubiquitous and important system controlling normal physiology throughout life. It regulates the normal functions of numerous systems in the body and, in many diseases, its lack or overexpression is causative of many of the complications associated with that disease state. For these reasons it is actively being studied, and, although a large body of information has been obtained over the past decades, with the advent of new technologies we are now capable of learning much more. With this new information should come a better understanding of the diseases and potential remedies.

Received August 31, 1999.

Accepted September 20, 1999.


    References
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 Introduction
 The IGF System (Fig....
 Complications/Diseases
 Conclusions
 References
 

  1. Daughaday WH, Hall K, Raben MS, Salmon WD Jr, van den Brande JL, van Wyk JJ. 1972 Somatomedin: proposed designation for sulphation factor. Nature. 235:107.[Medline]
  2. Daughaday WH, Rotwein P. 1989 Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr Rev. 10:68–91.[Abstract]
  3. LeRoith D, Werner H, Beitner-Johnson D, Roberts CT Jr. 1995 Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev. 16:143–163.[Medline]
  4. Louvi A, Accili D, Efstratiadis A. 1997 Growth-promoting interaction of IGF-II with the insulin receptor during mouse embryonic development. Dev Biol. 189:33–48.[CrossRef][Medline]
  5. Frasca F, Pandini G, Scalia P, et al. 1999 Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol. 19:3278–3288.[Abstract/Free Full Text]
  6. Jones JI, Clemmons DR. 1995 Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 16:3–34.[Medline]
  7. Chin E, Zhou J, Dai J, Baxter RC, Bondy CA. 1994 Cellular localization and regulation of gene expression for components of the insulin-like growth factor ternary binding protein complex. Endocrinology. 134:2498–2504.[Abstract]
  8. Daughaday WH, Reeder C. 1966 Synchronous activation of DNA synthesis in hypophysectomized rat cartilage by growth hormone. J Lab Clin Med. 68:357–368.[Medline]
  9. Isaksson OG, Jansson JO, Gause IA. 1982 Growth hormone stimulates longitudinal bone growth directly. Science. 216:1237–1239.[Medline]
  10. D’Ercole AJ, Applewhite GT, Underwood LE. 1980 Evidence that somatomedin is synthesized by multiple tissues in the fetus. Dev Biol. 75:315–328.[Medline]
  11. Yakar S, Liu JL, Stannard B, et al. 1999 Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci USA. 96:7324–7329.[Abstract/Free Full Text]
  12. Baker J, Liu JP, Robertson EJ, Efstratiadis A. 1993 Role of insulin-like growth factors in embryonic and postnatal growth. Cell. 75:73–82.[Medline]
  13. Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. 1993 Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell. 75:59–72.[Medline]
  14. Guler HP, Zapf J, Froesch ER. 1987 Short-term metabolic effects of recombinant human insulin-like growth factor I in healthy adults. N Engl J Med. 317:137–140.[Abstract]
  15. Orlowski CC, Ooi GT, Brown DR, Yang YW, Tseng LY, Rechler MM. 1991 Insulin rapidly inhibits insulin-like growth factor-binding protein-1 gene expression in H4-II-E rat hepatoma cells. Mol Endocrinol. 5:1180–1187.[Abstract]
  16. Woods KA, Camacho-Hubner C, Savage MO, Clark AJ. 1996 Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med. 335:1363–1367.[Free Full Text]
  17. Dunger DB, Cheetham TD, Crowne EC. 1995 Insulin-like growth factors (IGFs) and IGF-I treatment in the adolescent with insulin-dependent diabetes mellitus. Metabolism. 44:119–123.[Medline]
  18. Cheetham TD, Clayton KL, Taylor AM, Holly J, Matthews DR, Dunger DB. 1994 The effects of recombinant human insulin-like growth factor I on growth hormone secretion in adolescents with insulin dependent diabetes mellitus. Clin Endocrinol (Oxf). 40:515–522.[Medline]
  19. Cheetham TD, Holly JM, Clayton K, Cwyfan-Hughes S, Dunger DB. 1995 The effects of repeated daily recombinant human insulin-like growth factor I administration in adolescents with type 1 diabetes. Diabet Med. 12:885–892.[Medline]
  20. Morrow LA, O’Brien MB, Moller DE, Flier JS, Moses AC. 1994 Recombinant human insulin-like growth factor-I therapy improves glycemic control and insulin action in the type A syndrome of severe insulin resistance. J Clin Endocrinol Metab. 79:205–210.[Abstract]
  21. Schoenle EJ, Zenobi PD, Torresani T, Werder EA, Zachmann M, Froesch ER. 1991 Recombinant human insulin-like growth factor I (rhIGF I) reduces hyperglycaemia in patients with extreme insulin resistance. Diabetologia. 34:675–679.[Medline]
  22. Koller EA, Green L, Gertner JM, Bost M, Malozowski SN. 1998 Retinal changes mimicking diabetic retinopathy in two nondiabetic, growth hormone-treated patients. J Clin Endocrinol Metab. 83:2380–2383.[Abstract/Free Full Text]
  23. Smith LE, Kopchick JJ, Chen W, et al. 1997 Essential role of growth hormone in ischemia-induced retinal neovascularization. Science. 276:1706–1709.[Abstract/Free Full Text]
  24. Pierce EA, Avery RL, Foley ED, Aiello LP, Smith LE. 1995 Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. Proc Natl Acad Sci USA. 92:905–909.[Abstract]
  25. Jaffa AA, LeRoith D, Roberts CT Jr, Rust PF, Mayfield RK. 1994 Insulin-like growth factor I produces renal hyperfiltration by a kinin- mediated mechanism. Am J Physiol. 266:F102–107.
  26. Landau D, Chin E, Bondy C, et al. 1995 Expression of insulin-like growth factor binding proteins in the rat kidney: effects of long-term diabetes. Endocrinology. 136:1835–1842.[Abstract]
  27. Baserga R. 1994 Oncogenes and the strategy of growth factors. Cell. 79:927–930.[Medline]
  28. Kalebic T, Tsokos M, Helman LJ. 1994 In vivo treatment with antibody against IGF-1 receptor suppresses growth of human rhabdomyosarcoma and down-regulates p34cdc2. Cancer Res. 54:5531–5534.[Abstract]
  29. Trojan J, Johnson TR, Rudin SD, Ilan J, Tykocinski ML. 1993 Treatment and prevention of rat glioblastoma by immunogenic C6 cells expressing antisense insulin-like growth factor I RNA (see comments). Science. 259:94–97.[Medline]
  30. Chen JC, Shao ZM, Sheikh MS, et al. 1994 Insulin-like growth factor-binding protein enhancement of insulin-like growth factor-I (IGF-I)-mediated DNA synthesis and IGF-I binding in a human breast carcinoma cell line. J Cell Physiol. 158:69–78.[Medline]
  31. Leal SM, Liu Q, Huang SS, Huang JS. 1997 The type V transforming growth factor ß receptor is the putative insulin-like growth factor-binding protein 3 receptor. J Biol Chem. 272:20572–20576.[Abstract/Free Full Text]
  32. Ogawa O, Eccles MR, Szeto J, et al. 1993 Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms’ tumour. Nature. 362:749–751.[CrossRef][Medline]
  33. Wang W, Kumar P, Epstein J, Helman L, Moore JV, Kumar S. 1998 Insulin-like growth factor II and PAX3-FKHR cooperate in the oncogenesis of rhabdomyosarcoma. Cancer Res. 58:4426–4433.[Abstract]
  34. Slatter RE, Elliott M, Welham K, et al. 1994 Mosaic uniparental disomy in Beckwith-Wiedemann syndrome. J Med Genet. 31:749–753.[Abstract]
  35. Reeve AE. 1996 Role of genomic imprinting in Wilms’ tumour and overgrowth disorders. Med Pediatr Oncol. 27:470–475.[CrossRef][Medline]
  36. Werner H, Shen-Orr Z, Rauscher FJ 3rd, Morris JF, Roberts CT Jr, LeRoith D. 1995 Inhibition of cellular proliferation by the Wilms’ tumor suppressor WT1 is associated with suppression of insulin-like growth factor I receptor gene expression. Mol Cell Biol. 15:3516–3522.[Abstract]
  37. Shapiro DN, Jones BG, Shapiro LH, Dias P, Houghton PJ. 1994 Antisense-mediated reduction in insulin-like growth factor-I receptor expression suppresses the malignant phenotype of a human alveolar rhabdomyosarcoma. J Clin Invest. 94:1235–1242.[Medline]
  38. Neuenschwander S, Roberts CT Jr, LeRoith D. 1995 Growth inhibition of MCF-7 breast cancer cells by stable expression of an insulin-like growth factor I receptor antisense ribonucleic acid. Endocrinology. 136:4298–4303.[Abstract]
  39. Daughaday WH, Trivedi B. 1992 Measurement of derivatives of proinsulin-like growth factor-II in serum by a radioimmunoassay directed against the E-domain in normal subjects and patients with nonislet cell tumor hypoglycemia. J Clin Endocrinol Metab. 75:110–115.[Abstract]
  40. Eastman RC, Carson RE, Orloff DG, et al. 1992 Glucose utilization in a patient with hepatoma and hypoglycemia. Assessment by a positron emission tomography. J Clin Invest. 89:1958–1963.[Medline]
  41. Le Roith D. 1997 Seminars in medicine of the Beth Israel Deaconess Medical Center. Insulin-like growth factors. N Engl J Med. 336:633–640.[Free Full Text]
  42. Juul A, Holm K, Kastrup KW, et al. 1997 Free insulin-like growth factor I serum levels in 1430 healthy children and adults, and its diagnostic value in patients suspected of growth hormone deficiency. J Clin Endocrinol Metab. 82:2497–2502.[Abstract/Free Full Text]
  43. Smith WJ, Nam TJ, Underwood LE, Busby WH, Celnicker A, Clemmons DR. 1993 Use of insulin-like growth factor-binding protein-2 (IGFBP-2), IGFBP-3, and IGF-I for assessing growth hormone status in short children. J Clin Endocrinol Metab. 77:1294–1299.[Abstract]