Research Area

IGF Family


Overview

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

Members of IGF family

Table 1. IGF family related products

  • IGF-1

Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a protein that in humans is encoded by the IGF1 gene. IGF-1 has also been referred to as a "sulfation factor" and its effects were termed "nonsuppressible insulin-like activity" (NSILA) in the 1970s. IGF-1 is a hormone similar in molecular structure to insulin. It plays an important role in childhood growth and continues to have anabolic effects in adults. A synthetic analog of IGF-1, mecasermin, is used for the treatment of growth failure. IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges. IGF-1 has a molecular weight of 7,649 Daltons. 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).

Figure1. IGF1 protein

  • IGF-2

Insulin-like growth factor 2 (IGF-2) is one of three protein hormones that share structural similarity to insulin. The MeSH definition reads: "A well-characterized neutral peptide believed to be secreted by the liver and to circulate in the blood. It has growth-regulating, insulin-like and mitogenic activities. The growth factor has a major, but not absolute, dependence on somatotropin. It is believed to be a major fetal growth factor in contrast to Insulin-like growth factor 1, which is a major growth factor in adults". 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.

Cellular functions

IGF-1 is a primary mediator of the effects of growth hormone (GH). Growth hormone is made in the anterior pituitary gland, and is released into the blood stream, and then stimulates the liver to produce IGF-1. IGF-1 then stimulates systemic body growth, and has growth-promoting effects on almost every cell in the body, especially skeletal muscle, cartilage, bone, liver, kidney, nerves, skin, hematopoietic cell, 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-1 is one of the most potent natural activators of the AKT signaling pathway, a stimulator of cell growth and proliferation, and a potent inhibitor of programmed cell death.

The major role of IGF-2 is as a growth promoting hormone during gestation. In the process of folliculogenesis, IGF-2 is created by thecal cells to act in an autocrine manner on the theca cells themselves, and in a paracrine manner on granulosa cells in the ovary. IGF2 promotes granulosa cell proliferation during the follicular phase of the menstrual cycle, acting alongside follicle stimulating hormone (FSH). After ovulation has occurred, IGF-2 promotes progesterone secretion during the luteal phase of the menstrual cycle, together with luteinizing hormone (LH). Thus, IGF2 acts as a co-hormone together with both FSH and LH.

Role in disease

Rare diseases characterized by inability to make or respond to IGF-1 produce a distinctive type of growth failure. One such disorder, termed Laron dwarfism does not respond at all to growth hormone treatment due to a lack of GH receptors. The FDA has grouped these diseases into a disorder called severe primary IGF deficiency. Patients with severe primary IGFD typically present with normal to high GH levels, height below 3 standard deviations (SD), and IGF-1 levels below 3 SD. Severe primary IGFD includes patients with mutations in the GH receptor, post-receptor mutations or IGF mutations, as previously described. Patients with severe primary insulin-like growth factor-1 deficiency (IGFD), called Laron syndrome, may be treated with either IGF-1 alone or in combination with IGFBP-3. Mecasermin (brand name Increlex) is a synthetic analog of IGF-1 which is approved for the treatment of growth failure. IGF-1 has been manufactured recombinantly on a large scale using both yeast and E. coli. IGF-1 has been shown to be effective in animal models of stroke when combined with erythropoietin. Both behavioural and cellular improvements were found. Therapeutic administration of neurotrophic proteins (IGF-1) is associated with potential reversal of degeneration of spinal cord motor neuron axons in certain peripheral neuropathies.

A study at the Mount Sinai School of Medicine found that IGF-2 may be linked to memory and reproduction. A study at the European Neuroscience Institute-Goettingen (Germany) found that fear extinction-induced IGF2/IGFBP7 signalling promotes the survival of 17- to 19-day-old newborn hippocampal neurons. This suggests that therapeutic strategies that enhance IGF2 signalling and adult neurogenesis might be suitable to treat diseases linked to excessive fear memory such as PTSD. Doege-Potter syndrome is a paraneoplastic syndrome in which hypoglycemia is associated with the presence of one or more non-islet fibrous tumors in the pleural cavity. Loss of imprinting of IGF2 is a common feature in tumors seen in Beckwith-Wiedemann syndrome. As IGF2 promotes development of fetal pancreatic beta cells, it is believed to be related to some forms of diabetes mellitus. Preeclampsia induces a decrease in methylation level at IGF2 demethylated region, and this might be among the mechanisms behind the association between intrauterine exposure to preeclampsia and high risk for metabolic diseases in the later life of the infants.

References:

  1. Cohen P, Peehl DM, Lamson G, Rosenfeld RG (1991). "Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins in primary cultures of prostate epithelial cells". Journal of Clinical Endocrinology and Metabolism. 73 (2): 401–7.
  2. Woods AG, Guthrie KM, Kurlawalla MA, Gall CM (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.
  3. 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. 36 (2–3): 119–218.

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