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Physiology of insulin-like growth factor 1

Physiology of insulin-like growth factor 1
Author:
David R Clemmons, MD
Section Editor:
Peter J Snyder, MD
Deputy Editor:
Kathryn A Martin, MD
Literature review current through: Jan 2024.
This topic last updated: Jan 18, 2024.

INTRODUCTION — Insulin-like growth factor 1 (IGF-1) is a hormone that functions as the major mediator of growth hormone (GH)-stimulated somatic growth, as well as a mediator of GH-independent anabolic responses in many cells and tissues. IGF-1 is a small peptide (molecular weight 7647) that circulates in serum bound to high affinity binding proteins. IGF-1 is an unusual peptide in this regard since it is more than 99 percent protein-bound.

IGF-1 is synthesized by multiple mesenchymal cell types. As a result, there are two major mechanisms of IGF-1 regulation:

IGF-1 that is synthesized in the liver and secreted into the blood is under the control of GH.

Autocrine/paracrine IGF-1 is synthesized in peripheral tissues, such as bone. Its synthesis is controlled by GH and by factors that are secreted locally by the surrounding cell types. Some of the secreted autocrine/paracrine IGF-1 enters into the systemic circulation. Therefore, understanding the regulation of autocrine/paracrine synthesis of IGF-1 is necessary to interpret changes in serum IGF-1 concentrations.

IGF-1 exerts its effects via activation of the IGF-1 receptor [1]. This receptor is widely distributed, which enables blood-transported IGF-1 to coordinate balanced growth among multiple tissues and organs. In contrast, autocrine/paracrine IGF-1 can stimulate local, unbalanced growth independently of systemic GH. Examples of this type of growth regulation are wound healing and growth of the contralateral kidney after unilateral nephrectomy.

This review will cover the fundamental aspects of the control of IGF-1 synthesis, secretion by tissues and cell types, transport of IGF-1 in blood, the role of IGF-binding proteins (IGFBPs), and regulation of IGF-1 actions in target tissues. The physiology of GH is discussed elsewhere. (See "Physiology of growth hormone".)

IGF GENES AND STRUCTURE — The insulin-like growth factor 1 (IGF-1), IGF-2, and insulin genes are part of the same family [2]. The IGF-1 gene is a complex, multicomponent gene with six exons, with the mature peptide being encoded by exons 3 and 4. Several forms of IGF-1 mRNA are transcribed, including a 6 kb form that is regulated by growth hormone (GH).

Mature IGF-1 contains 70 amino acids and IGF-2 67 amino acids. Proinsulin has a longer C-peptide region. All three peptides contain A, B, and C domains.

IGF-1 and -2 also contain D-domain extensions of eight and six amino acids, respectively, that are not cleaved, and are secreted as part of single chain proteins. Three-dimensional analyses by nuclear magnetic resonance (NMR) and x-ray crystallography as well as site-directed mutagenesis have revealed the following [3]:

Tyrosines 24, 60, and, to some extent, 31 are critical for IGF-1 receptor recognition. Phenylalanine 24, valine 44, and arginine 36, 37, and 57 also are important [3].

The specific amino acids in the B domain in positions 3, 4, 15, and 16 are required for binding to any of the six forms of IGF-binding proteins (IGFBPs). Residues 49, 50, and 51 of the A domain are critical for recognition by four of the six IGFBPs.

IGF-1 RECEPTORS — The insulin-like growth factor 1 (IGF-1) receptor (sometimes designated type 1 IGF receptor) is the primary mediator of the physiologic actions of IGF-1. The IGF-2/mannose-6-phosphate receptor (type 2 IGF receptor) is of lesser importance.

IGF-1 receptor — The IGF-1 receptor is present in multiple cell types and tissues, which probably accounts for the ability of IGF-1 to stimulate balanced, symmetric growth [1]. Receptor number is regulated by growth hormone (GH) and thyroxine (T4) and is tightly controlled within a range of 20 to 35,000 receptors per cell. Other growth factors, such as platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF), can also stimulate an increase the number of IGF-1 receptors.

The biochemical structure of the IGF-1 receptor is similar to that of the insulin receptor and other growth factor receptors (figure 1). It is a heterotetrameric glycoprotein composed of two alpha subunits and two beta subunits [1].

The alpha subunit contains the IGF-binding domain and binds with an affinity constant of 10(-9) M for IGF-1; the affinity constant is sixfold lower for IGF-2 and 200 to 300-fold lower for insulin.

The beta subunit contains a transmembrane domain followed by a tyrosine kinase (TK) domain. This domain contains an ATP-binding motif and a catalytic lysine at position 1003 that is required for TK activity.

Receptor activation — Ligand binding to the receptor alpha subunit triggers a conformational change in the receptor, leading to autoactivation of TK activity, followed by autophosphorylation of six tyrosines, including a triple tyrosine motif at positions 1149, 1150, and 1151. Mutation of these tyrosines results in abolition of IGF-1 signaling.

The activated receptor phosphorylates insulin receptor substrate-1 and -2 (IRS-1 and -2), which are also phosphorylated by the insulin receptor [4]. Following receptor autophosphorylation, IRS-1 binds to the receptor at tyrosine 950, which leads to IRS-1 tyrosine phosphorylation. The receptor also can directly phosphorylate another signaling protein: Shc. Hybrid receptors containing an alpha-beta IGF half receptor paired with an alpha-beta insulin half receptor have been described. The physiologic significance of hybrid receptors is not well defined, but they may mediate the insulin-like actions of IGF-1.

Following its tyrosine phosphorylation, IRS-1 binds to other signaling molecules (such as Grb-2 and p85) through a direct interaction between the IRS-1 phosphotyrosines and Src homology 2 (SH2) domains contained in these proteins (figure 2). Grb-2 forms a complex with the Ras-activating protein son of sevenless (SOS); this complex leads to p21 Ras activation, which activates downstream components of the mitogen-activated protein kinase (MAP kinase) pathway (figure 2). Activation of this pathway is important for stimulation of cell growth by IGF-1. The IGF-1 receptor also phosphorylates Shc. Like phosphorylated IRS-1, Shc can bind to Grb-2 and activates the RAS-MAP kinase pathway leading to stimulation of cell growth.

Tyrosine-phosphorylated IRS-1 also binds to the p85 subunit of PI-3 kinase, leading to PI3-kinase activation. This generates inositol triphosphate and activation of protein tyrosine kinase-B (also termed AKT). This kinase can activate mTOR, p70S6 kinase, and GSK-3-beta, which are important for stimulation of protein synthesis and glucose transport. This pathway is also important for IGF-1 stimulation of cell motility, inhibition of apoptosis, and stimulation of cellular differentiation.

An important function of IGF-1 receptor-induced signaling is the prevention of apoptosis. When cells in culture have been stimulated to undergo apoptosis, the presence of IGF-1 can prevent them from activating downstream signaling components of the apoptotic pathway.

Receptor overexpression (eg, cells expressing >1 million receptors per cell) can result in cell transformation, ie, the ability of cells to form tumors when injected into mice. However, this degree of increase in receptor number is rarely detected in human tumors. Overexpression of the IGF-1 receptor can also abrogate the requirement of tumor cells for exposure to other growth factors, such as PDGF and epidermal growth factor (EGF) [5]. Certain oncogenes that lead to cellular transformation, such as Src, require the presence of an intact IGF-1 receptor [5]. Whether targeting the IGF-1 receptor will provide an effective anticancer therapeutic strategy continues to be an area of active investigation [6].

IGF-2/mannose 6 phosphate receptor — The IGF-2/mannose-6-phosphate receptor is less important for growth stimulation but is important for regulation of IGF-1 and -2 activities, both by sequestering the hormones and promoting their degradation [7]. Its structure is different from the IGF-1 receptor, being a single chain protein that also binds avidly to mannose-6-phosphate residues on lysosomal enzymes. The receptor binds IGF-2 with an 80-fold greater affinity than IGF-1 and does not bind to insulin. It is rapidly endocytosed and recirculates from endosomes back to the cell surface, a process that is stimulated by insulin.

IGF-BINDING PROTEINS — The insulin-like growth factor (IGF) binding proteins (IGFBPs) are a family of six high-affinity proteins whose affinities for IGF-1 and -2 are greater than the IGF-1 receptor [8]. One or more members of this family are present in all extracellular fluids, and they control the ability of IGF-1 and -2 to bind to receptors. In most cases, less than 1 percent of the total IGF-1 in plasma is in an unbound state. Insulin does not bind to these proteins.

A major function of the IGFBPs is to transport IGF. They control access to the extravascular space, as well as tissue localization and distribution. IGFBP-3 is the most abundant form in plasma with the highest affinity for IGF-1 and is in a saturated state. IGFBP-2 is the second most abundant binding protein. Although present in lower concentrations, IGFBP-1 can account for the greatest changes in free IGF-1 since it is usually unsaturated, and its levels can fluctuate as much as fivefold during a 24-hour period.

The structures of the six IGFBPs show a great deal of similarity. A high degree of conservation of sequence is present in the N- and C-terminal domains of each protein. The IGF binding site for IGFBP-3 and -5 has been localized to a hydrophobic patch that occurs in the latter part of the amino terminus. This region is also conserved in IGFBP-1, -2, -4, and -6.

High affinity binding requires this site, as well as correct folding of a critical region in the C-terminus, which apparently aligns with the N-terminal site. The midregion that connects the N– and C-terminal domains (termed the linker region) is a site of proteolytic cleavage, which results in loss of IGF binding. The amino acid sequences in this region are not conserved among family members, and these differences account for some of the unique properties of each protein.

Structural differences — In addition to their common features, some unique features are present in each of these proteins that account specific features account for some differences in physiologic function that have been described [8].

IGFBP-1 contains an Arg-Gly-Asp sequence near its N-terminus. This allows it to bind to the alpha-5-beta-1 integrin; such binding appears to stimulate cell migration and inhibit protein breakdown.

IGFBP-2 also contains an Arg-Gly-Asp sequence near its C-terminus, and it can bind to alpha-5-beta-1 integrin. It contains a unique heparin binding domain in the linker region that mediates its binding to the cell surface receptor, RPTP-beta.

IGFBP-3 is N-glycosylated and is the major IGF binding moiety in plasma as more than 75 percent of circulating IGF-1 is bound to this protein. IGFBP-3 concentrations are increased by growth hormone (GH) administration, and it functions as the major GH responsive carrier of IGF-1 and -2. IGFBP-3 binds to another plasma protein, acid labile subunit (ALS), which prolongs its half-life and stabilizes IGF-1 binding to this ternary complex in plasma, increasing its half-life to 16 hours.

IGFBP-4 often inhibits IGF activity. It is cleaved by proteases that are present in many extracellular fluids. This renders it unable to bind IGF-1 and -2 and allows controlled release of free IGF to receptors.

IGFBP-5 binds to extracellular matrix (ECM), which lowers its affinity for IGF-1 eightfold. This allows ECM-associated IGFBP-5 to enhance, rather than inhibit, IGF-1 activity by releasing free IGF-1 in the extracellular space. IGFBP-5 is rapidly cleaved in most physiologic fluids to a non-IGF binding 22 kDa fragment.

IGFBP-6 has a much greater affinity for IGF-2 as compared with IGF-1. It appears to be inhibitory in most biologic test systems.

Regulation of plasma IGFBPs — Plasma concentrations of IGF-binding protein (IGFBP)-3 and ALS are increased by GH, as is IGF-1 (see 'IGFBP-3' below). Each component of this ternary complex maintains the half-life of the other components, resulting in greater stabilization (eg, 16 hours for the tertiary complex).

IGFBP-3 — As noted above, IGF-binding protein (IGFBP)-3 is the most abundant plasma IGFBP, followed by IGFBP-2 and -4. ALS and IGF-1 are the most GH-dependent gene products, although there is also some increase in IGFBP-3. Other hormones, such as testosterone, estrogen, and thyroxine (T4), also regulate IGFBP-3 synthesis. Plasma IGFBP-3 is reduced in deficiency states of each of these three hormones and returns to normal if replacement therapy is given.

Another important variable that controls the plasma IGFBP-3 concentration is proteolysis. A protease in human pregnancy serum rapidly degrades IGFBP-3 into non-IGF-1 binding fragments. This protease is also active in diabetes.

IGFBP-2 — The affinity of IGF-binding protein (IGFBP)-2 for IGF-1 is substantially less than that of IGFBP-3, and IGFBP-2 has a much shorter half-life (90 minutes versus 16 hours). This explains why more than 75 percent of circulating IGF-1 is bound to IGFBP-3. However, IGFBP-2 has an important function in that it rapidly regulates the amount of free IGF-1 that is available to enter the extravascular space and bind to receptors in peripheral tissues. IGFBP-2 can cross the capillary wall and may provide a transport vehicle for IGF-1 out of the vasculature. IGFBP-2 plays a role in hematopoietic cell proliferation and acquisition of normal bone mass [9].

IGFBP-2 concentrations are decreased in response to GH or insulin. IGFBP-2 is also increased in response to IGF-1 administration to humans. Nutritional restriction results in an increase in IGFBP-2 and a reduction in free IGF-1. In contrast, obesity is associated with a decrease in IGFBP-2 and an increase in free IGF-1.

IGFBP-1 — Plasma IGF-binding protein (IGFBP)-1 is acutely regulated by insulin [10]. It is increased five- to sixfold by fasting, which inhibits insulin release, and it is reduced by feeding or the administration of insulin. The net effect is that IGFBP-1 levels fluctuate widely during a 24-hour period, depending upon food intake. This results in major changes in free IGF-1, since IGFBP-3 and -2 levels fluctuate much less. Although the amount of IGF binding capacity that changes in response to meals is small, the amount of free IGF-1 is also small; thus, a large percentage of the free fraction of IGF-1 can be altered in response to small changes in total IGF binding capacity.

Administration of IGFBP-1 to animals results in increased glucose concentrations, suggesting that it may have a glucoregulatory function. Plasma IGFBP-1 values have been used as a marker of hepatic insulin sensitivity, being elevated in insulin resistant states. They increase progressively over time in individuals who develop type 2 diabetes [11].

IGFBP-4 and -5 — IGF-binding protein (IGFBP)-4 concentrations in serum are regulated by the protease pregnancy-associated plasma protein-A (PAPP-A), which cleaves IGFBP-4, thereby releasing IGFs. They are also regulated by parathyroid hormone (PTH) and correlate with the ability of PTH to alter bone turnover. IGFBP-5 can also form a tertiary complex with acid labile subunit, and its plasma concentrations are regulated by GH.

Proteolysis of IGFBPs — An additional level of regulation occurs via proteolysis of the IGFBPs. A protease PAPP-A cleaves several forms of IGFBPs to release free IGF-I or IGF-II to the receptor. Proof that this process regulates IGF actions was provided by a study that showed when PAPP-A was deleted in mice, the mice were small at birth and did not undergo catch-up growth [12].

REGULATION OF CIRCULATING IGF-1 — The liver is the source of most (75 percent) of plasma insulin-like growth factor 1 (IGF-1), as proven by organ-specific gene targeting studies [13]. Variables that regulate synthesis and release by the liver, primarily growth hormone (GH), also regulate its plasma concentrations. Variables that regulate serum IGF-binding protein-3 (IGFBP-3) can also have major effects on IGF-1 concentrations.

Plasma IGF-1 levels rise sevenfold from very low concentrations at birth (20 to 60 ng/mL) to peak values at puberty [14]. Concentrations then fall rapidly in the second decade, reaching values that are 40 to 50 percent of the maximum pubertal levels by age 20. They then decline slowly by an additional 50 percent up to age 60 years [15]. Part of this change is due to age-dependent changes in GH secretion.

There is also an important genetic determinant of plasma IGF-1. Twin studies have shown that approximately 40 percent of each individual's IGF-1 variability can be accounted for by undefined genetic factors that are linked to final adult height. Several polymorphisms in the IGF-1 gene have been identified, and they account for some of the variability in IGF-1 concentrations in the normal population [16]. Gene polymorphisms also occur in IGFBP-3, and they contribute to variability of total IGF concentrations.

Growth hormone — GH is a major determinant of plasma IGF-1, and GH-deficient children have plasma IGF-1 concentrations that are often below the 95 percent confidence interval. (See "Diagnosis of growth hormone deficiency in children", section on 'IGF-1 and IGFBP-3'.)

The effects of GH on plasma IGF-1 are complex. Although it stimulates IGF-1 gene transcription and secretion by the liver, part of the increase is controlled by concurrent stimulation of IGFBP-3 and acid labile subunit (ALS). Together, these three proteins form a stable ternary complex; any factor that attenuates the relative increase in any one of the three components will produce a major reduction in serum IGF-1.

Administration of GH to GH-deficient subjects results in a six- to sevenfold increase in IGF-1 concentrations. Mean IGF-1 values in acromegaly are seven times the normal age-adjusted mean [17], and the severity of the IGF-1 abnormality correlates with the amount of soft tissue growth. It also correlates with the amount of GH secretion in acromegaly, up to mean 24-hour GH values of 20 ng/mL. (See "Causes and clinical manifestations of acromegaly".)

Nutritional status — Nutritional status is an important determinant of plasma IGF-1. Minimum intakes of 20 kcal/kg per day of energy and 0.6 g/kg of protein are necessary to maintain normal plasma values. Fasting for seven days results in a 50 percent decrease in plasma IGF-1 values. A decline is also seen in diseases associated with malnutrition, such as hepatic failure, inflammatory bowel disease, and renal failure. Much, but not all, of the change in IGF-1 levels is mediated by a malnutrition-linked decrease in GH sensitivity and, to some extent, downregulation of GH receptors. In contrast, obesity is associated with a decrease in total IGF-1 and increase in free IGF-1, as well as enhanced hepatic sensitivity to GH stimulation of IGF-1. However, the increase in free IGF-1 suppresses GH and insulin secretion, resulting in impairment of carbohydrate metabolism [18].

Other hormones — Plasma IGF-1 is reduced in hypothyroidism and increases with thyroxine (T4) replacement. In comparison, estrogen has minimal effects on plasma IGF-1.

REGULATION OF TISSUE IGF-1 — As mentioned above, insulin-like growth factor 1 (IGF-1) is synthesized in peripheral tissues, as well as the liver [19], and peripheral tissue synthesis contributes to plasma concentrations.

Bone and cartilage are two important skeletal sources of IGF-1 mRNA. Parathyroid hormone (PTH) regulates IGF-1 gene transcription in bone. Growth hormone (GH) also increases IGF-1 synthesis by osteoblasts and chondrocytes, suggesting this local synthesis contributes to regulation of statural growth.

Erythroid cell precursors synthesize IGF-1 in response to erythropoietin.

IGF-1 expression is regulated in the ovary, and follicle-stimulating hormone (FSH) administration increases IGF-1 concentrations in follicular fluid.

IGF-1 crosses the blood-brain barrier to a limited extent. As a result, local synthesis, which occurs in the central nervous system, provides an important source of IGF-1.

IGF-1 is synthesized in satellite cells and myoblasts in skeletal muscle. Following injury, there is a wave of IGF-1 synthesis that correlates with reparative cell division [20]. IGF-1 synthesis is also increased during muscle hypertrophy, particularly in models of cardiac hypertrophy due to pressure overload.

The kidney is an important local source of IGF-1. Following unilateral nephrectomy during compensatory growth of the contralateral kidney, there is a major increase in IGF-1 mRNA expression.

MAJOR PHYSIOLOGIC EFFECTS OF IGF-1 — Three types of experimental model systems have been utilized to analyze the actions of insulin-like growth factor 1 (IGF-1) in vivo: administration of purified IGF-1 to whole animals, deletion of IGF-1 gene expression or overexpression of IGF-1 in transgenic mouse models, and administration of IGF-1 to humans.

In addition, tissue- or cell type-specific deletion of IGF-1 synthesis has been utilized to study the contribution of specific cells or organs to maintaining serum IGF-1 concentrations and the role of IGF-binding protein (IGFBP) in localized growth regulation.

Whole animal studies — When administered to hypophysectomized animals, IGF-1 stimulates balanced growth in all tissues. A rate-limiting factor for the ability of IGF-1 to stimulate growth is the induction of hypoglycemia. This results in major limitations on the amount of IGF-1 that can be given to animals. If hypoglycemia is avoided, then administration of IGF-1 will mimic the effect of growth hormone (GH) on linear growth.

IGF-1 administration can also reverse the catabolic effect of nutrient deprivation or administration of glucocorticoids. In addition, IGF-1 increases wound healing, raises the glomerular filtration rate, and stimulates whole body protein accretion. Infusion of IGF-1 into insulin-deficient diabetic rats results in improved growth and improved utilization of glucose.

If IGFBP-3 is administered with IGF-1, there is enhanced bone mineralization and increased linear growth compared with administration of IGF-1 alone. Part of this effect of concomitant administration of IGFBP-3 is that hypoglycemia is not induced; as a result, high concentrations of IGF-1 can be achieved, which result in better growth stimulation compared with the lower concentrations that are attained with IGF-1 alone.

Transgenic animal models — In animals in which GH expression has been deleted, expression of the IGF-1 transgene results in stimulation of balanced growth, and if adequate expression of IGF-1 is achieved, growth is equal to animals that secrete GH [21]. If the transgene is variably expressed, then organ growth may not be symmetric. For example, mice that have expression predominantly in pancreas, kidney, and brain have greater increases in the size of these organs.

Gene knockout experiments have been useful in determining the effects of IGF-1 on somatic growth. As an example, animals in which the IGF-1 gene is completely deleted have fetal growth retardation (60 percent of normal birth weight and length) [22]. They grow poorly after birth, and only 10 to 20 percent of these animals survive to adulthood. If the IGF-1 receptor is deleted, then at birth the animals are 45 percent of normal size, and they die immediately due to inadequate development of skeletal muscle in the diaphragm [23].

If IGF-1 gene expression is deleted only in the liver, the animals are born normal size but have only 25 percent of the normal serum IGF-1 concentration [13]. In striking contrast to animals with total IGF-1 deletion, these animals grow at a near-normal rate postnatally (approximately 6 to 8 percent growth retardation). If peripherally synthesized IGF-1 is eliminated and hepatic synthesis is retained, growth is normal only if supraphysiologic serum concentrations (eg, increased fourfold) are present [24]. Therefore, both autocrine/paracrine IGF-1 and liver-derived IGF-1 are important for normal postnatal growth, and genetic studies show that they contribute equally to final height [23].

In terms of glucose metabolism, animals with total IGF-1 deletion have not been analyzed in detail. However, they are not overtly hyperglycemic and do not require insulin administration to maintain a normal blood glucose. Animals in which IGF-1 gene expression has been deleted in the liver are also normoglycemic and respond normally to a glycemic stimulus. However, they are insulin resistant, and insulin administration does not reduce glucose to the same extent as in control animals [25]. When tyrosine phosphorylation of the insulin receptor was examined in skeletal muscle, the animals showed impaired responsiveness to insulin, both in terms of phosphorylation of the insulin receptor and stimulation of IRS-1 phosphorylation. This suggests that lowering plasma IGF-1 concentration induces insulin resistance in muscle.

Effects of IGF-1 administration to humans — Insulin-like growth factor (IGF)-1 infusion into calorically restricted humans restores nitrogen balance to normal. Similarly, coadministration of GH and IGF-1 induces positive nitrogen balance in calorically restricted humans [26]. The effect that is achieved is substantially greater than that seen with IGF-1 alone, probably because GH also stimulates an increase in serum IGFBP-3. Other effects of IGF-1 administration include:

A decrease in blood glucose if sufficient concentrations are given [27].

A threefold increase in IGFBP-2 concentrations and a 25 percent increase in glomerular filtration rate.

Stimulation of whole body protein synthesis, and inhibition of proteolysis. The combination of GH plus IGF-1 has a greater effect on protein synthesis compared with IGF-1 alone.

Partial reversal of the catabolic effect of glucocorticoids on protein synthesis.

An anabolic effect on bone, as demonstrated by increases in markers of bone formation in patients with low bone mineral density who receive IGF-1. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Therapies not recommended'.)

Administration of IGF-1 to patients with type 2 diabetes results in a 3.4-fold improvement in insulin sensitivity [27]. Whether subjects are receiving insulin or oral hypoglycemic agents, mean glucose can be improved substantially in diabetics who receive IGF-1 injections.

Injections of free IGF-1 also cause dose-dependent side effects, which include retinal edema, Bell's palsy, and severe myalgias. The frequency of these side effects can usually be reduced if IGF-1 doses of 40 mcg/kg twice daily or less are administered [28]. IGF-1 is not approved for treatment of type 2 diabetes, but it has been used effectively for blood glucose control in rare patients with extreme insulin resistance syndromes.

IGF-1 therapy is effective in patients with GH insensitivity due to GH receptor mutations and in patients with short stature and very low serum IGF-1 (eg, <2.5 standard deviations [SDs]). Adverse effects, such as enhanced growth of tonsils, facial soft tissue, and kidneys, have been seen in some children. Currently, IGF-1 therapy is approved for children with short stature (<-3.0 SDs) or IGF-1 level that is <-3.0 SDs and normal to elevated GH levels. (See "Growth hormone treatment for idiopathic short stature", section on 'Recombinant human IGF-1'.)

MECHANISMS OF ACTION OF IGF-1 — Insulin-like growth factor 1 (IGF-1) is a potent stimulator of DNA synthesis in vitro. Most cell types in culture possess IGF-1 receptors and respond to its addition by increases in DNA and protein synthesis and cell size [29]. During normal physiologic conditions, the IGF-1 receptor is the major mediator of IGF-1 actions.

Following IGF-1 binding to its receptor, the receptor undergoes a conformational change that activates its tyrosine kinase (TK) activity. The TK autophosphorylates tyrosines, which act as docking sites for the signaling proteins Shc and insulin receptor substrate (IRS)-1 or -2. The IRS proteins are phosphorylated by the receptor TK then bind to the p85 subunit of the PI-3 kinase leading to activation of protein kinase B and stimulation of protein synthesis as well as inhibition of apoptosis. The signaling protein Shc is also phosphorylated, enabling it to bind to Grb-2, which leads to activation of mitogen-activated protein (MAP) kinase and stimulation of DNA synthesis and cell growth. IGF-1 has also been shown in vitro to:

Stimulate multiple metabolic reactions that are important for carbohydrate metabolism, such as glucose transport, glucose oxidation, fatty acid transport, and lipid synthesis.

Act as a cell cycle regulatory growth factor; unlike platelet-derived growth factor (PDGF) or fibroblast growth factor (FGF), IGF-1 usually does not stimulate quiescent cells to enter the G1 phase of the cell cycle. However, once cells have entered the G1 phase, it is an important factor for progression to "S" phase.

In several injury models, there is a major increase of IGF-1 synthesis by the cell types that will repair the injury. This secreted IGF-1 then binds to the same cell or adjacent cells and stimulates DNA synthesis in reparative cell types. This has been shown for fibroblasts, endothelium, cartilage, smooth muscle, skeletal muscle, and neural tissue.

IGF-1 also has a number of other actions:

In some systems, IGF-1 is a potent inhibitor of apoptosis, particularly hematopoietic and neuronal systems. In many tumor cell types, IGF-1 is required for inhibition of apoptosis. As an example, during development, IGF-1 is a potent inhibitor of neuronal, myocyte, and oligodendrocyte cell death. During follicular development, IGF-1 stimulation by gonadotropins prevents apoptosis of developing cells within the follicle.

IGF-1 induces differentiation in several cell types including skeletal myoblasts, vascular smooth muscle and endothelium, chondrocytes, and osteoblasts. The expression of specific proteins that are required for cellular differentiation, such as myogenin in skeletal muscle or osteocalcin in osteoblasts, is enhanced [30]. Any decrease in autocrine-produced IGF-1 will inhibit this process. IGF-binding proteins (IGFBPs) also function to modulate the differentiation response to IGF-1 [31]. Time-dependent, context-specific exposure of myoblasts or osteoblasts to IGF-1 results in stimulation of differentiation at critical time points. In addition, differentiation markers are induced by IGF-1 in osteoclasts, cardiomyocytes, and neural cells.

IGF-1 stimulates specialized functions in endocrine tissues, including enhancement of the effects of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) on production of steroids by ovarian granulosa cells, testosterone secretion by Leydig cells, the effects of corticotropin (ACTH) on adrenal cortical cell steroidogenesis, and the response of thyroid follicular cells to thyroid-stimulating hormone (TSH).

These receptors are all G protein-coupled receptors that interact with a family of proteins termed beta arrestins. IGF-1 receptor binding to beta arrestin can alter IGF-1 signaling [32]. This interaction may be clinically relevant in Graves' hyperthyroidism. A monoclonal antibody to the IGF-1 receptor can inhibit the progression of Graves' eye disease (that is caused by autoantibodies that stimulate the TSH receptor). The monoclonal antibody appears to inhibit the cooperative interaction of the TSH and IGF-1 receptors that is mediated through beta arrestin [33]. (See "Pathogenesis of Graves' disease".)

In pathophysiologic states, tissue sensitivity to IGF-1 can be altered. For example, during hyperglycemia, certain cell types, such as vascular cells, have enhanced sensitivity to IGF-1 [34]. This is due to a change in signal transduction in which IRS-1 is downregulated and a transmembrane protein, SHPS-1, is activated in response to hyperglycemia and IGF-1 receptor stimulation. This results in increased activation of the MAP and PI-3 kinase pathways via an IRS-1-independent mechanism. This leads to pathophysiologic changes such as increased vascular smooth muscle cell proliferation, angiogenesis, altered capillary permeability, and podocyte dysfunction. These changes may be important in the development of diabetic complications [34].

SUMMARY — Insulin-like growth factor 1 (IGF-1) is a small peptide that circulates in serum bound (more than 99 percent) to high-affinity binding proteins. IGF-1 is synthesized by multiple mesenchymal cell types. There are two major sources of IGF-1: circulating IGF-1 that is synthesized in liver and secreted into the blood, and autocrine/paracrine IGF-1 synthesized in peripheral tissues.

IGF-1 receptors – The IGF-1 receptor is the primary mediator of the physiologic actions of IGF-1. The IGF-1 receptor is present in multiple cell types and tissues, which probably accounts for the ability of IGF-1 to stimulate balanced, symmetric growth. Receptor number is regulated by growth hormone (GH) and thyroxine (T4) and is tightly controlled within a range of 20 to 35,000 receptors per cell. (See 'IGF-1 receptors' above.)

IGF-binding proteins – The IGF-binding proteins (IGFBPs) are a family of six high-affinity proteins whose affinities for IGF-1 and -2 are greater than the IGF-1 receptor. One or more members of this family are present in all extracellular fluids, and they control the ability of IGF-1 and -2 to bind to receptors. In most cases, less than 1 percent of the total IGF-1 in plasma is in an unbound state. (See 'IGF-binding proteins' above.)

Regulation of circulating IGF-1 – The liver is the source of most (75 percent) of plasma IGF-1. Variables that regulate synthesis and release by the liver, primarily GH, also regulate its plasma concentrations. Nutritional and thyroid status also affect plasma IGF-1. (See 'Regulation of circulating IGF-1' above.)

Regulation of tissue IGF-1 – IGF-1 is synthesized in peripheral tissues, as well as the liver, and peripheral tissue synthesis contributes to plasma concentrations. Its regulators are described above. (See 'Regulation of tissue IGF-1' above.)

Effects of IGF-1 in humans – IGF-1 therapy is effective (and approved for clinical use) in children with GH insensitivity due to GH receptor mutations, and in children with short stature and very low serum IGF-1. Other potential effects of IGF-1 administration are described above. (See 'Effects of IGF-1 administration to humans' above.)

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Topic 3801 Version 17.0

References

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