IGFs, which are hormones involved in regulating cellular proliferation, differentiation, and metabolism, resemble insulin in both structure and function. There are two hormones in this family, IGF-I and IGF-II, which are produced in various tissues and have autocrine, paracrine, and endocrine actions. IGF-I is the primary form found in most adult tissues, while IGF-II is mainly produced in the fetus and plays a role in regulating the growth of both the fetus and the placenta independently of GH. Both IGF-I and IGF-II have a similar structure to proinsulin, with IGF-I sharing 42% structural homology with proinsulin. It is worth noting that IGFs and insulin have receptor cross-reactivity, and high concentrations of IGFs can mimic the metabolic actions of insulin. Both IGF-I and IGF-II interact with type I IGF receptors, which have similarities to insulin and epidermal growth factor (EGF) receptors and possess intrinsic tyrosine kinase activity. However, IGF-II also binds to the type II IGF/mannose-6-phosphate receptor, which differs from the insulin receptor and lacks intrinsic tyrosine kinase activity. The type II receptor likely functions to restrict IGF-II signaling through the type I receptor. IGFs promote glucose and amino acid uptake, as well as protein and DNA synthesis. Originally referred to as somatomedins due to their growth-mediating effects on cartilage, bone, and other organs, IGFs are now known to be produced in various extrahepatic tissues and exert both autocrine and paracrine actions. While some of these actions are under the control of GH, others are not. In the case of bone, for example, IGF-I has both endocrine and paracrine effects on linear growth, some of which do not depend on GH. Other hormones such as parathyroid hormone (PTH) and estradiol also stimulate IGF-I production by osteoblasts. Additionally, GH has stimulating effects on the growth plate that are independent of IGF-I. The liver is considered the main source of the circulating pool of IGF-I, and nearly all circulating IGFs bind to IGF binding proteins (IGFBP) in the serum. IGFBP-3 specifically binds to IGF and associates with another protein called the acid labile subunit (ALS). GH stimulates the liver to produce IGF-I, IGFBP-3, and ALS. The complex formed by IGFBP-3/ALS/IGF-I facilitates the transport and availability of IGF-I. Although IGFBPs generally inhibit the actions of IGFs, they significantly increase the biological half-life of IGFs, extending it up to 12 hours. There are also IGFBP proteases that degrade IGFBPs and play a role in generating free (active) IGFs locally. This is particularly relevant in the context of IGF-responsive cancers, such as prostate cancer, where one or more IGFBP proteases may be overexpressed. GH has a dual role in metabolism that heavily depends on the physiological context. Simplistically, its dual roles are to promote growth and protein anabolism when there is favorable nutritional status and to switch fuel consumption to lipids, while sparing glucose in the fasted state.
IGFs are multifunctional hormones that regulate cellular proliferation, differentiation, and metabolism. These protein hormones resemble insulin in structure and function. The two hormones in this family, IGF-I and IGF-II, are produced in many tissues and have autocrine, paracrine, and endocrine actions. IGF-I is the major form produced in most adult tissues. IGF-II is the major form produced in the fetus, where it regulates growth of both the fetus and the placenta in a GH-independent manner. Both hormones are structurally similar to proinsulin, with IGF-I exhibiting 42% structural homology with proinsulin. IGFs and insulin show receptor cross-reactivity; IGFs in high concentration mimic the metabolic actions of insulin. Both IGF-I and IGF-II act through type I IGF receptors, which are similar to insulin and epidermal growth factor (EGF) receptors and contain intrinsic tyrosine kinase activity. However, IGF-II also binds to the type II IGF/mannose-6-phosphate receptor. This receptor does not resemble the insulin receptor, does not have intrinsic tyrosine kinase activity, and probably functions to limit IGF-II signaling through the type I receptor. IGFs stimulate glucose and amino acid uptake and protein and DNA synthesis. They were initially called somatomedins because of their growth-mediating actions on cartilage, bone, and other organs. It was originally proposed that IGF-I is produced exclusively in the liver upon GH stimulation. During puberty, when GH levels increase (
Fig. 41.19 ), IGF-I levels increase in parallel. However, it is now known that IGFs are produced in many extrahepatic tissues, exhibiting both autocrine and paracrine actions. Some of these are under the control of GH, whereas others are not. In bone, for example, IGF-I has both endocrine and paracrine effects on linear growth, some of which are GH independent. Hormones such as parathyroid hormone (PTH) and estradiol are also effective stimuli for IGF-I production by osteoblasts. At the same time, GH exerts stimulatory effects on the growth plate that are independent of IGF-I. The liver appears to be the predominant source of the circulating pool of IGF-I (see
Fig. 41.19 •Fig. 41.18 LifetimepatternofGHsecretion.GHlevelsarehigherinchildrenthaninadults,withapeakperiodduringpuberty.GHsecretiondeclineswithaging.
Essentially all circulating IGFs are transported in serum bound to IGF binding proteins (IGFBP). IGFBP-3 binds to IGF then associates with another protein called the acid labile subunit (ALS) (see
Fig. 41.19 ). GH stimulates hepatic production of IGF-I, IGFBP-3, and ALS. The IGFBP-3/ALS/IGF-I complex mediates transport and bioavailability of IGF-I. Although IGFBPs generally inhibit IGF action, they greatly increase the biological half-life of IGFs (up to 12 hours). IGFBP proteases degrade IGFBP and play a role in locally generating free (i.e., active) IGFs. This is of interest in the context of IGF-responsive cancers (e.g., prostate cancer), which may overexpress one or more IGFBP proteases.
GH plays a dual role in metabolism that is highly dependent on physiological context. At the risk of oversimplification, its dual roles are to: (1) promote growth and protein anabolism when nutritional status is favorable, and (2) switch fuel consumption to lipids, sparing glucose in the fasted state.