Insulin-like growth factor
The insulin-like growth factors (IGFs) are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment. This complex system (often referred to as the IGF "axis") consists of two cell-surface receptors (IGF1R and IGF2R), two ligands (Insulin-like growth factor 1 (IGF-1) and Insulin-like growth factor 2 (IGF-2)), a family of seven high-affinity IGF-binding proteins (IGFBP1 to IGFBP7), as well as associated IGFBP degrading enzymes, referred to collectively as proteases.
The IGF "axis" is also commonly referred to as the Growth Hormone/IGF-1 Axis. Insulin-like growth factor 1 (commonly referred to as IGF-1 or at times using Roman numerals as IGF-I) is mainly secreted by the liver as a result of stimulation by growth hormone (GH). IGF-1 is important for both the regulation of normal physiology, as well as a number of pathological states, including cancer. The IGF axis has been shown to play roles in the promotion of cell proliferation and the inhibition of cell death (apoptosis). Insulin-like growth factor 2 (IGF-2, at times IGF-II) is thought to be a primary growth factor required for early development while IGF-1 expression is required for achieving maximal growth. Gene knockout studies in mice have confirmed this, though other animals are likely to regulate the expression of these genes in distinct ways. While IGF-2 may be primarily fetal in action it is also essential for development and function of organs such as the brain, liver, and kidney.
Factors that are thought to cause variation in the levels of GH and IGF-1 in the circulation include an individual's genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level, body mass index (BMI), disease state, race, estrogen status, and xenobiotic intake.
IGF-1 has an involvement in regulating neural development including neurogenesis, myelination, synaptogenesis, and dendritic branching and neuroprotection after neuronal damage. Increased serum levels of IGF-I in children have been associated with higher IQ.
IGF-1 shapes the development of the cochlea through controlling apoptosis. Its deficit can cause hearing loss. Serum level of it also underlies a correlation between short height and reduced hearing abilities particularly around 3–5 years of age, and at age 18 (late puberty).
The IGFs are known to bind the IGF-1 receptor, the insulin receptor, the IGF-2 receptor, the insulin-related receptor and possibly other receptors. The IGF-1 receptor is the "physiological" receptor—IGF-1 binds to it at significantly higher affinity than it binds the insulin receptor. Like the insulin receptor, the IGF-1 receptor is a receptor tyrosine kinase—meaning the receptor signals by causing the addition of a phosphate molecule on particular tyrosines. The IGF-2 receptor only binds IGF-2 and acts as a "clearance receptor"—it activates no intracellular signaling pathways, functioning only as an IGF-2 sequestering agent and preventing IGF-2 signaling.
Organs and tissues affected by IGF-1
Since many distinct tissue types express the IGF-1 receptor, IGF-1's effects are diverse. It acts as a neurotrophic factor, inducing the survival of neurons. It may catalyse skeletal muscle hypertrophy, by inducing protein synthesis, and by blocking muscle atrophy. It is protective for cartilage cells, and is associated with activation of osteocytes, and thus may be an anabolic factor for bone. Since at high concentrations it is capable of activating the insulin receptor, it can also complement for the effects of insulin. Receptors for IGF-1 are found in vascular smooth muscle, while typical receptors for insulin are not found in vascular smooth muscle.
IGF-1 and IGF-2 are regulated by a family of proteins known as the IGF-binding proteins. These proteins help to modulate IGF action in complex ways that involve both inhibiting IGF action by preventing binding to the IGF-1 receptor as well as promoting IGF action possibly through aiding in delivery to the receptor and increasing IGF half-life. Currently, there are seven characterized IGF Binding Proteins (IGFBP1 to IGFBP7). There is currently significant data suggesting that IGFBPs play important roles in addition to their ability to regulate IGFs. IGF-1 and IGFBP-3 are GH dependent, whereas IGFBP-1 is insulin regulated. IGFBP-1 production from the liver is significantly elevated during insulinopenia while serum levels of bioactive IGF-1 is increased by insulin.
Diseases affected by IGF
Studies of recent interest show that the Insulin/IGF axis play an important role in aging. Nematodes, fruit-flies, and other organisms have an increased life span when the gene equivalent to the mammalian insulin is knocked out. It is somewhat difficult to relate this finding to the mammals, however, because in the smaller organism there are many genes (at least 37 in the nematode Caenorhabditis elegans) that are "insulin-like" or "IGF-1-like", whereas in the mammals insulin-like proteins comprise only seven members (insulin, IGFs, relaxins, EPIL, and relaxin-like factor). The human insulin-like genes have apparently distinct roles with some but less crosstalk presumably because there are multiple insulin-receptor-like proteins in humans. Simpler organisms typically have fewer receptors; for example, only one insulin-like receptor exists in the nematode C. elegans. Additionally, C. elegans do not have specialized organs such as the (Islets of Langerhans), which sense insulin in response to glucose homeostasis. Moreover, IGF1 affects lifespan in nematodes by causing dauer formation, a developmental stage of C. elegans larva. There is no mammalian correlate. Therefore, it is an open question as to whether either IGF-1 or insulin in the mammal may perturb aging, although there is the suggestion that dietary restriction phenomena may be related.
Other studies are beginning to uncover the important role the IGFs play in diseases such as cancer and diabetes, showing for instance that IGF-1 stimulates growth of both prostate and breast cancer cells. Researchers are not in complete agreement about the degree of cancer risk that IGF-1 poses.[excessive citations]
- Younis, Shady (February 27, 2018). "The ZBED6–IGF2 axis has a major effect on growth of skeletal muscle and internal organs in placental mammals". PNAS. 9 (115): E2048–E2057. doi:10.1073/pnas.1719278115. PMC 5834713. PMID 29440408.
- Takahashi Y, Kipnis DM, Daughaday WH (September 1968). "Growth hormone secretion during sleep". The Journal of Clinical Investigation. 47 (9): 2079–90. doi:10.1172/JCI105893. PMC 297368. PMID 5675428.
- Giustina A, Mazziotti G, Canalis E (August 2008). "Growth hormone, insulin-like growth factors, and the skeleton". Endocrine Reviews. 29 (5): 535–59. doi:10.1210/er.2007-0036. PMC 2726838. PMID 18436706.
- Sutton J, Lazarus L (October 1976). "Growth hormone in exercise: comparison of physiological and pharmacological stimuli". Journal of Applied Physiology. 41 (4): 523–7. doi:10.1152/jappl.19188.8.131.523. PMID 985395.
- Gunnell D, Miller LL, Rogers I, Holly JM (November 2005). "Association of insulin-like growth factor I and insulin-like growth factor-binding protein-3 with intelligence quotient among 8- to 9-year-old children in the Avon Longitudinal Study of Parents and Children". Pediatrics. 116 (5): e681-6. doi:10.1542/peds.2004-2390. PMID 16263982.
- Welch D, Dawes PJ (October 2007). "Childhood hearing is associated with growth rates in infancy and adolescence". Pediatric Research. 62 (4): 495–8. doi:10.1203/PDR.0b013e3181425869. PMID 17667854.
- Boucher, Jeremie; Tseng, Yu-Hua; Kahn, C. Ronald (2010-05-28). "Insulin and Insulin-like Growth Factor-1 Receptors Act as Ligand-specific Amplitude Modulators of a Common Pathway Regulating Gene Transcription". The Journal of Biological Chemistry. 285 (22): 17235–17245. doi:10.1074/jbc.M110.118620. ISSN 0021-9258. PMC 2878077. PMID 20360006.
- Bornfeldt KE, Arnqvist HJ, Dahlkvist HH, Skottner A, Wikberg JE (April 1988). "Receptors for insulin-like growth factor-I in plasma membranes isolated from bovine mesenteric arteries". Acta Endocrinologica. 117 (4): 428–34. doi:10.1530/acta.0.1170428. PMID 2968745.
- Kenyon CJ (March 2010). "The genetics of ageing". Nature. 464 (7288): 504–12. Bibcode:2010Natur.464..504K. doi:10.1038/nature08980. PMID 20336132. S2CID 2781311.
- Pierce SB, Costa M, Wisotzkey R, Devadhar S, Homburger SA, Buchman AR, et al. (March 2001). "Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family". Genes & Development. 15 (6): 672–86. doi:10.1101/gad.867301. PMC 312654. PMID 11274053.
- Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G (August 1997). "daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans". Science. 277 (5328): 942–6. doi:10.1126/science.277.5328.942. PMID 9252323.
- Cohen P, Peehl DM, Lamson G, Rosenfeld RG (August 1991). "Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins in primary cultures of prostate epithelial cells". The Journal of Clinical Endocrinology and Metabolism. 73 (2): 401–7. doi:10.1210/jcem-73-2-401. PMID 1713219.
- Lippman ME (January 1993). "The development of biological therapies for breast cancer". Science. 259 (5095): 631–2. Bibcode:1993Sci...259..631L. doi:10.1126/science.8430312. PMID 8430312. S2CID 36985249.
- Papa V, Gliozzo B, Clark GM, McGuire WL, Moore D, Fujita-Yamaguchi Y, et al. (August 1993). "Insulin-like growth factor-I receptors are overexpressed and predict a low risk in human breast cancer". Cancer Research. 53 (16): 3736–40. PMID 8339284.
- Scarth JP (2006). "Modulation of the growth hormone-insulin-like growth factor (GH-IGF) axis by pharmaceutical, nutraceutical and environmental xenobiotics: an emerging role for xenobiotic-metabolizing enzymes and the transcription factors regulating their expression. A review". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 36 (2–3): 119–218. doi:10.1080/00498250600621627. PMID 16702112. S2CID 40503492.
- Woods AG, Guthrie KM, Kurlawalla MA, Gall CM (April 1998). "Deafferentation-induced increases in hippocampal insulin-like growth factor-1 messenger RNA expression are severely attenuated in middle aged and aged rats". Neuroscience. 83 (3): 663–8. doi:10.1016/S0306-4522(97)00539-3. PMID 9483550. S2CID 208782267.
- Rowlands MA, Holly JM, Gunnell D, Donovan J, Lane JA, Hamdy F, et al. (January 2012). "Circulating insulin-like growth factors and IGF-binding proteins in PSA-detected prostate cancer: the large case-control study ProtecT". Cancer Research. 72 (2): 503–15. doi:10.1158/0008-5472.CAN-11-1601. PMC 3272440. PMID 22106399.