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.