Insulin-like growth factor

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-632-7753

Overview

The insulin-like growth factors (IGFs) are polypeptides 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 (hGH). IGF1 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). IGF-II is thought to be a primary growth factor required for early development while IGF-I 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 intake⁴. The later inclusion of xenobiotic intake as a factor influencing GH-IGF status highlights the fact that the GH-IGF axis is a potential target for certain endocrine disrupting chemicals - see also endocrine disruptor.

IGF Targets

Almost every cell in the human body is affected by IGF-1, especially cells in muscle, cartilage, bone, liver, kidney, nerves, skin, and lungs. In addition to the insulin-like effects, IGF-1 can also regulate cell growth and development, especially in nerve cells, as well as cellular DNA synthesis.

IGF-2 is secreted by the brain, kidney, pancreas and muscle in mammals. It is more specific in action than IGF-1. In adult humans it is found at 600 times the concentration of insulin.

IGF Receptors

Further work is required to determine the main receptors used by these growth factors to elicit their effects. The IGF's are known to bind the IGF-1 receptor, the insulin receptor, the IGF-2 receptor, the insulin-related receptor and possible other receptors. The IGF-1 receptor seems to be the "physiologic" receptor - it binds IGF-1 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.

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 aging². 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 lower 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 relatively less crosstalk. On the other hand, lower organisms typically have fewer receptors (only 1 known in the nematode), and the roles of these other insulins are unknown. Furthermore lower 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^1,3,4. Researchers are not in complete agreement about the degree of cancer risk that IGF-1 poses.

See also

• Insulin-like growth factor 1
• Insulin-like growth factor 2
• Growth hormone treatment
• HGH controversies

References

1. Cohen, Pinchas, et al. "Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins in primary cultures of prostate epithelial". Journal of Clinical Endocrinology and Metabolism, Vol. 73, No. 2, 1991, pp. 401-07
2. F. Yaghmaie, O. Saeed, S.A. Garan, M.A. Voelker, A.M. Gouw, W. Freitag, H. Sternberg and P.S. Timiras "Age-dependent loss of insulin-like growth factor-1 receptor immunoreactive cells in the supraoptic hypothalamus is reduced in calorically restricted mice". International Journal of Developmental Neuroscience, Vol. 24, Issue 7, 2006, pp. 431-436
3. Lippman, Marc E. "The development of biological therapies for breast cancer". Science, Vol. 259, January 29, 1993, pp. 631-32
4. Papa, Vincenzo, et al. "Insulin-like growth factor-I receptors are overexpressed and predict a low risk in human breast cancer". Cancer Research, Vol. 53, 1993, pp. 3736-40
5. Scarth, J "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, Vol. 36, (2-3) pp. 119-218
6. Woods, Alisa G. "Deafferentation-induced increases in hippocampal insulin-like growth factor-1 messenger RNA expression are severely attenuated in middle aged and aged rats." Neuroscience, Vol. 83, (3) pp. 663-668