Theinsulin-like growth factors (IGFs) areproteins with highsequence similarity toinsulin. IGFs are part of acomplex system that cells use to communicate with theirphysiologic environment. This complex system (often referred to as the IGF "axis") consists of twocell-surface receptors (IGF1R andIGF2R), twoligands (IGF-1 andIGF-2), a family of seven high-affinityIGF-binding proteins (IGFBP1 toIGFBP7), as well as associatedIGFBP degradingenzymes, referred to collectively asproteases.
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 usingRoman numerals as IGF-I) is mainly secreted by the liver as a result of stimulation bygrowth hormone (GH). IGF-1 is important for both the regulation of normal physiology, as well as a number of pathological states, includingcancer. The IGF axis has been shown to play roles in the promotion ofcell proliferation and the inhibition ofcell death (apoptosis).
Insulin-like growth factor 2 (IGF-2, at times IGF-II) is thought to be a primarygrowth factor required for early development whileIGF-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 primarilyfetal in action it is also essential for development and function of organs such as thebrain,liver, andkidney.[1]
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, andxenobiotic intake.[2][3][4]
IGF-1 has an involvement in regulatingneural development includingneurogenesis,myelination,synaptogenesis, anddendritic branching andneuroprotection after neuronal damage. Increased serum levels of IGF-I in children have been associated with higherIQ.[5]
IGF-1 shapes the development of thecochlea through controllingapoptosis. Its deficit can causehearing loss. Serum level of it also underlies a correlation between shortheight and reduced hearing abilities particularly around 3–5 years of age, and at age 18 (latepuberty).[6]
The IGFs are known to bind theIGF-1 receptor, theinsulin receptor, theIGF-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 areceptor 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.[7]
Since many distinct tissue types express the IGF-1 receptor, IGF-1's effects are diverse. It acts as aneurotrophic factor, inducing the survival of neurons. It may catalyseskeletal musclehypertrophy, by inducingprotein synthesis, and by blockingmuscle atrophy. It is protective forcartilage cells, and is associated with activation ofosteocytes, and thus may be an anabolic factor forbone. Since at high concentrations it is capable of activating theinsulin receptor, it can also complement for the effects ofinsulin.[8] Receptors for IGF-1 are found in vascular smooth muscle, while typical receptors for insulin are not found in vascular smooth muscle.[9]
IGF-1 and IGF-2 are regulated by a family of proteins known as theIGF-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.[10]
Studies of recent interest show that the Insulin/IGF axis play an important role inaging.[11]Nematodes,fruit-flies, and other organisms have an increased life span when the gene equivalent to the mammalian insulin isknocked out. It is somewhat difficult to relate this finding to mammals, however, because there are many genes (at least 37 in the nematodeCaenorhabditis elegans[12]) in smaller organisms that are "insulin-like" or "IGF-1-like", whereas in mammals insulin-like proteins comprise only seven members (insulin, IGFs,relaxins, EPIL, and relaxin-like factor).[13] 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 nematodeC. elegans.[14] 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 causingdauer formation, a developmental stage ofC. 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.[15]
Other studies are beginning to uncover the important role the IGFs play in diseases such ascancer anddiabetes, 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.[16]