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production in liver and epiphyseal growth plates. Epiphyseal growth is stimulated primarily by autocrine/paracrine actions of IGF-I. Hepatic production of IGF-I stimulates circumferential growth of bone and acts primarily as a negative feedback regulator of GH secretion. Liver is the principal source of IGF-I in blood, but other GH target organs may also contribute a small amount to the circulating pool. Dashed arrow indicates inhibition.

production in liver and epiphyseal growth plates. Epiphyseal growth is stimulated primarily by autocrine/paracrine actions of IGF-I. Hepatic production of IGF-I stimulates circumferential growth of bone and acts primarily as a negative feedback regulator of GH secretion. Liver is the principal source of IGF-I in blood, but other GH target organs may also contribute a small amount to the circulating pool. Dashed arrow indicates inhibition.

relationship between GH and IGF-I is summarized in Fig. 5. GH acts directly on both the liver and its peripheral target tissues to promote IGF-I production. Liver is the principal source of IGF in blood, but target tissues also make some contributions. Stimulation of growth at the epiphyses is provided primarily by locally produced IGF-I acting in an autocrine/paracrine manner, while IGF-I produced in liver contributes to periosteal growth. The additional role of bloodborne IGF is regulation of GH secretion.

Properties of the Insulin-Like Growth Factors

Insulin-like growth factor I and II are small unbranched peptides that have molecular masses of about 7500 Da. They are encoded in separate genes and are expressed in a wide variety of cells. Their protein structures are very similar to each other and to proinsulin (see Chapter 41) both in terms of amino acid sequence and in the arrangement of disulfide bonds. The IGFs share about 50% amino acid identity with insulin. In contrast to insulin, however, the region corresponding to the connecting peptide is retained in the mature form of the IGFs which also have a C-terminal extension. Both IGF-I and IGF-II are present in blood throughout life but their concentrations differ at different stages of life.

Two receptors for the IGFs have been identified. The IGF-I receptor, which binds IGF-I with greater affinity than IGF-II, is remarkably similar to the insulin receptor and signals in a similar manner. The IGF-II receptor is structurally unrelated to the IGF-I receptor and binds IGF-II with a very much higher affinity than IGF-I. It consists of a single membrane-spanning protein with a short cytosolic domain that is thought to lack signaling capabilities. Curiously, the IGF-II receptor is identical to the mannose-6-phosphate receptor that binds mannose-6-phosphate groups on newly synthesized lysosomal enzymes and transfers them from the trans-Golgi vesicles to the endosomes and then to lysosomes. It may also transfer mannose-6-phosphate-containing glycoproteins from the extracellular fluid to the lysosomes by an endo-cytotic process. The IGF-II receptor likely plays an important role in clearing IGF-II from extracellular fluids.

The IGFs circulate in blood tightly bound to IGF binding proteins (IGFBPs). Six different IGFBPs, each the product of a separate gene, are found in mammalian plasma and extracellular fluids. Their affinities for both IGF-I and IGF-II are considerably higher than the affinity of the IGF-I receptor for either IGF-I or IGF-II. The combined binding capacity of all the IGFBPs in plasma is about twice the concentration of the IGFs, so that less than 1% of the IGFs are free. IGFBP-3, the synthesis of which is stimulated by GH, IGF-I, and insulin, is the most abundant form and is complexed with most of the IGF-I and IGF-II in plasma. The IGFBP-3 and its cargo of IGFs form a large 150-kDa ternary complex with a third protein, the so-called acid-labile subunit (ALS), the synthesis of which is also stimulated by GH. Consequently, the concentrations of both proteins are quite low in the blood of GH-deficient subjects and increase upon treatment with GH. The remainder of the IGFs in plasma are distributed among the other IGFBPs that do not bind to ALS and hence form complexes of about 50-kDa which are small enough to escape across the capillary endothelium. Of these, IGFBP-2 is the most important quantitatively. Its concentration in blood is increased in plasma of GH-deficient patients and is decreased by GH but rises dramatically after administration of IGF-I.

Normally, the binding capacity of IGFBP-3 is saturated, while the other IGFBPs have free binding sites. Consequently, the IGFs do not readily escape from the vascular compartment and have a half-life in blood of about 15 hours. Proteolytic "clipping" of IGFBP-3 by proteases present in plasma lowers its binding affinity and releases IGF-I, which may then form a lower molecular weight complex with other IGFBPs, which may then deliver it to the extracellular fluid. The major functions of the IGF binding proteins in blood are to provide a plasma reservoir of IGF-I and IGF-II, to slow their degradation, and to regulate their bioavailability.

The IGFBPs are synthesized locally in conjunction with IGF in a wide variety of cells and are widely distributed in extracellular fluid. Their biology is complex and not completely understood. It may be recalled that the IGFs mediate localized growth in response to a variety of signals in addition to GH. A wide variety of cells both produce and respond to IGF-I, which is a small and readily diffusible molecule. The IGFBPs may provide a means of restricting cell growth to the extent and location dictated by physiological demand. Because their affinity for both IGFs is so much greater than the affinity of the IGF-I receptor, the IGFBPs can successfully compete with the IGF-I receptor for binding free IGF and thus restrict their bioavailability. Conversely, the IGFBPs have also been found to enhance the actions of IGF-I. Some of the IGFBPs bind to extracellular matrices, where they may provide a local reservoir of growth factors that might be released by proteolytic modification of the binding or matrix proteins. Binding to the cell surface lowers the affinity of some of the binding proteins for the growth factor and thus provides a means of targeted delivery of IGF-I to receptive cells. In this way, the IGFBPs provide a means of specific tissue or cellular localization of the IGFs. Some evidence also suggests that IGFBPs may produce biological effects that are independent of the IGFs.

Effects of GH/IGF-I on Body Composition

Growth-hormone-deficient animals and human subjects have a relatively high proportion of fat, compared to water and protein, in their bodies. Treatment with GH changes the proportion of these bodily constituents to resemble the normal juvenile distribution. Body protein stores increase, particularly in muscle, accompanied by a relative decrease in fat. Despite their relatively higher fat content, subjects who are congenitally deficient in GH or are unresponsive to it actually have fewer total adipo-cytes than normal individuals. Their adiposity is due to an increase in the amount of fat stored in each cell. GH increases the proliferation of fat cell precursors through autocrine stimulation by IGF-I secretion by adipocyte precursor cells and can restore normal cellularity. Curiously, however, GH also restrains the differentiation of fat cell precursors into mature adipocytes. The overall decrease in body fat produced by GH results from decreased deposition of fat and accelerated fat mobilization and increased reliance of fat for energy production (see Chapter 42).

Most internal organs grow in proportion to body size, except liver and spleen, which may be disproportionately enlarged by prolonged treatment with GH. The heart may also be enlarged in acromegalic subjects in part from hypertension, which is frequently seen in these individuals, and in part from stimulation of cardiac myocyte growth by GH-induced IGF-I production. Conversely, GH deficiency beginning in childhood is associated with decreased myocardial mass due to decreased thickness of the ventricular walls. Treatment of these individuals leads to increased myocardial mass and performance. Skin and the underlying connective tissue also increase in mass, but GH does not appear to influence growth of the thyroid, gonads, or reproductive organs.

Changes in body composition and organ growth have been monitored by studying changes in the biochemical balance of body constituents (Fig. 6). When human subjects or experimental animals are given GH repeatedly for several days, there is net retention of nitrogen, reflecting increased protein synthesis. Urinary nitrogen is decreased, as is the concentration of urea in blood. Net synthesis of protein is increased without an accompanying change in the net rates of protein degradation. Increased retention of potassium reflects the increase in intracellular water that results from increased size and number of cells. An increase in sodium retention and the consequent expansion of extracellular volume are characteristic of GH replacement and may result from activation of sodium channels in the distal portions of the nephron. Increased phosphate retention reflects expansion of the cellular and skeletal mass and is brought about in part by activation of sodium phosphate cotransporters in the proximal tubules and activation of the 1 a-hydroxylase that catalyzes production of calcitriol (Chapter 43).

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