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 (IGF-1 and IGF-2), a family of six high-affinity IGF-binding proteins (IGFBP 1-6), as well as associated IGFBP degrading enzymes, referred to collectively as proteases.

IGF1/GH Axis
The IGF "axis" is also commonly referred to as the Growth Hormone/IGF1 Axis. Insulin-like growth factor 1 (IGF-1) 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) 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 known to cause variation in the levels of GH and IGF-1 in the circulation include an individuals genetic make-up, the time of day, their age, sex, exercise status, stress levels, genetics, nutrition level and body mass index (BMI), disease state, race, estrogen status and xenobiotic intake.

IGF-I 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 link to higher IQ.

IGF-1 shape 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).

IGF Receptors
The IGF's 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 "physiologic" 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 signalling pathways, functioning only as an IGF-2 sequestering agent and preventing IGF-2 signalling.

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 causes 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.

IGF-Binding Proteins
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 6 characterized IGF Binding Proteins (IGFBP1-6). There is currently significant data suggesting that IGFBPs play important roles in addition to their ability to regulate IGFs.

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 mammal, however, because in the smaller organism there are many genes (at least 37 in the nematode ) that are "insulin-like" or "IGF-1-like", whereas in the mammals insulin-like proteins comprise only 7 members (insulin, IGFs, relaxins, EPIL, and relaxin-like factor) and have apparently distinct roles with some but less crosstalk. On the other hand, simpler organisms typically have fewer receptors (only 1 known in the nematode) and the roles of these other insulins are unknown. Furthermore these animals do not have specialized organs (Islets of Langerhans), which sense insulin in response to glucose homeostasis. Therefore it is an open question as to whether either IGF1 or insulin in the mammal may perturb aging, although there is strong suggestion dietary restriction phenomena are 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.