**The Insulin-Like Growth Factor System in the Human Pathology**

Emrah Yerlikaya and Fulya Akin

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55213

## **1. Introduction**

#### **1.1. Physiology**

Insulin-like growth factors are single chain polypeptides. There are two principle IGFs referred to as IGF-I and IGF-II. IGF-1 is a polypeptide hormone with a molecular weight of 7.6-kDa structurally similar to insulin. In 1957, it is identified by Salmon and Daughaday. Because of the its ability to stimulate the sulfation of the cartilage proteoglycans, it was regarded as a sulphation factor [1]. The IGF-1 gene is on the long arm of chromosome 12q23– 23. IGF-1 gene contains 6 exons [2, 3]. The alternate extension peptide at carboxy terminal, encoded by exons 5 and 6 determines the subforms of IGF-1: IGF-1B and IGF-1A. The most abundant isoform of the IGF-1 (153 aminoacid) is IGF-1A [4, 5]. IGF1B peptide (195 amino acids) is a less abundant IGF1 isoform. IGF-2 is also a peptide with 67 amino acids and molecular weight of 7.4-kDa. IGF-2 is encoded by a gene on the short arm of chromosome 11 at position 15.5. This gene consists of nine exons [6]. In the plasma, 99% of IGFs are bound to a family of binding cysteine-rich proteins. There are six binding proteins (IGFBP-1 to IGFBP-6) [7]. They act as carriers for IGFs in the circulation, regulate the bioavailability of IGFs to spesific tissues and modulates the biological activities of IGF proteins. Six IGFbinding proteins (IGFBPs) can inhibit or enhance the actions of IGFs [8]. Potentiation of IGF activity by some of the IGFBPs, described for IGFBP-1 and IGFBP-3, is also documented for IGFBP-5. Each of IGFBPs is the product of a seperate gene. These genes share a common structural organization in which four conserved exons are located within genes ranging from 5 kb (IGFBP-1) to more than 30 kb (IGFBP-2 and IGFBP-5) [9]. IGFBPs contain N terminal and C terminal domains which are similar in aminoacid sequence. Post-translational modifications of IGFBP, including glycosylation, phosphorylation and proteolysis modify the affinities of the binding proteins to IGF. IGFs mediate their action on target cells by three

© 2013 Yerlikaya and Akin; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

receptors that bind IGFs with differing affinities. These receptors are type 1 IGF receptor, type 2 IGF receptor and Insulin receptors. The type 1 IGF receptor (IGF-1R), structurally homologous to the insulin receptor, exhibits four transmembrane spanning subunits and an intracellular tyrosine kinase domain [10]. The IGF-1R and IR are both synthesized as a precursor that is glycosylated on the extracellular regions, dimerized and proteolytically processed to yield separate α and β chains [11]. IGF-1R binds insulin, IGF-1, or IGF-2. IGF1R binds to IGF1 with greater affinity than IGF-2. IGF-1R affinity for insulin is lower than for IGF-1. Type 2 IGF receptor is structurally and functionally different from the IGF-1R. The receptor is a 250-kDa protein with a large extracellular domain, which binds M6P, lysoso‐ mal enzymes, and IGF-2 [12]. IGF-2R binds to IGF-2 with high affinity whereas IGF-1 binding is weak and insulin does not bind at all [13]. Binding of IGF-1 and IGF-2 to the cognate IGF-1R stimulates the intrinsic tyrosine kinase activity of this receptor [14]. Upon IGF binding, the tyrosine kinase activity of IGF-1 receptor leads to the phosphorylation of several substrates, including the insulin receptor substrate family of proteins (such as Insulin receptor substrate 1 (IRS-1), SHC (Src homology 2 domain containing) transforming protein 1 (Shc) and some others. Once phosphorylated, these docking proteins activate down‐ stream intracellular signaling through the Phosphatidylinositol 3-kinase (PI3K) or Growth factor receptor-bound protein 2 (GRB2)/ Son of sevenless homolog (SOS )/ v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras) pathways that ultimately leads to cellular proliferation [15,16].

ment it is not the only factor responsible for the increment in childhood. Serum estradiol concentrations correlate with IGF-1 in both men and women [22]. Stimulated and spontane‐ ous GH secretion is higher in young women than in postmenopausal women or young men, with the difference strongly correlated with circulating estradiol levels [23, 24, 25]. Use of oral estrogen resulted in a significant reduction in IGF1 levels but no effect of transdermal estrogen was shown in patients with hypopitutiarism [26]. Transdermally delivered estrogen stimulates IGF-1 production. When delivered orally, estrogen reduces IGF-1 [27]. IGF-1 mRNA expressed by endometrium. Progesterons increases IGF-1 expression İn the endome‐ trial stroma. There is circumstantial evidence to suggest a positive association between circulating levels of testosterone and IGF-1. Administration of testosterone to younger men with hypogonadism and boys with isolated gonadotropin-releasing hormone deficiency increases serum IGF-1 [28]. Endogenous testosterone levels correlate with IGF-1 in hypopi‐ tuitary women with unsubstituted growth hormone deficiency [29]. Serum dehydroepian‐ drosterone concentrations decline with age, and absolute concentrations in postmenopausal women correlate with serum IGF-1 [30]. Thyroxine is also another hormone affecting IGF-1 levels. In patients with T4 deficiency due to primary and central hypothyroidism IGF-1 and ALS are low at baseline. In most of these T4-treated patients, T4 therapy increased IGF-1 and ALS concentrations [31]. The major effect of thyroid hormones on IGF-1 and IGFBP-3 in vivo has been considered to occur by increased expression and secretion of growth hormone by the pituitary gland [32]. IGFBP-3 also increases with thyroxine replacement in primary hypothyroidism [33]. One key function of IGF-1 is the stimulation of anabolic processes and body growth. Protein and energy content of the diet influence plasma IGF-1 concentrations [34]. IGF-1 is reduced in conditions of energy restriction, such as shortterm fasting [35] and malnutrition [36]. Zinc deficiency is a common component of proteincalorie malnutrition. IGF-1 synthesis can be impaired by zinc deficiency. A reduction in circulating IGF-1 concentrations has been proposed as a potential mechanism for growth retardation induced by zinc deficiency [37]. Significant elevation in the IGF-1 level after zinc supplementation occurs [38]. Similarly, nutritional deprivation results in a major decrease in IGF-1 mRNA that can be restored with refeeding. In the population of healthy wellnourished men, greater dietary intakes of protein, zinc, red meat, and fish and seafood were associated with higher IGF-1 concentrations [39]. The anabolic effect of PTH may be mediated by local growth factors. PTH has been shown to stimulate IGF-1 production at the transcriptional and polypeptide levels [40]. Low IGF-1 and IGFBP-3 levels occurs in liver cirrhosis due to decreased synthesis and low IGF-1 levels may be involved in the develop‐ ment of cirrhotic complications including malnutrition, insulin resistance, impaired

The Insulin-Like Growth Factor System in the Human Pathology

http://dx.doi.org/10.5772/55213

199

Any factors affecting IGFBP concentrations in blood and extracellular fluids also affects the IGF levels and its avaibility to tissues. Binding of IGF-1 to ALS and IGFBPs form ternary complexes. Acid Labile Subunit (ALS) is a liver-derived protein that exists in a ternary complex with IGFBP-3 also with IGFBP-5. Formation of the ternary complexes restricts the IGFs to the circulation prolongs their half-lives and allows them to be stored at high concentration in plasma. ALS is a single-copy gene, and was mapped to bands A2-A3 of mouse chromosome 17 and to the short arm of human chromosome 16 at p13 3 [42, 43]. ALS has no affinity for free

immunity, and osteoporosis [41].

Ligand binding to IGF-1R activates the tyrosine kinase higher concentration of the antiapoptotic proteins bcl-2 and bcl-Xl, a lower level of the apoptotic proteins bax and bcl-xs activates phosphatidylinositol 3-kinase (P13-K), and activates protein kinase B (PKB/Akt) that also prevent apoptosis. Activation of PI 3-kinase generates inositol triphosphate activation of protein tyrosine kinase-B activate mTOR, p70/S6 kinase and GSK-3β results in protein glucose uptake, glycogen synthesis. Most IGF-1 is secreted by the liver and is transported to other tissues, acting as an endocrine hormone. IGF-1 is also secreted by other tissues, including cartilagenous cells, and acts locally as a paracrine hormone. In response to GH, IGF-1 synthesis is increased in connective tissues. Growth hormone released from the anterior lobe of the pituitary binds to receptors on the surface of liver cells which stimulates the synthesis and release of IGF-1 from them. STAT5B is a transcription factor mediating effect of GH on liver. Low IGF-1 and IGFBP-3 levels in cirrhosis occurs due to decreased hepatic synthesis [17, 18]. IGFBP-3 that binds 95% of circulating IGFs is also produced by the endothelial lining and Kupffer cells in the liver.

#### **2. Factors affecting IGF system**

IGF-1 peaks during puberty. Advanced age is associated with a progressive decrease in serum IGF-1 because GH secretion declines; 14% per decade of life [19, 20]. During lifetime, GH production is reduced nearly 30-fold. This decrement in IGF-1 is attributable to increased somatostatinergic tone and a generalized reduction in the pulses of GH-releasing hor‐ mones and GH-releasing peptides [21]. Although GH may be responsible for the decre‐

ment it is not the only factor responsible for the increment in childhood. Serum estradiol concentrations correlate with IGF-1 in both men and women [22]. Stimulated and spontane‐ ous GH secretion is higher in young women than in postmenopausal women or young men, with the difference strongly correlated with circulating estradiol levels [23, 24, 25]. Use of oral estrogen resulted in a significant reduction in IGF1 levels but no effect of transdermal estrogen was shown in patients with hypopitutiarism [26]. Transdermally delivered estrogen stimulates IGF-1 production. When delivered orally, estrogen reduces IGF-1 [27]. IGF-1 mRNA expressed by endometrium. Progesterons increases IGF-1 expression İn the endome‐ trial stroma. There is circumstantial evidence to suggest a positive association between circulating levels of testosterone and IGF-1. Administration of testosterone to younger men with hypogonadism and boys with isolated gonadotropin-releasing hormone deficiency increases serum IGF-1 [28]. Endogenous testosterone levels correlate with IGF-1 in hypopi‐ tuitary women with unsubstituted growth hormone deficiency [29]. Serum dehydroepian‐ drosterone concentrations decline with age, and absolute concentrations in postmenopausal women correlate with serum IGF-1 [30]. Thyroxine is also another hormone affecting IGF-1 levels. In patients with T4 deficiency due to primary and central hypothyroidism IGF-1 and ALS are low at baseline. In most of these T4-treated patients, T4 therapy increased IGF-1 and ALS concentrations [31]. The major effect of thyroid hormones on IGF-1 and IGFBP-3 in vivo has been considered to occur by increased expression and secretion of growth hormone by the pituitary gland [32]. IGFBP-3 also increases with thyroxine replacement in primary hypothyroidism [33]. One key function of IGF-1 is the stimulation of anabolic processes and body growth. Protein and energy content of the diet influence plasma IGF-1 concentrations [34]. IGF-1 is reduced in conditions of energy restriction, such as shortterm fasting [35] and malnutrition [36]. Zinc deficiency is a common component of proteincalorie malnutrition. IGF-1 synthesis can be impaired by zinc deficiency. A reduction in circulating IGF-1 concentrations has been proposed as a potential mechanism for growth retardation induced by zinc deficiency [37]. Significant elevation in the IGF-1 level after zinc supplementation occurs [38]. Similarly, nutritional deprivation results in a major decrease in IGF-1 mRNA that can be restored with refeeding. In the population of healthy wellnourished men, greater dietary intakes of protein, zinc, red meat, and fish and seafood were associated with higher IGF-1 concentrations [39]. The anabolic effect of PTH may be mediated by local growth factors. PTH has been shown to stimulate IGF-1 production at the transcriptional and polypeptide levels [40]. Low IGF-1 and IGFBP-3 levels occurs in liver cirrhosis due to decreased synthesis and low IGF-1 levels may be involved in the develop‐ ment of cirrhotic complications including malnutrition, insulin resistance, impaired immunity, and osteoporosis [41].

receptors that bind IGFs with differing affinities. These receptors are type 1 IGF receptor, type 2 IGF receptor and Insulin receptors. The type 1 IGF receptor (IGF-1R), structurally homologous to the insulin receptor, exhibits four transmembrane spanning subunits and an intracellular tyrosine kinase domain [10]. The IGF-1R and IR are both synthesized as a precursor that is glycosylated on the extracellular regions, dimerized and proteolytically processed to yield separate α and β chains [11]. IGF-1R binds insulin, IGF-1, or IGF-2. IGF1R binds to IGF1 with greater affinity than IGF-2. IGF-1R affinity for insulin is lower than for IGF-1. Type 2 IGF receptor is structurally and functionally different from the IGF-1R. The receptor is a 250-kDa protein with a large extracellular domain, which binds M6P, lysoso‐ mal enzymes, and IGF-2 [12]. IGF-2R binds to IGF-2 with high affinity whereas IGF-1 binding is weak and insulin does not bind at all [13]. Binding of IGF-1 and IGF-2 to the cognate IGF-1R stimulates the intrinsic tyrosine kinase activity of this receptor [14]. Upon IGF binding, the tyrosine kinase activity of IGF-1 receptor leads to the phosphorylation of several substrates, including the insulin receptor substrate family of proteins (such as Insulin receptor substrate 1 (IRS-1), SHC (Src homology 2 domain containing) transforming protein 1 (Shc) and some others. Once phosphorylated, these docking proteins activate down‐ stream intracellular signaling through the Phosphatidylinositol 3-kinase (PI3K) or Growth factor receptor-bound protein 2 (GRB2)/ Son of sevenless homolog (SOS )/ v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras) pathways that ultimately leads to cellular

Ligand binding to IGF-1R activates the tyrosine kinase higher concentration of the antiapoptotic proteins bcl-2 and bcl-Xl, a lower level of the apoptotic proteins bax and bcl-xs activates phosphatidylinositol 3-kinase (P13-K), and activates protein kinase B (PKB/Akt) that also prevent apoptosis. Activation of PI 3-kinase generates inositol triphosphate activation of protein tyrosine kinase-B activate mTOR, p70/S6 kinase and GSK-3β results in protein glucose uptake, glycogen synthesis. Most IGF-1 is secreted by the liver and is transported to other tissues, acting as an endocrine hormone. IGF-1 is also secreted by other tissues, including cartilagenous cells, and acts locally as a paracrine hormone. In response to GH, IGF-1 synthesis is increased in connective tissues. Growth hormone released from the anterior lobe of the pituitary binds to receptors on the surface of liver cells which stimulates the synthesis and release of IGF-1 from them. STAT5B is a transcription factor mediating effect of GH on liver. Low IGF-1 and IGFBP-3 levels in cirrhosis occurs due to decreased hepatic synthesis [17, 18]. IGFBP-3 that binds 95% of circulating IGFs is also produced by the endothelial lining and

IGF-1 peaks during puberty. Advanced age is associated with a progressive decrease in serum IGF-1 because GH secretion declines; 14% per decade of life [19, 20]. During lifetime, GH production is reduced nearly 30-fold. This decrement in IGF-1 is attributable to increased somatostatinergic tone and a generalized reduction in the pulses of GH-releasing hor‐ mones and GH-releasing peptides [21]. Although GH may be responsible for the decre‐

proliferation [15,16].

198 Hot Topics in Endocrine and Endocrine-Related Diseases

Kupffer cells in the liver.

**2. Factors affecting IGF system**

Any factors affecting IGFBP concentrations in blood and extracellular fluids also affects the IGF levels and its avaibility to tissues. Binding of IGF-1 to ALS and IGFBPs form ternary complexes. Acid Labile Subunit (ALS) is a liver-derived protein that exists in a ternary complex with IGFBP-3 also with IGFBP-5. Formation of the ternary complexes restricts the IGFs to the circulation prolongs their half-lives and allows them to be stored at high concentration in plasma. ALS is a single-copy gene, and was mapped to bands A2-A3 of mouse chromosome 17 and to the short arm of human chromosome 16 at p13 3 [42, 43]. ALS has no affinity for free IGF-1 or IGF-2 and very low affinity for uncomplexed IGFBP-3. Main binding protein of IGFs is IGFBP-3 and its synthesis is mainly determined by growth hormone. IGFBP-3 is the most abundant form of the IGFBPs. IGFBP-3 concentrations decreases in patientes with growth hormone deficiency and increaes by GH secretion. Testesterone administration adminstration increases IGFBP-3 levels in serum. IGFBP-3 level is also affected by thyroid hormone levels. Low IGFBP-3 levels were found in hypothyroid patients and IGFBP-3 levels are increased by thyroxine replacement in hypothyroid patients. The IGFBP-1 that is present in the circulation is also synthesized in the liver. At concentrations higher than IGF-1, IGFBP-1 inhibit DNA synthesis, glucose transportation [44]. Postprandial increase in serum insulin concentrations results in a four- to five-fold decrease in IGFBP-1 [45]. Intrauterine growth retardation correlates with high levels of serum IGF binding protein-1 (IGFBP-1). Overexpression of IGFBP-1 may affect body growth and skeletal formation as well as biomineralization. IGFBP-1 overexpression may also reduce carbohydrate resources necessary for growth and survival [46]. IGFBP-1 play roles in the endometrial and ovarian physiology. The IGFBP-2 that is present in the circulation originates from hepatocytes, GH is a main determinant of IGFBP-2 levels in circulation. IGF-1 is a potent stimulant of IGFBP-2 concentrations in serum. IGFBP-2 gene transcription is increased in starved rodents and plasma concentrations are increased in fasted humans [47]. IGFBP-2 has mostly inhibitory effects. IGF-1 stimulated collagen synthesis is inhibited by IGFBP-2.

humans, it is found that bone marrow IGF-1 concentrations were 40% lower in individuals with osteoporosis than in individuals without osteoporosis [51]. As compared to healthy controls, total bone mass was found lower in men with GH deficiency and The total BMD was found positively related to plasma IGF-1 and median of GH values [52]. GH deficiency in adulthood is associated with reduced BMD. IGF-1 may be an early marker for low bone mass [53]. Short term treatment with recombinant human IGF-1 in healthy postmenopausal women resulted in increases in bone turnover markers [54]. However, certain effects of the long-term

The Insulin-Like Growth Factor System in the Human Pathology

http://dx.doi.org/10.5772/55213

201

Linear bone growth at the epiphyseal plate occurs by a process that is similar to endochondral ossification. The epiphyseal plate between the epiphysis and the metaphysis grows by mitosis. This process continues throughout childhood and the adolescent years until the cartilage growth slows and finally stops. GH may act directly at the growth plate to amplify the production of chondrocytes from germinal zone precursors and then to induce local IGF-1 synthesis, which is thought to stimulate the clonal expansion of chondrocyte columns in an autocrine/paracrine manner [55, 56]. IGF-2 mRNA expression is higher in the proliferative and resting zones than the hypertrophic zone. IGF-1 and GH receptors are expressed throughout the growth plate. Molecular studies revealed that the causes of GH resistance are deletions[57] or mutations [58] in the GH receptor gene, resulting in the failure to generate IGF-1 and a

The expression of IGF-I, IGF-II, IGFBP-3, and ALS is tightly controlled by GH. STAT5B is a transcription factor mediating effect of GH on liver. Six cases of homozygous mutations of the signal transducer and activator of transcription STAT5B gene have also been described [59]. These mutations result in a type of dwarfism characterised by high serum GH values. Studies revealed that these patients cannot generate IGF-1. Several cases have been reported of mutations of the gene for the ALS, which encodes a protein which forms part of the ternary complex that transports IGF-1 in serum [60, 61]. These cases have markedly low serum IGF-1 concentrations and modest growth failure. Syndrome of GH resistance (insensitivity) was named by Elders et al as Laron dwarfism, a name subsequently changed to Laron syndrome [62]. Long term treatment of patients with LS promotes growth and, if treatment is started at an early age, there is a considerable potential for achieving height normalisation [63]. The recently available recombinant human insulin-like growth factor I has shown promise as a promoter of growth in children with Laron syndrome. Main adverse effects with IGF-1 treatment is hypoglycemia. Other adverse effects of IGF-1 treatment appear to be related to hyperstimulation of lymphoid tissue growth: tonsillar growth, snoring, sleep apnea, recurrent ear infections, thymic hypertrophy, and splenic enlargement [64, 65, 66, 67]. Injection site hypertrophy has been observed, but is generally amenable to proper rotation of injection sites. Arthralgias and myalgias have been reported in as many as 20% of recipients in uncontrolled studies, but are usually transient. Benign intracranial hypertension has been reported in ~4% of recipients. Although this number appears somewhat larger than that observed with GH

reduction in the synthesis of several other substances,including IGFBP-3.

treatment with IGF-1 is unknown.

**4. IGFs and growth**

The serum concentrations of intact IGFBP-4 are quite low. IGFBP-4 level is increased with low bone turnover and low parathyroid hormone levels. Sunlight exposure, vitamin D or its active metabolites also may regulate serum IGFBP-4. It may play a role in bone metabolism. IGFBP-5 circulates as incomplete fragments, intact IGFBP-5 is at very low levels. Its concentration are also regulated with GH ang IGF-1. IGFBP-6 inhibits the effects of IGF-2 in several tissues and cell types. IGFBP-6 differs from the other IGFBPs, it has a markedly higher affinity for IGF-2 than for IGF-1, whereas the other IGFBPs bind the two IGFs with similar affinities and IGFBP-2 has a slight IGF-2 binding preference [48, 49, 50].

However, IGF bioactivity in tissues is not determined by the circulating levels of IGFs, IGFBPS, ALS. Proteases that digest IGFBPs are also important in determining the acions of IGFs at tissue level. In addition IGFBPs have their own separate roles in the extravascular tissue compartment.

## **3. IGFs and bone**

Osteoblasts and preosteoblasts secrete IGF-1. Several bone trophic factors, estrogens, PTH stimulate the synthesis of the IGF-1 while glucocorticoids, FGF, PDGF, TGF-B decreases IGF1 expression.

IGF-1 released from the bone matrix during bone remodeling stimulates osteoblastic differ‐ entiation of recruited mesenchymal stem cells by activation of mammalian target of rapamycin (mTOR), thus maintaining proper bone microarchitecture and mass. It is well known that both BMD and serum concentration of IGF-1 decrease with age, in age-related osteoporosis in humans, it is found that bone marrow IGF-1 concentrations were 40% lower in individuals with osteoporosis than in individuals without osteoporosis [51]. As compared to healthy controls, total bone mass was found lower in men with GH deficiency and The total BMD was found positively related to plasma IGF-1 and median of GH values [52]. GH deficiency in adulthood is associated with reduced BMD. IGF-1 may be an early marker for low bone mass [53]. Short term treatment with recombinant human IGF-1 in healthy postmenopausal women resulted in increases in bone turnover markers [54]. However, certain effects of the long-term treatment with IGF-1 is unknown.

## **4. IGFs and growth**

IGF-1 or IGF-2 and very low affinity for uncomplexed IGFBP-3. Main binding protein of IGFs is IGFBP-3 and its synthesis is mainly determined by growth hormone. IGFBP-3 is the most abundant form of the IGFBPs. IGFBP-3 concentrations decreases in patientes with growth hormone deficiency and increaes by GH secretion. Testesterone administration adminstration increases IGFBP-3 levels in serum. IGFBP-3 level is also affected by thyroid hormone levels. Low IGFBP-3 levels were found in hypothyroid patients and IGFBP-3 levels are increased by thyroxine replacement in hypothyroid patients. The IGFBP-1 that is present in the circulation is also synthesized in the liver. At concentrations higher than IGF-1, IGFBP-1 inhibit DNA synthesis, glucose transportation [44]. Postprandial increase in serum insulin concentrations results in a four- to five-fold decrease in IGFBP-1 [45]. Intrauterine growth retardation correlates with high levels of serum IGF binding protein-1 (IGFBP-1). Overexpression of IGFBP-1 may affect body growth and skeletal formation as well as biomineralization. IGFBP-1 overexpression may also reduce carbohydrate resources necessary for growth and survival [46]. IGFBP-1 play roles in the endometrial and ovarian physiology. The IGFBP-2 that is present in the circulation originates from hepatocytes, GH is a main determinant of IGFBP-2 levels in circulation. IGF-1 is a potent stimulant of IGFBP-2 concentrations in serum. IGFBP-2 gene transcription is increased in starved rodents and plasma concentrations are increased in fasted humans [47]. IGFBP-2 has mostly inhibitory effects. IGF-1 stimulated collagen synthesis is

The serum concentrations of intact IGFBP-4 are quite low. IGFBP-4 level is increased with low bone turnover and low parathyroid hormone levels. Sunlight exposure, vitamin D or its active metabolites also may regulate serum IGFBP-4. It may play a role in bone metabolism. IGFBP-5 circulates as incomplete fragments, intact IGFBP-5 is at very low levels. Its concentration are also regulated with GH ang IGF-1. IGFBP-6 inhibits the effects of IGF-2 in several tissues and cell types. IGFBP-6 differs from the other IGFBPs, it has a markedly higher affinity for IGF-2 than for IGF-1, whereas the other IGFBPs bind the two IGFs with similar affinities and IGFBP-2

However, IGF bioactivity in tissues is not determined by the circulating levels of IGFs, IGFBPS, ALS. Proteases that digest IGFBPs are also important in determining the acions of IGFs at tissue level. In addition IGFBPs have their own separate roles in the extravascular

Osteoblasts and preosteoblasts secrete IGF-1. Several bone trophic factors, estrogens, PTH stimulate the synthesis of the IGF-1 while glucocorticoids, FGF, PDGF, TGF-B decreases IGF1

IGF-1 released from the bone matrix during bone remodeling stimulates osteoblastic differ‐ entiation of recruited mesenchymal stem cells by activation of mammalian target of rapamycin (mTOR), thus maintaining proper bone microarchitecture and mass. It is well known that both BMD and serum concentration of IGF-1 decrease with age, in age-related osteoporosis in

inhibited by IGFBP-2.

200 Hot Topics in Endocrine and Endocrine-Related Diseases

tissue compartment.

**3. IGFs and bone**

expression.

has a slight IGF-2 binding preference [48, 49, 50].

Linear bone growth at the epiphyseal plate occurs by a process that is similar to endochondral ossification. The epiphyseal plate between the epiphysis and the metaphysis grows by mitosis. This process continues throughout childhood and the adolescent years until the cartilage growth slows and finally stops. GH may act directly at the growth plate to amplify the production of chondrocytes from germinal zone precursors and then to induce local IGF-1 synthesis, which is thought to stimulate the clonal expansion of chondrocyte columns in an autocrine/paracrine manner [55, 56]. IGF-2 mRNA expression is higher in the proliferative and resting zones than the hypertrophic zone. IGF-1 and GH receptors are expressed throughout the growth plate. Molecular studies revealed that the causes of GH resistance are deletions[57] or mutations [58] in the GH receptor gene, resulting in the failure to generate IGF-1 and a reduction in the synthesis of several other substances,including IGFBP-3.

The expression of IGF-I, IGF-II, IGFBP-3, and ALS is tightly controlled by GH. STAT5B is a transcription factor mediating effect of GH on liver. Six cases of homozygous mutations of the signal transducer and activator of transcription STAT5B gene have also been described [59]. These mutations result in a type of dwarfism characterised by high serum GH values. Studies revealed that these patients cannot generate IGF-1. Several cases have been reported of mutations of the gene for the ALS, which encodes a protein which forms part of the ternary complex that transports IGF-1 in serum [60, 61]. These cases have markedly low serum IGF-1 concentrations and modest growth failure. Syndrome of GH resistance (insensitivity) was named by Elders et al as Laron dwarfism, a name subsequently changed to Laron syndrome [62]. Long term treatment of patients with LS promotes growth and, if treatment is started at an early age, there is a considerable potential for achieving height normalisation [63]. The recently available recombinant human insulin-like growth factor I has shown promise as a promoter of growth in children with Laron syndrome. Main adverse effects with IGF-1 treatment is hypoglycemia. Other adverse effects of IGF-1 treatment appear to be related to hyperstimulation of lymphoid tissue growth: tonsillar growth, snoring, sleep apnea, recurrent ear infections, thymic hypertrophy, and splenic enlargement [64, 65, 66, 67]. Injection site hypertrophy has been observed, but is generally amenable to proper rotation of injection sites. Arthralgias and myalgias have been reported in as many as 20% of recipients in uncontrolled studies, but are usually transient. Benign intracranial hypertension has been reported in ~4% of recipients. Although this number appears somewhat larger than that observed with GH treatment, it is usually transient, disappearing following temporary cessation of treatment. Craniofacial growth, sometimes with coarsening of features, has been described in a number of patients [64, 65, 66, 67].

Study, a prospective epidemiological study, the associations between IGF-1 and IGFBP-3 levels and subsequent prostate cancer risk among 152 patients and 152 age-matched controls were investigated. There was a significant linear trend between IGF-1 and prostate cancer risk [87]. Strong association between IGF-1 and IGFBP-3 levels and the risk of advanced prostate cancer but no association with early stage disease was found. Measurement of IGF-1 and IGFBP-3 levels may predict the risk of advanced stage prostate cancer years before the cancer is actually diagnosed and may be helpful in aiding decision making about treatment [88]. No trend in the relative risk of prostate cancer with increasing IGF-1 was found in another study; rather, the highest incidence of prostate cancer was in the lowest quartile of IGF-1, and the incidence in the other quartiles of IGF-1 was slightly lower but not statistically significantly different from incidence rates in the lowest quartile [89]. A multiethnic study was perforned to determine the associations between prediagnostic levels of IGF-1 and IGFBP-3 and risk of prostate cancer. In this study no association was observed for levels of IGF-1 or IGF-to-IGFBP-3 ratio and prostate cancer risk [90]. In one metaanalyze including included both retrospective and prospective studies and demonstrated that average 21% increase risk of prostate cancer per standard deviation increase in IGF-1. A stronger association of IGF-1 was found in more aggressive and advanced cancers in comparison to nonaggressive and localized ones [91]. Considerable evidence has accumulated that suggests that the IGF system is involved in the pathophysiology of prostate cancer. GH is believed to be the pituitary factor responsible for mammary ductal morphogenesis [92, 93]. It has been reported that IGF-1 or amino-terminally truncated IGF-1, des(1–3) IGF-1, mimic the action of GH on mammary development in hypophysectomized gonadectomized rats [94, 95]. IGF-1 mRNA is localized to stromal fibroblasts surrounding normal breast epithelium while high levels of IGF-2 mRNA are found in fibroblasts adjacent to malignant epithelium [96, 97]. Malignant breast epithelial cells can induce expression of IGF-2 in the stroma in vitro [98]. IGF-1R has been found on the surface of malignant breast epithelial cells [99] and IGFs provide radioprotection and resistance of breast cancer cells to chemotherapeutic agents [100, 101]. Some epidemiologic studies have associated high circulating levels of IGF-1 with increased risk of breast cancer among premenopausal women. In a meta-analysis, circulating levels of IGF-1 were not significantly higher in breast cancer patients than in controls for all women and for the postmenopausal group but were signifi‐ cantly higher for the premenopausal group [102]. Literature on the relationship between breast cancer risk and circulating concentrations of IGF-1 and IGFBP-3 showed an increased risk for premenopausal women with increasing levels of IGF-1 and IGFBP-3. More prospective studies

The Insulin-Like Growth Factor System in the Human Pathology

http://dx.doi.org/10.5772/55213

203

are needed to clarify the association between IGF-1 and IGFBP-3 and breast cancer.

Overexpression of IGF-2 mRNA and peptide has been described in human pheochromocyto‐ mas [103, 104]. Despite to this finding, very little tumoral IGF-2 is released into the circulation, unlike catecholamines [104]. IGF-1 also seems to be secreted by pheochromocytoma cells in an autocrine or paracrine manner. In rat pheochromocytoma PC12 cells IGF-1R has been shown to be important for the stimulation of cell replication [105]. Significant overexpression of the IGF-1R in human pheochromocytomas was found. [106]. IGF-1 was 10 times more potent in stimulating DNA synthesis than IGF-2, suggesting that these effects are mediated by the IGF-1R [107, 108]. In Wilms' tumor, a childhood kidney neoplasm expresses IGF-2 mRNA and protein [109]. Wilms' tumors contain receptors that recognize and respond to exogenous IGF

## **5. IGFs and cancer**

The IGF-1R can regulate cell-cycle progression through control of several cycle checkpoints. It can facilitate G0-G1 transition through activation of p70S6K, leading to phosphorylation of the S6 ribosomal protein and an increased ribosomal pool necessary for entry into the cycle [68]. It can promote G1-S transition by increasing cyclin D1 and CDK4 gene expression, leading to retinoblastoma protein phosphorylation, release of the transcription factor E2F, and synthesis of cyclin E [69, 70]. Alterations in cyclin D1 expression to play a role in tumor formation. IGF's are also important for the development and progression of angiogenesis in tumors. Tumor-induced neovascularization is one of the pathologic mechanisms lying underlying cancer metastasis. IGF-1 and IGF-2 can induce angiogenesis by stimulating the migration and morphological differentiation of endothelial cells [71, 72]. Hypoxia is a major trigger for tumor-dependent angiogenesis. IGF-1 and IGF-2 can induce the expression of hypoxia-inducible factor 1α and this can lead to the formation of the HIF-1/arylhydrocarbon receptor nuclear translocator complex which is involved in transcriptional regulation of hypoxia response element-containing genes such as VEGF [73], a major tumor-derived angiogenic factor. The IGF system can cooperate with other tyrosine kinase receptors such as the EGFR in the induction of angiogenesis [74].

Accumulating evidence has suggested that GH and IGF-1 may be important components of the pathophysiologic mechanisms that underlie the growth of neoplasms, including colorectal carcinoma [75, 76, 77, 78]. Many epidemiology studies have indicated that high levels of IGF - I or altered levels of its binding proteins, or both, are associated with an increased risk of the most common cancers, including cancers of the lung [79], colon and rectum [80], prostate, and breast [81].

Patients with acromegaly, who have elevated levels of circulating GH and IGF-1, may be at increased risk of developing colorectal adenoma and carcinoma [82, 83].

Two prospective epidemiologic studies [84, 85] have shown that higher plasma IGF-1 and lower plasma IGFBP-3 concentrations are associated with an increased risk of colorectal adenoma and cancer among both men and women. These observations suggest that the ratio of circulating IGF-1/IGFBP-3 may be a marker of circulating and tissue IGF-1 bioavailability. Cancer can cause proteolysis of insulin-like growth factor binding protein-3 and affect concentrations of IGFBP-2. These changes in IGF system can affect distribution and clearance of IGFs, thus bioavaibility of IGFs to spesific tissues. In vitro studies on human colon cancer cells, which showed that IGF-1 promoted cell proliferation, IGF-1 receptors were frequently overexpressed on colon cancer cells and IGF-1R blockade with a monoclonal antibody inhibited cell proliferation [85]. A larger case-control study from Sweden reported a similar positive association between IGF-1 level and prostate cancer risk [86]. In the Physicians' Health

Study, a prospective epidemiological study, the associations between IGF-1 and IGFBP-3 levels and subsequent prostate cancer risk among 152 patients and 152 age-matched controls were investigated. There was a significant linear trend between IGF-1 and prostate cancer risk [87]. Strong association between IGF-1 and IGFBP-3 levels and the risk of advanced prostate cancer but no association with early stage disease was found. Measurement of IGF-1 and IGFBP-3 levels may predict the risk of advanced stage prostate cancer years before the cancer is actually diagnosed and may be helpful in aiding decision making about treatment [88]. No trend in the relative risk of prostate cancer with increasing IGF-1 was found in another study; rather, the highest incidence of prostate cancer was in the lowest quartile of IGF-1, and the incidence in the other quartiles of IGF-1 was slightly lower but not statistically significantly different from incidence rates in the lowest quartile [89]. A multiethnic study was perforned to determine the associations between prediagnostic levels of IGF-1 and IGFBP-3 and risk of prostate cancer. In this study no association was observed for levels of IGF-1 or IGF-to-IGFBP-3 ratio and prostate cancer risk [90]. In one metaanalyze including included both retrospective and prospective studies and demonstrated that average 21% increase risk of prostate cancer per standard deviation increase in IGF-1. A stronger association of IGF-1 was found in more aggressive and advanced cancers in comparison to nonaggressive and localized ones [91]. Considerable evidence has accumulated that suggests that the IGF system is involved in the pathophysiology of prostate cancer. GH is believed to be the pituitary factor responsible for mammary ductal morphogenesis [92, 93]. It has been reported that IGF-1 or amino-terminally truncated IGF-1, des(1–3) IGF-1, mimic the action of GH on mammary development in hypophysectomized gonadectomized rats [94, 95]. IGF-1 mRNA is localized to stromal fibroblasts surrounding normal breast epithelium while high levels of IGF-2 mRNA are found in fibroblasts adjacent to malignant epithelium [96, 97]. Malignant breast epithelial cells can induce expression of IGF-2 in the stroma in vitro [98]. IGF-1R has been found on the surface of malignant breast epithelial cells [99] and IGFs provide radioprotection and resistance of breast cancer cells to chemotherapeutic agents [100, 101]. Some epidemiologic studies have associated high circulating levels of IGF-1 with increased risk of breast cancer among premenopausal women. In a meta-analysis, circulating levels of IGF-1 were not significantly higher in breast cancer patients than in controls for all women and for the postmenopausal group but were signifi‐ cantly higher for the premenopausal group [102]. Literature on the relationship between breast cancer risk and circulating concentrations of IGF-1 and IGFBP-3 showed an increased risk for premenopausal women with increasing levels of IGF-1 and IGFBP-3. More prospective studies are needed to clarify the association between IGF-1 and IGFBP-3 and breast cancer.

treatment, it is usually transient, disappearing following temporary cessation of treatment. Craniofacial growth, sometimes with coarsening of features, has been described in a number

The IGF-1R can regulate cell-cycle progression through control of several cycle checkpoints. It can facilitate G0-G1 transition through activation of p70S6K, leading to phosphorylation of the S6 ribosomal protein and an increased ribosomal pool necessary for entry into the cycle [68]. It can promote G1-S transition by increasing cyclin D1 and CDK4 gene expression, leading to retinoblastoma protein phosphorylation, release of the transcription factor E2F, and synthesis of cyclin E [69, 70]. Alterations in cyclin D1 expression to play a role in tumor formation. IGF's are also important for the development and progression of angiogenesis in tumors. Tumor-induced neovascularization is one of the pathologic mechanisms lying underlying cancer metastasis. IGF-1 and IGF-2 can induce angiogenesis by stimulating the migration and morphological differentiation of endothelial cells [71, 72]. Hypoxia is a major trigger for tumor-dependent angiogenesis. IGF-1 and IGF-2 can induce the expression of hypoxia-inducible factor 1α and this can lead to the formation of the HIF-1/arylhydrocarbon receptor nuclear translocator complex which is involved in transcriptional regulation of hypoxia response element-containing genes such as VEGF [73], a major tumor-derived angiogenic factor. The IGF system can cooperate with other tyrosine kinase receptors such as

Accumulating evidence has suggested that GH and IGF-1 may be important components of the pathophysiologic mechanisms that underlie the growth of neoplasms, including colorectal carcinoma [75, 76, 77, 78]. Many epidemiology studies have indicated that high levels of IGF - I or altered levels of its binding proteins, or both, are associated with an increased risk of the most common cancers, including cancers of the lung [79], colon and rectum [80], prostate, and

Patients with acromegaly, who have elevated levels of circulating GH and IGF-1, may be at

Two prospective epidemiologic studies [84, 85] have shown that higher plasma IGF-1 and lower plasma IGFBP-3 concentrations are associated with an increased risk of colorectal adenoma and cancer among both men and women. These observations suggest that the ratio of circulating IGF-1/IGFBP-3 may be a marker of circulating and tissue IGF-1 bioavailability. Cancer can cause proteolysis of insulin-like growth factor binding protein-3 and affect concentrations of IGFBP-2. These changes in IGF system can affect distribution and clearance of IGFs, thus bioavaibility of IGFs to spesific tissues. In vitro studies on human colon cancer cells, which showed that IGF-1 promoted cell proliferation, IGF-1 receptors were frequently overexpressed on colon cancer cells and IGF-1R blockade with a monoclonal antibody inhibited cell proliferation [85]. A larger case-control study from Sweden reported a similar positive association between IGF-1 level and prostate cancer risk [86]. In the Physicians' Health

increased risk of developing colorectal adenoma and carcinoma [82, 83].

of patients [64, 65, 66, 67].

202 Hot Topics in Endocrine and Endocrine-Related Diseases

**5. IGFs and cancer**

breast [81].

the EGFR in the induction of angiogenesis [74].

Overexpression of IGF-2 mRNA and peptide has been described in human pheochromocyto‐ mas [103, 104]. Despite to this finding, very little tumoral IGF-2 is released into the circulation, unlike catecholamines [104]. IGF-1 also seems to be secreted by pheochromocytoma cells in an autocrine or paracrine manner. In rat pheochromocytoma PC12 cells IGF-1R has been shown to be important for the stimulation of cell replication [105]. Significant overexpression of the IGF-1R in human pheochromocytomas was found. [106]. IGF-1 was 10 times more potent in stimulating DNA synthesis than IGF-2, suggesting that these effects are mediated by the IGF-1R [107, 108]. In Wilms' tumor, a childhood kidney neoplasm expresses IGF-2 mRNA and protein [109]. Wilms' tumors contain receptors that recognize and respond to exogenous IGF [110]. Deletions or point mutations of the Wilms tumor suppressor gene-1 (WT-1) on chromo‐ some 11p13 are associated with Wilms' tumors. WT1 binds to multiple sites in the promoter region of the IGF-2 gene, and that it acts as a potent repressor of IGF-2 transcription [111]. A molecular basis for the overexpression of IGF-2 in Wilms' tumor may have autocrine effects in tumor progression.

64% of the cases with hepatomas, adrenal carcinomas, and gastrointestinal malignancies accounting for others [124, 125]. Endogenous IGFs which circulate in adults fail to exert their immense potential hypoglycaemic activity because they are largely trapped within the vascular space due to their sequestration in a high molecular weight protein complex. IGF-2 leads to an increased peripheral glucose uptake in different tissues as well as inhibition of hepatic gluconeogenesis and lipolysis [126]. IGF-2 has also been shown to have high affinity binding with the insulin receptor. The insulin receptor exon 11+ (IR-B) isoform is the form best known for the classic metabolic responses induced upon insulin binding and this isoform has low affinity for the IGFs. IGF-2 binds with high affinity to the insulin receptor exon 11− (IR-A) isoform of the IR. Activation of IR-A leads to mitogenic responses similar to those described for the IGF-1R [127]. IGF-2 gene can be expressed to produce proteins of various molecular weights. The most active form, with regard to binding of IGF receptors, is 7.5kDa [128]. IGF-2 gene expression regulation, post-translational processing of the 156-amino acid IGF-2 precur‐ sor is abnormal in tumors [129]. Larger forms lack posttranslational cleavage plays role in hypoglycemia. Incompletely processed IGF-II (Big-IGF-II) has a strongly reduced affinity for ALS. Impaired formation of the 150 kDa complex, tumour-derived 'big'-IGF-II primarily forms smaller binary complexes with IGFBPs and a greater fraction may stay in the free unbound form [130, 131, 132]. These smaller complexes have a greater capillary permeability and thus are thought to increase IGF bioavailability to the tissues, resulting in hypoglycaemia through action on the insulin receptors and IGF1R [133]. Patients whose underlying condition is one of GH resistance, especially if it is complete and at the level of the GHR, having lost the counterregulatory effects of GH, are susceptible to hypoglycemia with the IGF-1 treatment [134].

The Insulin-Like Growth Factor System in the Human Pathology

http://dx.doi.org/10.5772/55213

205

Administration of IGF-I with meals may overcome with this problem.

Reduced IGF-1 levels have been proposed to have a role in diabetes [135]. In animal studies deletion of IGF-1 gene expression in liver caused increased GH secretion and reduced insülin sensitivity. A positive association between low IGF-1 levels and glucose intolerance/ diabetes in a sample of 615 subjects aged 45-65 years was found [136]. In contrast, recent‐ ly Rajpatak et al did not find an independent association between IGF-1 and diabetes among 922 subjects aged >/=65 yrs from the Cardiovascular Health Study [137]. In a study was to evaluate the association between IGF-1 level and insulin resistance, both low and high normal IGF-1 levels are found to be related to insulin resistance [138]. A study in 7,665 subjects showed that low and high baseline IGF-1 serum concentrations were both related to a higher risk of developing type 2 diabetes within 5 years [139]. This U-shaped associa‐ tion seems to be likely in face of a higher prevalence of metabolic syndrome or type 2 diabetes in patients with GH deficiency [140]. A state of low IGF-1 levels, as well as with acromegaly [141], a disease characterized by high IGF-1 levels, although endogenous GH secretion may confound short-term glucose homeostasis in these patients. IGF-1 administra‐ tion reduces the GH hypersecretion of adolescents and adults with type 1 diabetes [142, 143]. IGF-1 administration increases systemic IGF-1 levels, resulting in reduced GH secretion

**7. IGFs and diabetes**

IGF-1R is expressed in pancreatic cancer cell lines and human pancreatic cancers and also IGF-1 is markedly overexpressed in these cancers [112]. The anti-IGF-1R antibody inhibited the action of IGF-1 on cell proliferation. Moderately strong IGF-2R immunoreactivity was present in the cytoplasm of islet cells and mild cytoplasmic immunoreactivity was evident occasionally in ductal and acinar cells. In the pancreatic cancers, regions of strong IGF-2R immunoreactivity were present in the duct-like cancer cells within the tumor mass often exhibiting nuclear localization [113].

IGF-2R may contribute to the pathobiology of pancreatic cancer. Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP-3) was found to be selectively overexpressed in pancreatic ductal adenocarcinoma tissues but not in benign pancreatic tissues. The highest rate of expression was seen in poorly differentiated cancers. Overall survival was found to be significantly shorter in patients with IGF2BP-3 expressing tumors [114]. Enhanced expression of IGF-1 and IGF-2 mRNA transcripts has been demonstrated in gliomas, meniningiomas, and other tumours [115]. Patients with malignant CNS tumours showed increased IGFBP-2 concentrations in CSF. Patients with CNS tumours and microscopically detectable malignant cells in their CSF had the highest IGFBP-2 values [116]. The IGFs have important roles in the normal ovary and exert intra-ovarian control in the replication and differentiation processes of folliculogenesis. [117, 118]. The IGFs, their receptors and IGFBPs were identified in ovarian tumours. IGFBP-2 levels are high in the sera of patients with epithelial ovarian cancer and they may be useful as a possible tumour marker [119, 120]. Primary ovarian epithelial cell lines derived from previously untreated ovarian cancers expressed all major components of the IGF system and were able to demonstrate functional responses to exogenous IGFs [121]. Expression of the IGF-2 gene was more than 300-fold higher in ovarian cancers compared with normal ovarian surface epithelium samples. High IGF-2 expression was associated with advanced stage disease at diagnosis, high-grade cancers and sub-optimal surgical cytoreduction. Relative IGF-2 expression was regarded as an independent predictor of poor survival [122]. IGF-1 mRNA expression and peptide concentrations were also analyzed in epithelial ovarian cancer. High levels of free IGF-1 peptide were associated with elevated risk of disease progression. Women with high IGF-1 mRNA and peptide were found to be at greater risk for disease progression compared to those with low in both [123].

## **6. IGFs and hypoglycemia**

Hypoglyaemia from malignant tumours is rare. This is the only paraneoplastic syndrome caused by the IGF2 overproduction. This phenomenon, referred to as non islet cell tumour hypoglycaemia (NICTH). Hypoglycaemia secondary to mesenchymal tumours account for 64% of the cases with hepatomas, adrenal carcinomas, and gastrointestinal malignancies accounting for others [124, 125]. Endogenous IGFs which circulate in adults fail to exert their immense potential hypoglycaemic activity because they are largely trapped within the vascular space due to their sequestration in a high molecular weight protein complex. IGF-2 leads to an increased peripheral glucose uptake in different tissues as well as inhibition of hepatic gluconeogenesis and lipolysis [126]. IGF-2 has also been shown to have high affinity binding with the insulin receptor. The insulin receptor exon 11+ (IR-B) isoform is the form best known for the classic metabolic responses induced upon insulin binding and this isoform has low affinity for the IGFs. IGF-2 binds with high affinity to the insulin receptor exon 11− (IR-A) isoform of the IR. Activation of IR-A leads to mitogenic responses similar to those described for the IGF-1R [127]. IGF-2 gene can be expressed to produce proteins of various molecular weights. The most active form, with regard to binding of IGF receptors, is 7.5kDa [128]. IGF-2 gene expression regulation, post-translational processing of the 156-amino acid IGF-2 precur‐ sor is abnormal in tumors [129]. Larger forms lack posttranslational cleavage plays role in hypoglycemia. Incompletely processed IGF-II (Big-IGF-II) has a strongly reduced affinity for ALS. Impaired formation of the 150 kDa complex, tumour-derived 'big'-IGF-II primarily forms smaller binary complexes with IGFBPs and a greater fraction may stay in the free unbound form [130, 131, 132]. These smaller complexes have a greater capillary permeability and thus are thought to increase IGF bioavailability to the tissues, resulting in hypoglycaemia through action on the insulin receptors and IGF1R [133]. Patients whose underlying condition is one of GH resistance, especially if it is complete and at the level of the GHR, having lost the counterregulatory effects of GH, are susceptible to hypoglycemia with the IGF-1 treatment [134]. Administration of IGF-I with meals may overcome with this problem.

## **7. IGFs and diabetes**

[110]. Deletions or point mutations of the Wilms tumor suppressor gene-1 (WT-1) on chromo‐ some 11p13 are associated with Wilms' tumors. WT1 binds to multiple sites in the promoter region of the IGF-2 gene, and that it acts as a potent repressor of IGF-2 transcription [111]. A molecular basis for the overexpression of IGF-2 in Wilms' tumor may have autocrine effects

IGF-1R is expressed in pancreatic cancer cell lines and human pancreatic cancers and also IGF-1 is markedly overexpressed in these cancers [112]. The anti-IGF-1R antibody inhibited the action of IGF-1 on cell proliferation. Moderately strong IGF-2R immunoreactivity was present in the cytoplasm of islet cells and mild cytoplasmic immunoreactivity was evident occasionally in ductal and acinar cells. In the pancreatic cancers, regions of strong IGF-2R immunoreactivity were present in the duct-like cancer cells within the tumor mass often exhibiting nuclear

IGF-2R may contribute to the pathobiology of pancreatic cancer. Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP-3) was found to be selectively overexpressed in pancreatic ductal adenocarcinoma tissues but not in benign pancreatic tissues. The highest rate of expression was seen in poorly differentiated cancers. Overall survival was found to be significantly shorter in patients with IGF2BP-3 expressing tumors [114]. Enhanced expression of IGF-1 and IGF-2 mRNA transcripts has been demonstrated in gliomas, meniningiomas, and other tumours [115]. Patients with malignant CNS tumours showed increased IGFBP-2 concentrations in CSF. Patients with CNS tumours and microscopically detectable malignant cells in their CSF had the highest IGFBP-2 values [116]. The IGFs have important roles in the normal ovary and exert intra-ovarian control in the replication and differentiation processes of folliculogenesis. [117, 118]. The IGFs, their receptors and IGFBPs were identified in ovarian tumours. IGFBP-2 levels are high in the sera of patients with epithelial ovarian cancer and they may be useful as a possible tumour marker [119, 120]. Primary ovarian epithelial cell lines derived from previously untreated ovarian cancers expressed all major components of the IGF system and were able to demonstrate functional responses to exogenous IGFs [121]. Expression of the IGF-2 gene was more than 300-fold higher in ovarian cancers compared with normal ovarian surface epithelium samples. High IGF-2 expression was associated with advanced stage disease at diagnosis, high-grade cancers and sub-optimal surgical cytoreduction. Relative IGF-2 expression was regarded as an independent predictor of poor survival [122]. IGF-1 mRNA expression and peptide concentrations were also analyzed in epithelial ovarian cancer. High levels of free IGF-1 peptide were associated with elevated risk of disease progression. Women with high IGF-1 mRNA and peptide were found to be at greater risk for

Hypoglyaemia from malignant tumours is rare. This is the only paraneoplastic syndrome caused by the IGF2 overproduction. This phenomenon, referred to as non islet cell tumour hypoglycaemia (NICTH). Hypoglycaemia secondary to mesenchymal tumours account for

disease progression compared to those with low in both [123].

**6. IGFs and hypoglycemia**

in tumor progression.

204 Hot Topics in Endocrine and Endocrine-Related Diseases

localization [113].

Reduced IGF-1 levels have been proposed to have a role in diabetes [135]. In animal studies deletion of IGF-1 gene expression in liver caused increased GH secretion and reduced insülin sensitivity. A positive association between low IGF-1 levels and glucose intolerance/ diabetes in a sample of 615 subjects aged 45-65 years was found [136]. In contrast, recent‐ ly Rajpatak et al did not find an independent association between IGF-1 and diabetes among 922 subjects aged >/=65 yrs from the Cardiovascular Health Study [137]. In a study was to evaluate the association between IGF-1 level and insulin resistance, both low and high normal IGF-1 levels are found to be related to insulin resistance [138]. A study in 7,665 subjects showed that low and high baseline IGF-1 serum concentrations were both related to a higher risk of developing type 2 diabetes within 5 years [139]. This U-shaped associa‐ tion seems to be likely in face of a higher prevalence of metabolic syndrome or type 2 diabetes in patients with GH deficiency [140]. A state of low IGF-1 levels, as well as with acromegaly [141], a disease characterized by high IGF-1 levels, although endogenous GH secretion may confound short-term glucose homeostasis in these patients. IGF-1 administra‐ tion reduces the GH hypersecretion of adolescents and adults with type 1 diabetes [142, 143]. IGF-1 administration increases systemic IGF-1 levels, resulting in reduced GH secretion

and improves insulin sensitivity in adults with type 1 diabetes [144]. Also in patients with types 2 diabetes, glycemic control improves with IGF-1 treatment [145]. In one study, subcutaneous administration of of recombinant human IGF-1 (for 6 weeks) significantly lowered blood glucose. Glycosylated hemoglobin, which was 10.4% pretreatment, de‐ clined to 8.1% at the end of therapy and this improvement in glycemic control was accompanied by a change in body composition with a 2.1% loss in body fat without change in total body weight [146]. Paracrine or autocrine effects of IGF-1 may paly a role in the pathogenesis of diabetic complications. Hyperglycemia and IGF-1 stimulate the endothe‐ lial cell migration, and tubular formation is induced by a combination of IGF-1 and hyperglycemia [147]. Animal models have provided direct evidence that IGF-1 contributes to the development of retinopathy induced by retinal ischemia. Active capillary prolifera‐ tion has been documented after implantation of intracorneal pellets containing IGF-1 [148]. The progression of retinopathy is slowed in diabetic patients with hypopituitarism who have low serum IGF-1 levels [149, 150]. Patients with more rapid progression of their retinop‐ athy had the highest levels of IGF-1 in the vitreous [151]. However, Data concerning the relationship between serum IGF-1 levels and diabetic retinopathy is contradictory. Some studies have shown no association between serum IGF-I levels and the development or progression of diabetic retinopathy. In patients with diabetic retinopathy IGF-1 reducing treatment strategies with either somatostatins or pegvisomant have been tried. Glomerular hypertrophy is thought to be one of the key early changes in the development of diabetic nephropathy. IGF-I has been associated with renal/glomerular hypertrophy and compensa‐ tory renal growth. Epithelial, mesangial, and endothelial cells derived from the kidney respond to IGF-1 binding with increased protein synthesis, migration, and proliferation. Both GH and IGF-I increase renal plasma flow and glomerular filtration rate. Microalbumi‐ nuric patients display higher levels of urinary IGF-1, urinary GH, and plasma IGF-1 than normoalbuminuric diabetic subjects [152]. Patients with microalbuminuria had higher levels of urinary IGFBP-3 even when compared to patients without microalbuminuria matched for metabolic control [152, 153, 154]. Hyperglycemic conditions limit the protective role of IGF-I against podocyte apoptosis. IGFBP-3 can facilitate podocyte apoptosis. Podocyte structur‐ al changes also contribute to the pathogenesis of albuminuria in diabetes. IGF-1 binding to its type 1 receptors stimulates mesengial cell proliferation [155]. Mesengial cell prolifera‐ tion is one of the factors that contributes diabetic nephropathy.

**Author details**

Emrah Yerlikaya\*

**References**

825–36.

4.

1093.

and Fulya Akin

tors I and II. Growth Factors 1991;5:3–18.

search Communications 1992;187:1219–1226.

superfamily. Endocrine Reviews 1999;20: 761–87.

lar and Cellular Endocrinology1997;1:123–159.

factor II receptors. Annu Rev Biochem 1992; 61 : 307-30.

Pamukkale University Division of Endocrinology and Metabolism, Denizli, Turkey

[1] Salmon W, Daughaday W. Journal of Laboratory and Clinical Medicine 1957;49 (6):

The Insulin-Like Growth Factor System in the Human Pathology

http://dx.doi.org/10.5772/55213

207

[2] Brissenden JE, Ullrich A, Francke U. Human chromosomal mapping of genes for in‐ sulin-like growth factors 1 and 2 and epidermal growth factor. Nature 1984;310:781–

[3] Rotwein P. Structure, evolution, expression and regulation of insulin-like growth fac‐

[4] Sussenbach JS, Steenbergh PH, Holthuizen P. Structure and expression of the human

[5] Jansen E, Steenbergh PH, van Schaik FM, Sussenbach JS. The human IGF-1 gene con‐ tains two cell type-specifically regulated promoters. Biochemical and Biophysical Re‐

[6] Baxter RC. Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities. American Journal of Physiology-Endo 2000; 278:967-E976

[7] Hwa V, Oh Y, Rosenfeld RG. The insulin-like growth factor binding protein (IGFBP)

[8] Yu H, Rohan T. Role of the insulin-like growth factor family in cancer development and progression. Journal of the National Cancer Institute. 2000; 92:1472-89.

[9] Baxter RC. Molecular aspects of insulin-like growth factor binding proteins. Molecu‐

[10] Morgan, DO, Jarnagin K. and Roth RA. Purification and characterization of the re‐

[11] Adams TE, Epa VC, Garrett TP, Ward CW. Structure and function of the type 1 insu‐ lin-like growth factor receptor. Cellular and Molecular Life Sciences 2000; 57:1050–

[12] Kornfeld S. Structure and function of the mannose-6-phosphate/insulin like growth

ceptor for insulin-like growth factor 1. Biochemistry 1986; 25:5560-5564.

insulin-like growth factor genes. Growth Regulation 1992;2:1–9.

Higher IGF-1 bioavailability may protect against the onset of ischemic heart disease [156, 157]. Potential beneficial actions of IGF-1 in cardiovascular physiology include increased nitric oxide synthesis and K+ channel opening [158,159] and this may explain the im‐ paired small-vessel function associated with low IGF-1 levels in patients with cardiovascu‐ lar syndrome X [159]. Higher IGF-1 bioavailability may offer improved metabolic control and prevent vascular complications in type 2 diabetic patients. In contrast to this finding, posttranslational phosphorylation of IGFBP-1 increases its affinity for IGF-1 and modify IGF bioavailability. Low circulating levels of hpIGFBP-1 are found to be closely correlated with macrovascular disease and hypertension in type 2 diabetes [160]. further studies are needed to better understand the true value of the IGF-1/IGFBP axis in macrovascular complica‐ tions of diabetes.

## **Author details**

and improves insulin sensitivity in adults with type 1 diabetes [144]. Also in patients with types 2 diabetes, glycemic control improves with IGF-1 treatment [145]. In one study, subcutaneous administration of of recombinant human IGF-1 (for 6 weeks) significantly lowered blood glucose. Glycosylated hemoglobin, which was 10.4% pretreatment, de‐ clined to 8.1% at the end of therapy and this improvement in glycemic control was accompanied by a change in body composition with a 2.1% loss in body fat without change in total body weight [146]. Paracrine or autocrine effects of IGF-1 may paly a role in the pathogenesis of diabetic complications. Hyperglycemia and IGF-1 stimulate the endothe‐ lial cell migration, and tubular formation is induced by a combination of IGF-1 and hyperglycemia [147]. Animal models have provided direct evidence that IGF-1 contributes to the development of retinopathy induced by retinal ischemia. Active capillary prolifera‐ tion has been documented after implantation of intracorneal pellets containing IGF-1 [148]. The progression of retinopathy is slowed in diabetic patients with hypopituitarism who have low serum IGF-1 levels [149, 150]. Patients with more rapid progression of their retinop‐ athy had the highest levels of IGF-1 in the vitreous [151]. However, Data concerning the relationship between serum IGF-1 levels and diabetic retinopathy is contradictory. Some studies have shown no association between serum IGF-I levels and the development or progression of diabetic retinopathy. In patients with diabetic retinopathy IGF-1 reducing treatment strategies with either somatostatins or pegvisomant have been tried. Glomerular hypertrophy is thought to be one of the key early changes in the development of diabetic nephropathy. IGF-I has been associated with renal/glomerular hypertrophy and compensa‐ tory renal growth. Epithelial, mesangial, and endothelial cells derived from the kidney respond to IGF-1 binding with increased protein synthesis, migration, and proliferation. Both GH and IGF-I increase renal plasma flow and glomerular filtration rate. Microalbumi‐ nuric patients display higher levels of urinary IGF-1, urinary GH, and plasma IGF-1 than normoalbuminuric diabetic subjects [152]. Patients with microalbuminuria had higher levels of urinary IGFBP-3 even when compared to patients without microalbuminuria matched for metabolic control [152, 153, 154]. Hyperglycemic conditions limit the protective role of IGF-I against podocyte apoptosis. IGFBP-3 can facilitate podocyte apoptosis. Podocyte structur‐ al changes also contribute to the pathogenesis of albuminuria in diabetes. IGF-1 binding to its type 1 receptors stimulates mesengial cell proliferation [155]. Mesengial cell prolifera‐

206 Hot Topics in Endocrine and Endocrine-Related Diseases

tion is one of the factors that contributes diabetic nephropathy.

tions of diabetes.

Higher IGF-1 bioavailability may protect against the onset of ischemic heart disease [156, 157]. Potential beneficial actions of IGF-1 in cardiovascular physiology include increased nitric oxide synthesis and K+ channel opening [158,159] and this may explain the im‐ paired small-vessel function associated with low IGF-1 levels in patients with cardiovascu‐ lar syndrome X [159]. Higher IGF-1 bioavailability may offer improved metabolic control and prevent vascular complications in type 2 diabetic patients. In contrast to this finding, posttranslational phosphorylation of IGFBP-1 increases its affinity for IGF-1 and modify IGF bioavailability. Low circulating levels of hpIGFBP-1 are found to be closely correlated with macrovascular disease and hypertension in type 2 diabetes [160]. further studies are needed to better understand the true value of the IGF-1/IGFBP axis in macrovascular complica‐ Emrah Yerlikaya\* and Fulya Akin

Pamukkale University Division of Endocrinology and Metabolism, Denizli, Turkey

## **References**


[13] Tong PY, Tollefsen SE, Kornfeld S. The cation-independent mannose 6-phosphate re‐ ceptor binds insulin-like growth factor 2. Journal of Biological Chemistry 1988;263:2585–8.

[26] Isotton AL, Wender MC, Casagrande A, Rollin G, Czepielewski MA. Effects of oral and transdermal estrogen on IGF1, IGFBP3, IGFBP1, serum lipids, and glucose in pa‐ tients with hypopituitarism during GH treatment: a randomized study. European

The Insulin-Like Growth Factor System in the Human Pathology

http://dx.doi.org/10.5772/55213

209

[27] Greendale GA, Delstein S, Barrett Connor E. Endogenous sex steroids and bone min‐ eral density in older men and women. Journal of Bone and Mineral Research

[28] Hobbs CJ, Plymate SR, Rosén CJ, Adler RA: Testosterone administration increases in‐ sulinlike growth factor I levels in normal men. Journal of Clinical Endocrinology &

[29] Fisker S, Jørgensen JOL, Vahl N, Ørskov H, Christiansen JS. Impact of gender and androgen status on IGF-1 levels in normal and GH deficient adults. European Jour‐

[30] DePugola G, Lespite L, Grizzulli VA. IGF-1 and DHEA-S in obese females. Interna‐

[31] Schmid C, Zwimpfer C, Brändle M, Krayenbühl PA, Zapf J, Wiesli P. Effect of thyro‐ xine replacement on serum IGF-1, IGFBP-3 and the acid-labile subunit in patients with hypothyroidism and hypopituitarism Clinical Endocrinology 2006: 65;706–711

[32] Nanto-Salonen K & Muller HL, Hoffman AR, Vu TH & Rosenfeld RG. Mechanisms of thyroid hormone action on the insulin-like growth factor system: all thyroid hor‐ mone effects are not growth hormone mediated. Endocrinology 1993; 132:781–788.

[33] Schmid C, Brandle M, Zwimpfer C, Zapf J & Wiesli P. Effect of thyroxine replace‐ ment on creatinine, insulin-like growth factor 1, acid-labile subunit, and vascular en‐

[34] Isley WL, Underwood LE, Clemmons DR. Changes in plasma somatomedin-C in re‐ sponse to diets with variable protein and energy content. Journal of Parenteral and

[35] Clemmons DR, Klibanski A, Underwood LE et al. Reduction of plasma immunoreac‐ tive somatomedin-C during fasting in humans. Journal of Clinical Endocrinology &

[36] Untermann TG, Vazquez RM, Slas AJ, Martyn PA, Phillips LS. Nutrition and somato‐ medin. XIII. Usefulness of somatomedin-C in nutritional assessment. Am J Med 1985;

[37] Prasad A. Zinc and growth. Journal of the American College of Nutrition 1996; 15:

[38] Nakamura T, Nishiyama S, Suginohara YF, Matsuda I, Higashi A. Mild to moderate

zinc deficiency in short children. Journal of Pediatrics 1993; 123: 65–9.

dothelial growth factor. Clinical Chemistry 2004; 50:228–231.

tional Journal of Obesity an Related Metabolic Disorders 1993;11:481–3.

Journal of Endocrinology 2012 ;166(2):207-13.

1997;12:1833–43.

Metabolism 1993; 77: 776–779.

nal of Endocrinology 1999; 141:601–608.

Enteral Nutrition 1984; 8: 407-411.

Metabolism 1981; 53: 1247-1250.

78: 228-234.

341–42.


[26] Isotton AL, Wender MC, Casagrande A, Rollin G, Czepielewski MA. Effects of oral and transdermal estrogen on IGF1, IGFBP3, IGFBP1, serum lipids, and glucose in pa‐ tients with hypopituitarism during GH treatment: a randomized study. European Journal of Endocrinology 2012 ;166(2):207-13.

[13] Tong PY, Tollefsen SE, Kornfeld S. The cation-independent mannose 6-phosphate re‐ ceptor binds insulin-like growth factor 2. Journal of Biological Chemistry

[14] Vincent AM, Feldman EL. Control of cell survival by IGF signaling pathways.

[15] [15]. Kuemmerle JF. IGF-1 elicits growth of human intestinal smooth muscle cells by activation of PI3K, PDK-1, and p70S6 kinase. American journal of physiology.

[16] Galvan V, Logvinova A, Sperandio S, Ichijo H, Bredesen DE. Type 1 insulin-like growth factor receptor signaling inhibits apoptosis signal-regulating kinase 1 (ASK1).

[17] Donaghy A, Ross R, Gimson A, et al. Growth hormone, insulinlike growth factor-1, and insulinlike growth factor binding proteins 1 and 3 in chronic liver disease. Hepa‐

[18] Wu YL, Ye J, Zhang S, et al. Clinical significance of serum IGF-1, IGF-2 and IGFBP-3

[19] Veldhuis JD, Iranmanesh A, Weltman A. Elements in the pathophysiology of dimin‐

[20] Toogood AA, O'Neil PA, Shalet SA. Beyond the somatopause: GHD in adults over

[21] Hoffman AR, Lieberman SA, Butterfield G, Thompson J, Hintz RRL, Ceda GP, Mar‐ cus R. Functional consequences of the somatopause and its treatment. Endocrine

[22] Greendale GA, Delstein S, Barrett Connor E. Endogenous sex steroids and bone min‐ eral density in older men and women. Journal of Bone and Mineral Research

[23] Ho KY, Evans WS, Blizzard RM, Veldhuis JD, Merriam GR, Samojlik E, Furlanetto R, Rogol AD, Kaiser DL, Thorner MO. Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentra‐

[24] Thompson RG, Rodriguez A, Kowarski A, Blizzard RM. Growth hormone: metabolic clearance rates, integrated concentrations, and production rates in normal adults and

[25] Van den Berg G, Veldhuis JD, Frolich M, Roelfsema F. An amplitude-specific diver‐ gence in the pulsatile mode of growth hormone (GH) secretion underlies the gender difference in mean GH concentrations in men and premenopausal women. Journal of

the effect of prednisone. Journal of Clinical Investigation 1972; 51:3193–3199.

tions. Journal of Clinical Endocrinology & Metabolism 1987; 64:51–58.

Clinical Endocrinology & Metabolism 1996; 81:2460–2467.

in liver cirrhosis. World Journal of Gastroenterology 2004; 10(18):2740-3.

age 60. Journal of Clinical Endocrinology & Metabolism 1996;81:460–3.

Growth hormone & IGF research 2002;12(4):193-7.

The Journal of biological chemistry 2003;278(15):13325-32.

ished GH secretion in aging humans. Endocrine 1997;7:41–8.

1988;263:2585–8.

208 Hot Topics in Endocrine and Endocrine-Related Diseases

2003;284(3):G411-22

tology 1995; 21(3):680-8.

1997;7:73–6.

1997;12:1833–43.


[39] Larsson SC, Wolk K, Brismar K, and Wolk A. Association of diet with serum insulinlike growth factor 1 in middle-aged and elderly men American Journal of Clinical Nutrition 2005; 81(5):1163-1167.

[50] Bach LA, Hsieh S, Sakano K, Fujiwara H, Perdue JF & Rechler MM. Binding of mu‐ tants of human insulin-like growth factor 2 to insulin-like growth factor binding pro‐

The Insulin-Like Growth Factor System in the Human Pathology

http://dx.doi.org/10.5772/55213

211

[51] Xian L, Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal

[52] Johansson AG, Burman P, Westermark K, Ljunghall S. The bone mineral density in acquired growth hormone deficiency correlates with circulating levels of insulin-like

[53] Liu J, Zhao H, Ning G, Zhang YCL, Sun L, Xu YZM, Chen J. IGF-1 as an early marker for low bone mass or osteoporosis in premenopausal and postmenopausal women

[54] Ghiron LJ, Thompson JL, Holloway L, Hintz RL, Butterfield GE, Hoffman AR, Mar‐ cus R. Effects of recombinant insulin-like growth factor-I and growth hormone on bone turnover in elderly women. Journal of Bone and Mineral Research 1995;

[55] Nilsson O, Marino R, De Luca F, Phillip M, Baron J. Endocrine regulation of the

[56] Ohlsson C, Bengtsson BA, Isaksson OG, Andreassen TT, Slootweg MC. Growth hor‐

[57] Godowski PJ, Leung DW, Meacham LR, et al. Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in 2 patients with Laron type dwarfism. Proceedings of the National Academy of Sciences

[58] Amselem S, Duquesnoy P, Attree O, et al. Laron dwarfism and mutations of the growth hormone-receptor gene. New England Journal of Medicine 1989;321:989–95.

[59] Rosenfeld RG, Belgorsky A, Camacho-Hubner C, Savage MO, Wit JM & Hwa V. De‐ fects in growth hormone receptor signaling as causes of short stature. Trends in En‐

[60] Domene HM, Bengolea SV, Martinez AS, Ropelato MG, Pennisi P, Scaglia P, Hein‐ rich JJ & Jasper HG. Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit. New England Journal of Medi‐

[61] Hwa V, Haeusler G, Pratt KL, Little B, Frisch H, Koller D & Rosenfeld RG. Total ab‐ sence of functional acid labile subunit, resulting in severe insulin-like growth factor deficiency and moderate growth failure. Journal of Clinical Endocrinology and Me‐

teins 1–6. Journal of Biological Chemistry 1993; 268 9246–9254.

growth factor I. Journal of Internal Medicine 1992; 232(5):447-52.

Journal of Bone and Mineral Metabolism 2008;26:159–164.

stem cells. Nature Medicine 2012: 18;1095–1101.

growth plate. Horm Res. 2005;64(4):157-65

mone and bone. Endocr Rev. 1998; 19(1):55-79.

10:1844–1852.

1989;86:8083–7.

docrinology 2007; 18 134–141.

cine 2004; 350:570–577.

tabolism 2006; 91:1826–1831.


[50] Bach LA, Hsieh S, Sakano K, Fujiwara H, Perdue JF & Rechler MM. Binding of mu‐ tants of human insulin-like growth factor 2 to insulin-like growth factor binding pro‐ teins 1–6. Journal of Biological Chemistry 1993; 268 9246–9254.

[39] Larsson SC, Wolk K, Brismar K, and Wolk A. Association of diet with serum insulinlike growth factor 1 in middle-aged and elderly men American Journal of Clinical

[40] Schmid C, Schläpfer I, Peter M, Böni-Schnetzler M, Schwander J, Zapf J, Froesch ER. Growth hormone and parathyroid hormone stimulate IGFBP-3 in rat osteoblasts.

[41] Aleem E, Elshayeb A, Elhabachi N, Mansour AR, Gowily A, Hela A. Serum IGFBP-3 is a more effective predictor than IGF-1 and IGF-2 for the development of hepatocel‐ lular carcinoma in patients with chronic HCV infection. Oncology Letters 2012;

[42] Boisclair YR, Seto D, Hsieh S, Hurst KR & Ooi GT. Organization and chromosomal localization of the gene encoding the mouse acid labile subunit of the insulin-like growth factor binding complex. Proceedings of the National Academy of Sciences

[43] Suwanichkul A, Boisclair YR, Olney RC, Durham SK & Powell DR. Conservation of a growth hormone-responsive promoter element in the human and mouse acid-labile

[44] Burch WW, Correa J, Shively JE, Powell DR. The 25-kilodalton insulin-like growth factor (IGF)-binding protein inhibits both basal and IGF-1 mediated growth in chick embroyonic pelvic cartilage in vitro. Journal of Clinical Endocrinology & Metabolism

[45] Busby WH, Snyder DK, Clemmons DR. Radioimmunoassay of a 26,000-dalton plas‐ ma insulin-like growth factor-binding protein: control by nutritional variables. Jour‐

[46] Lagha NB , Seurin D, Bouc YL, Binoux, M, Berdal A , Menuelle P and Babajko S. In‐ sulin-Like Growth Factor Binding Protein (IGFBP-1) Involvement in Intrauterine Growth Retardation: Study on IGFBP-1 Overexpressing Transgenic Mice. Endocri‐

[47] Clemmons DR, Busby WH, Snyder DK. Variables con- trolling the secretion of insu‐ lin-like growth factor binding protein-2 in normal human subjects. Journal of Clinical

[48] Roghani M, Hossenlopp P, Lepage P, Balland A & Binoux M. Isolation from human cerebrospinal fluid of a new insulin-like growth factor-binding protein with a selec‐

[49] Bach LA. Insulin-like growth factor binding protein-6: The 'forgotten' binding pro‐

nal of Clinical Endocrinology & Metabolism. 1988 Dec;67(6):1225-30.

Nutrition 2005; 81(5):1163-1167.

210 Hot Topics in Endocrine and Endocrine-Related Diseases

3:704-712

1990; 70:173

nology 2006;147(10): 4730-4737.

Endocrinology & Metabolism 1991, 73, 727-733.

tive affinity for IGF-2. FEBS Letters 1989;255 253–258.

tein? Hormone and Metabolic Research 1999; 31:226–234.

1996;93:10028–10033.

American Journal of Physiology. 1994; 267: 226-33

subunit genes. Endocrinology 2000; 141 833–838.


[62] Laron Z, Parks JS, eds. Lessons from Laron syndrome (LS) 1966–1992. A model of GH and IGF-1 action and interaction. Pediatric and Adolescent Endocrinology 1993;24:1–367.

[74] Samani AA, Yakar S, LeRoith D and Brodt P. The Role of the IGF system in cancer growth and metastasis: Overview and recent insights Endocrine Reviews 2007;28(1):

The Insulin-Like Growth Factor System in the Human Pathology

http://dx.doi.org/10.5772/55213

213

[75] LeRoith D, Baserga R, Helman L, Roberts CT Jr. Insulin-like growth factors and can‐

[76] Baserga R. The insulin growth factor I receptor: a key to tumour growth? Cancer Re‐

[77] Singh P, Rubin R. Insulin-like growth factors and binding proteins in colon cancer.

[78] Tricoli JV, Rall LB, Karakousis CP, Herrara L, Petrelli NJ, Bell GI, et al. Enhanced lev‐ els of insulin-like growth factor mRNA in human colon carcinomas and liposarco‐

[79] Karamouzis MV, Papavassiliou AG. The IGF -1 network in lung carcinoma therapeu‐

[80] Durai R, Davies M, Yang W, et al. Biology of insulin-like growth factor binding pro‐ tein-4 and its role in cancer. International Journal of Oncology 2006; 28:1317–25. [81] Renehan AG, Zwahlen M, Minder C, O'Dwyer ST, Shalet SM, Egger M. Insulin-like growth factor ( IGF )- I, IGF binding protein- 3, and cancer risk: systematic review

[82] Jenkins PJ, Besser GM, Fairclough PD. Colorectal neoplasia in acromegaly. Gut 1999;

[83] Orme SM, McNally RJ, Cartwright RA, Belchetz PE. Mortality and cancer incidence in acromegaly: a retropsective cohort study. United Kingdom Acromegaly Study

[84] Giovannucci E, Pollak MN, Platz EA, Willett WC, Stampfer MJ, Majeed N, et al. A prospective study of plasma insulin-like growth factor-1 and binding protein-3 and the risk of colorectal neoplasia in women. Cancer Epidemiology, Biomarkers & Pre‐

[85] Ma J, Pollak MN, Giovannucci E, Chan JM, Tao Y, Hennekens C, et al. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-1 and IGF binding protein-3. Journal of the National Cancer Institute 1999 ;

[86] Wolk A, Mantzoros CS, Andersson SO, Bergström H, Signorello LB, Lagiou P, et al. Insulin-like growth factor 1 and prostate cancer risk: a population-based, case-control

study. Journal of the National Cancer Institute 1998; 90(12):911-5.

Group. Journal of Clinical Endocrinology & Metabolism 1998; 83:2730–4.

cer. Annals of Internal Medicine 1995; 122:54–9.

20–47

44:585–7.

91:620–5.

vention 2000; 9:345–49.

search 1995; 55:249–52.

Gastroenterology 1993;105:1218–37.

mas. Cancer Research 1986;46:6169–73.

tics. Trends in Molecular Medicine 2006; 12:595–602.

and meta-regression analysis. Lancet 2004;363:1346–53.


[74] Samani AA, Yakar S, LeRoith D and Brodt P. The Role of the IGF system in cancer growth and metastasis: Overview and recent insights Endocrine Reviews 2007;28(1): 20–47

[62] Laron Z, Parks JS, eds. Lessons from Laron syndrome (LS) 1966–1992. A model of GH and IGF-1 action and interaction. Pediatric and Adolescent Endocrinology

[63] Ranke MB, Savage MO, Chatelain PG, et al. Long-term treatment of growth hormone

[64] Guevara-Aguirre J, Rosenbloom AL, Vasconez O, Martinez V, Gargosky SE, Allen L & Rosenfeld RG. Two-year treatment of growth hormone (GH) receptor deficiency with recombinant insulin-like growth factor I in 22 children: comparison of two dos‐ age levels and to GH-treated GH deficiency. Journal of Clinical Endocrinology and

[65] Ranke MB, Savage MO, Chatelain PG, Preece MA, Rosenfeld RG & Wilton P. Longterm treatment of growth hormone insensitivity syndrome with IGF-1. Results of the

[66] Backeljauw PF & Underwood LE. Therapy for 6.5–7.5 years with recombinant insu‐ lin-like growth factor I in children with growth hormone insensitivity syndrome: a Clinical Research Center Study. Journal of Clinical Endocrinology and Metabolism

[67] Chernausek SD, Backeljauw PF, Frane J, Kuntze J & Underwood LE. Long-term treat‐ ment with recombinant IGF-1 in children with severe IGF-1 deficiency due to growth hormone insensitivity. Journal of Clinical Endocrinology and Metabolism 2007; 92

[68] Dupont J, Pierre A, Froment P, Moreau C. The insulin-like growth factor axis in cell

[69] Rosenthal SM, Cheng ZQ. Opposing early and late effects of insulin-like growth fac‐ tor I on differentiation and the cell cycle regulatory retinoblastoma protein in skeletal myoblasts. Proceedings of the National Academy of Sciences 1995; 92:10307–10311

[70] Dupont J, Karas M, LeRoith D. The potentiation of estrogen on insulin-like growth factor I action in MCF-7 human breast cancer cells includes cell cycle components.

[71] Shigematsu S, Yamauchi K, Nakajima K, Iijima S, Aizawa T, Hashizume K. IGF-1 regulates migration and angiogenesis of human endothelial cells. Endocrine Journal

[72] Lee OH, Bae SK, Bae MH, Lee YM, Moon EJ, Cha HJ, Kwon YG, KimKW. Identifica‐ tion of angiogenic properties of insulin-like growth factor II in in vitro angiogenesis

[73] Zelzer E, Levy Y, Kahana C, Shilo BZ, Rubinstein M, Cohen B. Insulin induces tran‐ scription of target genes through the hypoxia inducible factor HIF-1α/ARNT. EMBO

cycle progression. Hormone and Metabolic Research 2003; 35:740–750

Journal of Biological Chemistry 2000; 275:35893–35901.

models. British Journal of Cancer 2000; 82: 385–391

insensitivity syndrome with IGF-1. Hormone Research 1999;51:128–34.

European Multicentre Study. Hormone Research 1999; 51:128–134.

1993;24:1–367.

212 Hot Topics in Endocrine and Endocrine-Related Diseases

Metabolism 1997; 82:629–633.

2001; 86:1504–1510.

902–910.

1999; 46: 59–S62

Journal 17:5085–5094.


[87] Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, Hennekens CH, Pollak M. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science. 1998; 279(5350):563-6.

[99] Pollak MN, Perdue JF, Margolese RG, Baer K, Richard M. Presence of somatomedin receptors on primary human breast and colon carcinomas. Cancer Letters 1987;

The Insulin-Like Growth Factor System in the Human Pathology

http://dx.doi.org/10.5772/55213

215

[100] Dunn SE, Hardman RA, Kari FW, Barrett JC. Insulin-like growth factor 1 alters drug sensitivity of HBL100 human breast cancer cells by inhibition of apoptosis induced

[101] Gooch JL, Van Den Berg CL, Yee D. Insulin-like growth factor-1 rescues breast cancer cells from chemotherapy induced cell death – proliferative and anti-apoptotic effects.

[102] [102]. Shi R, Yu H, McLarty J, Glass J. IGF-1 and breast cancer: a meta-analysis. Inter‐

[103] 103] Haselbacher GK, Irminger JC, Zapf J, Ziegler WH, Humbel RE. Insulin-like growth factor 2 in human adrenal pheochromocytomas and Wilms tumors: expres‐ sion at the mRNA and protein level. Proceedings of the National Academy of Scien‐

[104] Gelato MC, Vassalotti J. Insulin-like growth factor-2: possible local growth factor in pheochromocytoma. Journal of Clinical Endocrinology and Metabolism. 1990; 71(5):

[105] Dahmer MK, Hart PM, Perlman RL. Studies on the effect of insulin-like growth factor 1 on catecholamine secretion from chromaffin cells. Journal of Neurochemistry 1990;

[106] Christian Fottner C, Timo Minnemann T, Sarah Kalmbach S and Matthias M Weber MM. Overexpression of the insulin-like growth factor I receptor in human pheochro‐

[107] Dahmer MK, Perlman RL. Insulin and insulin-like growth factors stimulate desoxyri‐ bonucleic acid synthesis in PC12 pheochromocytoma cells. Endocrinology 1988; 122

[108] Nielsen FC, Gammeltoft S. Insulin-like growth factors are mitogens for rat pheochro‐ mocytoma PC 12 cells. Biochemical and Biophysical Research Communications 1988;

[109] Ren-Qiu Q, Schmitt S, Ruelicke T, Stallmach T and Schoenle EJ. Autocrine regulation of growth by insulin like growth Factor-2 mediated by type 1 IGF-Receptor in Wilms

[110] Gansler T, Allen KD, Burant CF, Inabnett T, Scott A, Buse MG, Sens DA, Garvin AJ. Detection of type 1 insulinlike growth factor (IGF) receptors in Wilms' tumors. Amer‐

mocytomas. Journal of Molecular Endocrinology 2006 Apr;36(2):279-87.

by diverse anticancer drugs. Cancer Research 1997; 57:2687–2693.

Breast Cancer Research and Treatment 1999; 56:1–10.

national Journal of Cancer. 2004; 111(3):418-23.

tumor cells. Pediatric Research 1996 ;39:160–165.

ican Journal of Pathology. 1988 ;130(3):431-5.

38:223–230.

ces 1987; 84 1104–1106.

1168-74.

54 931–936.

2109–2113.

154:1018–1023.


[99] Pollak MN, Perdue JF, Margolese RG, Baer K, Richard M. Presence of somatomedin receptors on primary human breast and colon carcinomas. Cancer Letters 1987; 38:223–230.

[87] Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, Hennekens CH, Pollak M. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective

[88] Chan JM et al. Insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 as pre‐ dictors of advanced-stage prostate cancer. Journal of the National Cancer Institute.

[89] [89]. Schaefer C, Gary D. Friedman, Charles P. Quesenberry Jr. IGF-1 and Prostate

[90] BorugianMJ, Spinelli JJ, Sun Z, Kolonel LN, Girvan IO, Pollak MD, Whittemore AS, Wu AH and Gallagher RP. Prostate Cancer Risk in Relation to Insulin-like Growth Factor (IGF)-I and IGF-Binding Protein-3: A Prospective Multiethnic Study. Cancer

[91] Rowlands MA, David Gunnell D, Ross Haris R, Vatten LJ, Holly JMP and Martin RM. Circulating insulin-like growth factor (IGF) peptides and prostate cancer risk: a systematic review and meta-analysis. International Journal of Cancer 2009; 124(10):

[92] Kleinberg DL, Ruan W, Catanese V, Newman CB & Feldman M. Non-lactogenic ef‐ fects of growth hormone on growth and insulin-like growth factor-1 messenger ribo‐

[93] Feldman M, Ruan W, Cunningham BC, Wells JA & Kleinberg DL. Evidence that the growth hormone receptor mediates differentiation and development of the mamma‐

[94] Ruan W, Newman CB & Kleinberg DL. Intact and amino-terminally shortened forms of insulin-like growth factor 1 induce mammary gland differentiation and develop‐

[95] Ruan W, Catanese V, Wieczorek R, Feldman M & Kleinberg DL. Estradiol enhances the stimulatory effect of insulin-like growth factor- 1 (IGF-1) on mammary develop‐ ment and growth hormone-induced IGF-1 messenger ribonucleic acid. Endocrinolo‐

[96] Pekonen F, Partanen S, Makinen T & Rutanen EM. Receptors for epidermal growth factor and insulin-like growth factor 1 and their relation to steroid receptors in hu‐

[97] Toropainen EM, Lipponen PK & Syrjanen KJ. Expression of insulin-like growth fac‐ tor 2 in female breast cancer as related to established prognostic factors and long-

[98] Singer C, Rasmussen A, Smith HS, Lippman ME, Lynch HT, Cullen KJ. Malignant breast epithelium selects for insulin-like growth factor-2 expression in breast stroma:

evidence for paracrine function. Cancer Research 1995; 55:2448–2454.

ment. Proceedings of the National Academy of Sciences 1992; 89:0872–10876.

nucleic acid of rat mammary gland. Endocrinology 1990; 126:3274–3276.

Epidemiology, Biomarkers & Prevention 2008; 17:252-254.

ry gland. Endocrinology 1993; 133:1602–1608.

man breast cancer. Cancer Research 1988; 48:1343–1347.

term prognosis. AntiCancer Research 1995; 15:2669–2674.

study. Science. 1998; 279(5350):563-6.

2002; 94:1099-1106.

214 Hot Topics in Endocrine and Endocrine-Related Diseases

2416–2429.

gy 1995; 136:1296–1302.

Cancer. Science 1998; 282:199


[111] Drummond IA, Madden SL, Rohwer-Nutter P, Bell GI, Sukhatme VP, Rauscher FJ. Repression of the insulin-like growth factor II gene by the Wilms tumor suppressor WT1. Science. 1992; 257(5070):674-8.

[123] Brokaw J, Katsaros D, Wiley A, Lu L, Su D, Sochirca O, de la Longrais IA, Mayne S, Risch H, Yu H. IGF-1 in epithelial ovarian cancer and its role in disease progression.

The Insulin-Like Growth Factor System in the Human Pathology

http://dx.doi.org/10.5772/55213

217

[124] Odell WD, Wolfsen AR. Humoral Syndromes associated with cancer. Annual Review

[125] Blackman, NR, Rosen SW, Weintraub BD. Ectopic Hormones. Advances in Internal

[126] Zachariah S, Brackenbridge A, Jones DR. Effects of IGF-2 on glucose metabolism. En‐

[127] Denley A, Wallace JC, Cosgrove LJ, Forbes BE. The insulin receptor isoform exon 11− (IR-A) in cancer and other diseases: a review. Hormone and Metabolic Research

[128] Kiess W, Yang Y, Kessler U, et al. Insulin-like growth factor 2 and the IGF-2 man‐ nose-6-phosphate receptor—the myth continues. Hormone Research. 1994 ;41: 66–73.

[129] Duguay SJ, Jin Y, Stein J, Duguay AN, Gardner P and Steiner DF. Post-translational processing of the insulin like growth factor-2 precursor: Analysis of O-glycosylation and endoproteolysis The Journal of Biological Chemistry 1998; 273:18443-18451. [130] Daughaday WH, Kapadia M. Significance of abnormal serum binding of insulin-like growth factor II in the development of hypoglycemia in patients with non-islet-cell

[131] Zapf J, Schmid C, Guler HP, Waldvogel M, Hauri C, Futo E, Hossenlopp P, Binoux M & Froesch ER. Regulation of binding proteins for insulin-like growth factors (IGF) in humans. Increased expression of IGF binding protein 2 during IGF I treatment of healthy adults and in patients with extrapancreatic tumor hypoglycemia. Journal of

[132] Zapf J, Futo E, Peter M & Froesch ER Can 'big' insulin-like growth factor II in serum of tumor patients account for the development of extrapancreatic tumor hypoglyce‐

[133] de Groot JW, Rikhof B, van Doorn J, Bilo HJ, Alleman MA, Honkoop AH, van der Graaf WT. Non-islet cell tumour-induced hypoglycaemia: a review of the literature

[134] Rosenfeld RG, Rosenbloom AL & Guevara-Agurre J. Growth hormone (GH) insensi‐ tivity due to primary GH receptor deficiency. Endocrine Reviews 1994; 15:369–390.

[135] Clemmons DR. Role of insulin-like growth factor iin maintaining normal glucose ho‐

Growth Factors. 2007; 25(5):346-54.

of Medicine 1978; 29:379-406.

docrine Abstracts 2006;11:220

tumors. PNAS 1989; 86:6778–6782.

Clinical Investigation 1990; 86:952–961.

mia? Journal of Clinical Investigation 1992; 90:2574–2584.

meostasis. Hormone Research 2004; 62(1):77-82.

including two new cases. Endocr Relat Cancer. 2007; 14:979-93.

Medicine 1978; 23: 85-113.

2003; 35:778–785.


[123] Brokaw J, Katsaros D, Wiley A, Lu L, Su D, Sochirca O, de la Longrais IA, Mayne S, Risch H, Yu H. IGF-1 in epithelial ovarian cancer and its role in disease progression. Growth Factors. 2007; 25(5):346-54.

[111] Drummond IA, Madden SL, Rohwer-Nutter P, Bell GI, Sukhatme VP, Rauscher FJ. Repression of the insulin-like growth factor II gene by the Wilms tumor suppressor

[112] Hakam A, Fang Q, Karl R, Coppola D. Coexpression of IGF-1R and c-Src proteins in human pancreatic ductal adenocarcinoma. Digestive Diseases and Sciences.

[113] Ishiwata T, Bergmann U, Kornmann M, Lopez M, Beger HG and Korc M. Altered ex‐ pression of insulin like growth factor-2 receptor in human pancreatic cancer. Pan‐

[114] David F Schaeffer DF, Daniel R Owen DR et al. Insulin-like growth factor 2 mRNA binding protein 3 overexpression in pancreatic ductal adenocarcinoma correlates

[115] Russo, VC, Gluckman, PD, Feldman, EL, et al. The insulin-like growth factor system and its pleiotropic functions in brain. Endocrine Reviews 2005; 26: 916-43.

[116] Müller HL, Oh Y, Lehrnbecher T, et al. Insulin-like growth factor-binding protein-2 concentrations in cerebrospinal fluid and serum of children with malignant solid tu‐ mors or acute leukemia. Journal of Clinical Endocrinology & Metabolism 1994;

[117] Adashi EY, Resnick CE, D'Ercole AJ, Svoboda ME, van Wyk JJ. Insulin-like growth factors as intraovarian regulators of granulosa cell growth and function. Endocrine

[118] Giordano G, Barreca A, Minuto F. Growth factors in the ovary. Journal of Endocrino‐

[119] Karasik A, Menczer J, Pariente C, Kanety H. Insulin-like growth factor-1 and IGFbinding protein-2 are increased in cyst fluids of epithelial ovarian cancer. Journal of

[120] Flyvberg A, Mogenson O, Mogensen B & Nielsen OS. Elevated serum insulin-like growth factor binding protein 2 and decreased IGFBP-3 in epithelial ovarian cancer: correlation with cancer antigen 125 and tumorassociated trypsin inhibitor. Journal of

[121] Conover CA, Hartmann LC, Bradley S, Stalboerger P, Klee GG, Kalli KR, et al. Bio‐ logical characterization of human epithelial ovarian cancer cells in primary culture: the insulin-like growth factor system. Experimental Cell Research 1998; 238:439– 49.

[122] Sayer RA, Lancaster JM, Pittman J, Gray J, Whitaker R, Marks JR, Berchuck A. High insulin-like growth factor-2 gene expression is an independent predictor of poor sur‐ vival for patients with advanced stage serous epithelial ovarian cancer. Gynecologic

WT1. Science. 1992; 257(5070):674-8.

with poor survival BMC Cancer 2010; 10:59

2003;48(10):1972-8.

216 Hot Topics in Endocrine and Endocrine-Related Diseases

creas 1997; 4;367-373.

79:428–34

Reviews 1985; 6:400-420.

Oncology 2005; 96(2):355-61.

logical Investigations 1992; 15:689-707.

Clinical Endocrinology and Metabolism1994;78:271-276.

Clinical Endocrinology and Metabolism 1997; 82:2308-2313.


[136] Sandhu MS, Heald AH, Gibson JM, Cruickshank JK, Dunger DB, Wareham NJ. Cir‐ culating concentrations of insulin-like growth factor-I and development of glucose intolerance: a prospective observational study. Lancet 200; 359(9319):1740-5.

[147] Shigematsu S, Yamauchi K, Nakajima K, Iijima S, Aizawa T, Hashizume K. IGF-1 regulates migration and angiogenesis of human endothelial cells. Endocrinology

The Insulin-Like Growth Factor System in the Human Pathology

http://dx.doi.org/10.5772/55213

219

[148] Grant MB, Mames RN, Fitzgerald C, et al. Insulin-like growth factor I acts as an an‐ giogenic agent in rabbit cornea and retina: comparative studies with basic fibroblast

[149] Merimee TJ. A follow-up study of vascular disease in growth-hormone-deficient

[150] Merimee TJ, Fineberg SE, McKusick VA, Hall J. Diabetes mellitus and sexual ateliotic dwarfism: a comparative study. Journal of Clinical Investigation 1970;49:1096. [151] Merimee TJ, Zapf J, Froesch ER. Insulin-like growth factors. Studies in diabetics with and without retinopathy. New England Journal of Medicine 1983; 309:527.

[152] Spagnoli A, Chiarelli F, Vorwerk P, Boscherini B, Rosenfeld RG. Evaluation of the components of insulin-like growth factor (IGF)-IGF binding protein system in adoles‐ cents with type 1 diabetes and persistent microalbuminuria: relationship with in‐ creased urinary excretion of IGFBP-3 18 kD N-terminal fragment. Clinical

[153] Verrotti A, Cieri F, Petitti MT, Morgese G, Chiarelli F. Growth hormone and IGF-1 in diabetic children with and without microalbuminuria. Diabetes, Nutrition and Me‐

[154] Shinada M, Akdeniz A, Panagiotopoulos S, Jerums G, Bach LA. Proteolysis of insu‐ lin-like growth factor-binding protein-3 is increased in urine from patients with dia‐ betic nephropathy. Journal of Clinical Endocrinology and Metabolism 2000; 85 :1163–

[155] Abrass C, Raugi G, Gabourel L, Lovet DH. Insulin and insulin-like growth factor I binding to cultured rat glomerular mesangial cells. Endocrinology 1988;123:2432–

[156] Juul A, Scheike T, Davidsen M, Gyllenborg J, Jorgensen T: Low serum insulin-like growth factor 1 is associated with increased risk of ischemic heart disease: a popula‐

[157] Conti E, Crea F, Andreotti F: IGF-1 and risk of ischemic heart disease. Circulation

[158] Muniyappa R, Walsh MF, Rangi JS, Zayas RM, Standley PR, Ram JL. Insulin-like growth factor 1 increases vascular smooth muscle nitric oxide production. Life Sci‐

tion-based case control study. Circulation 106:939–944.

dwarfs with diabetes. New England Journal of Medicine 1978;298: 1217.

1999;46:59-62.

growth factor. Diabetologia 1993; 36:282.

Endocrinology 1999; 51: 587–596

tabolism 1999;12:271–276.

2004; 110: 2260-2265.

ence 61:925–931, 1997.

1169.

2439.


[147] Shigematsu S, Yamauchi K, Nakajima K, Iijima S, Aizawa T, Hashizume K. IGF-1 regulates migration and angiogenesis of human endothelial cells. Endocrinology 1999;46:59-62.

[136] Sandhu MS, Heald AH, Gibson JM, Cruickshank JK, Dunger DB, Wareham NJ. Cir‐ culating concentrations of insulin-like growth factor-I and development of glucose

[137] Rajpathak SN, Gunter MJ, Wylie-Rosett J, Ho GY, Kaplan RC, Muzumdar R, Rohan TE, Strickler HD. The role of insulin-like growth factor-I and its binding proteins in glucose homeostasis and type 2 diabetes. Diabetes/Metabolism Research and Re‐

[138] Friedrich N, Thuesen B, Jørgensen T, Juul A, Spielhagen C, Wallaschofksi H and Lin‐ neberg A. The association between IGF-1 and insulin resistance: A general popula‐

[139] Schneider HJ, Friedrich N, Klotsche J, et al. Prediction of incident diabetes mellitus by baseline IGF1 levels. European Journal of Endocrinology 2011;164:223–229. [140] van der Klaauw AA, Biermasz NR, Feskens EJ, et al. The prevalence of the metabolic syndrome is increased in patients with GH deficiency, irrespective of long-term sub‐ stitution with recombinant human GH. European Journal of Endocrinology

[141] Melmed S. Medical progress: acromegaly. New England Journal of Medicine

[142] Cheetham T, Jones J, Taylor AM, Holly J, Matthews DR, Dunger DB: The effects of recombinant insulin-like growth factor-I administration on growth hormone levels and insulin requirements in adolescents with type 1 diabetes mellitus. Diabetologia

[143] Carroll PV, Umpleby M, Ward GS, Imuere S, Alexander E, Dunger D, Sönksen PH, Russell-Jones DL: rhIGF-1 administration reduces insulin requirements, decreases growth hormone secretion, and improves the lipid profile in adults with IDDM. Dia‐

[144] Paul V. Carroll, Emanuel R. Christ, A. Margot Umpleby, Ian Gowrie, Nicola Jackson, Susan B. Bowes, Roman Hovorka, Premila Croos, Peter H. Sönksen, and David L. Russell-Jones. IGF-1 Treatment in Adults With Type 1 Diabetes Effects on Glucose and Protein Metabolism in the Fasting State and During a Hyperinsulinemic-Eugly‐

[145] Zenobi PD, Jaeggi-Groisman SE, Riesen WF, Roder ME, Froesch ER: Insulin like growth factor-1improves glucose and lipid metabolism in type II diabetes mellitus.

[146] Moses AC, Young SC, Morrow LA, O'Brien M, Clemmons DR. Recombinant human insulin-like growth factor I increases insulin sensitivity and improves glycemic con‐

cemic Amino Acid Clamp. Diabetes 49:789–796, 2000.

Journal of Clinical Investigation 90:2234–2241, 1993

trol in type II diabetes. Diabetes. 1996;45(1):91-100.

tion study in Danish adults. Diabetes Care. 2012 Apr;35(4):768-73.

intolerance: a prospective observational study. Lancet 200; 359(9319):1740-5.

views 2009; 25(1):3-12.

218 Hot Topics in Endocrine and Endocrine-Related Diseases

2007;156:455–462.

2006;355:2558–2573.

1993; 36:678–681

betes 1997; 46:1453–1458.


[159] E Andreotti FE, Sestito A, Riccardi P, Menini E, Crea F, Maseri A, Lanza GA. Mark‐ edly reduced insulin-like growth factor-1 associated with insulin resistance in syn‐ drome X patients. American Journal of Cardiology 2002; 89:973–975

**Chapter 9**

**Pediatric Nonalcoholic Fatty Liver Disease**

Paralleling the burgeoning epidemics of childhood obesity, nonalcoholic fatty liver dis‐ ease (NAFLD) is now recognized as the most common cause of chronic liver disease in

NAFLD is a clinic-pathological condition defined by the accumulation of intrahepatic trigly‐

NAFLD encompasses a wide spectrum of liver damage, ranging from asymptomatic steato‐ sis with elevated or normal aminotransferases to steatosis with inflammation, ballooning de‐ generation and pericellular fibrosis (Nonalcoholic Steatohepatitis, NASH) to cirrhosis [2,3]. Although there are limited long-term data on the natural history of NAFLD in children, NASH is increasingly diagnosed in obese children [4] and it may progress to cirrhosis even in this age group [2,5]. In addition, children with NAFLD have a 13.6-fold higher risk of

mortality or requiring a liver transplant as compared to age/sex matched controls [6].

During the last years there has been a growing interest in the relationship between NAFLD

Several lines of evidence have shown that in obese children and adolescents excessive accumulation of IHTF is associated with important alterations in glucose, fatty acid (FA), lipoprotein metabolism and inflammation, suggesting that IHTF represents a strong risk factor for the development of the Metabolic Syndrome (MetS) and type 2 diabetes melli‐

and reproduction in any medium, provided the original work is properly cited.

© 2013 D'Adamo et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

ceride fat (IHTF) content in the absence of alcohol consumption [1,2].

and the development of metabolic and cardiovascular diseases [7-9].

Ebe D'Adamo, M. Loredana Marcovecchio, Tommaso de Giorgis, Valentina Chiavaroli, Cosimo Giannini, Francesco Chiarelli and

Additional information is available at the end of the chapter

Angelika Mohn

**1. Introduction**

children [1,2].

tus (T2D) [7-10].

http://dx.doi.org/10.5772/53463

[160] Heald AH, Siddals KW, Fraser W, Taylor W, Kaushal K, Morris J, Young RJ, White A, Gibson JM. Low circulating levels of insulin-like growth factor binding protein-1 are closely associated with the presence of macrovascular disease and hypertension in type 2 diabetes. Diabetes 2002 Aug;51(8):2629-36.
