Insulin-like growth factor 1

Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a is_associated_with::protein that in humans is encoded by the IGF1 is_associated_with::gene. IGF-1 has also been referred to as a "is_associated_with::sulfation factor" and its effects were termed "nonsuppressible insulin-like activity" (NSILA) in the 1970s.

IGF-1 is a is_associated_with::hormone similar in molecular structure to is_associated_with::insulin. It plays an important role in childhood growth and continues to have anabolic effects in adults. A synthetic analog of IGF-1, is_associated_with::mecasermin,  is used for the treatment of is_associated_with::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.

Synthesis and circulation
IGF-1 is produced primarily by the is_associated_with::liver as an is_associated_with::endocrine hormone as well as in target tissues in a paracrine/autocrine fashion. Production is stimulated by is_associated_with::growth hormone (GH) and can be retarded by undernutrition, growth hormone insensitivity, lack of growth hormone receptors, or failures of the downstream signalling pathway post GH receptor including SHP2 and is_associated_with::STAT5B. Approximately 98% of IGF-1 is always bound to one of 6 binding proteins (IGF-BP). IGFBP-3, the most abundant protein, accounts for 80% of all IGF binding. IGF-1 binds to IGFBP-3 in a 1:1 molar ratio.IGFBP-1 is regulated by insulin.

IGF-1 is produced throughout life. The highest rates of IGF-1 production occur during the pubertal growth spurt. The lowest levels occur in infancy and old age.

Protein intake increases IGF-1 levels in humans, independent of total calorie consumption. Factors that are known to cause variation in the levels of is_associated_with::growth hormone (GH) and IGF-1 in the circulation include: insulin levels, genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, race, estrogen status and is_associated_with::xenobiotic intake.

Fasting, including is_associated_with::intermittent fasting, can reduce IGF-1 levels rapidly and dramatically. It may be, however, that fasting increases IGF-1 levels because fasting causes very low blood sugar, which in turn stimulates the release of growth hormone by the pituitary, which in turn increases IGF-1.

Mechanism of action
Its primary action is mediated by binding to its specific receptor, the is_associated_with::insulin-like growth factor 1 receptor (IGF1R), which is present on many cell types in many tissues. Binding to the IGF1R, a is_associated_with::receptor tyrosine kinase, initiates intracellular signaling; IGF-1 is one of the most potent natural activators of the is_associated_with::AKT signaling pathway, a stimulator of cell growth and proliferation, and a potent inhibitor of programmed cell death. IGF-1 binds to at least two cell surface receptors: the is_associated_with::IGF-1 receptor (IGF1R), and the is_associated_with::insulin receptor. The is_associated_with::IGF-1 receptor seems to be the "physiologic" receptor – it binds IGF-1 at significantly higher affinity than the IGF-1 that is bound to the insulin receptor. Like the insulin receptor, the IGF-1 receptor is a receptor is_associated_with::tyrosine kinase – meaning it signals by causing the addition of a phosphate molecule on particular tyrosines. IGF-1 activates the insulin receptor at approximately 0.1 times the potency of  insulin. Part of this signaling may be via IGF1R/Insulin Receptor heterodimers (the reason for the confusion is that binding studies show that IGF1 binds the insulin receptor 100-fold less well than insulin, yet that does not correlate with the actual potency of IGF1 in vivo at inducing phosphorylation of the insulin receptor, and hypoglycemia).

IGF-1 is a primary mediator of the effects of is_associated_with::growth hormone (GH). Growth hormone is made in the is_associated_with::anterior pituitary gland, is released into the blood stream, and then stimulates the is_associated_with::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 is_associated_with::muscle, is_associated_with::cartilage, is_associated_with::bone, is_associated_with::liver, is_associated_with::kidney, is_associated_with::nerves, is_associated_with::skin, is_associated_with::hematopoietic cell, and is_associated_with::lungs. In addition to the is_associated_with::insulin-like effects, IGF-1 can also regulate is_associated_with::cell growth and development, especially in nerve cells, as well as cellular is_associated_with::DNA synthesis.

Insulin-like growth factor 1 receptor (IGF-1R) and other tyrosine kinase growth factor receptors signal through multiple pathways. A key pathway is regulated by phosphatidylinositol-3 kinase (PI3K) and its downstream partner, the mammalian target of rapamycin (mTOR). Rapamycins complex with FKBPP12 to inhibit the mTORC1 complex. mTORC2 remains unaffected and responds by upregulating Akt, driving signals through the inhibited mTORC1. Phosphorylation of eukaryotic initiation factor 4e (eif-4E) [4EBP] by mTOR inhibits the capacity of 4EBP to inhibit eif-4E and slow metabolism.

Insulin-like growth factor 1 has been shown to bind and interact with all the IGF-1 binding proteins (IGFBPs), of which there are seven: is_associated_with::IGFBP1, is_associated_with::IGFBP2, is_associated_with::IGFBP3, is_associated_with::IGFBP4, is_associated_with::IGFBP5, is_associated_with::IGFBP6, and is_associated_with::IGFBP7. Some IGFBPs are inhibitory. For example, both IGFBP-2 and IGFBP-5 bind IGF-1 at a higher affinity than it binds its receptor. Therefore, increases in serum levels of these two IGFBPs result in a decrease in IGF-1 activity.

Related growth factors
IGF-1 is closely related to a second protein called "IGF-2". IGF-2 also binds the IGF-1 receptor. However, IGF-2 alone binds a receptor called the "IGF-2 receptor" (also called the mannose-6 phosphate receptor). The insulin-like growth factor-II receptor (IGF2R) lacks signal transduction capacity, and its main role is to act as a sink for IGF-2 and make less IGF-2 available for binding with IGF-1R. As the name "insulin-like growth factor 1" implies, IGF-1 is structurally related to insulin, and is even capable of binding the insulin receptor, albeit at lower affinity than insulin.

A is_associated_with::splice variant of IGF-1 sharing an identical mature region, but with a different E domain is known as mechano-growth factor (MGF).

Dwarfism
Rare diseases characterized by inability to make or respond to IGF-1 produce a distinctive type of growth failure. One such disorder, termed is_associated_with::Laron dwarfism does not respond at all to is_associated_with::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. As a result, these patients cannot be expected to respond to GH treatment.

People with Laron syndrome have strikingly low rates of cancer and is_associated_with::diabetes.

Acromegaly
is_associated_with::Acromegaly is s a is_associated_with::syndrome that results when the is_associated_with::anterior pituitary gland produces excess is_associated_with::growth hormone (GH). A number of disorders may increase the pituitary's GH output, although most commonly it involves a tumor called is_associated_with::pituitary adenoma, derived from a distinct type of cell (is_associated_with::somatotrophs). It leads to anatomical changes and metabolic dysfunction caused by elevated GH and insulin-like growth factor I (IGF-I) levels.

Diagnostic test
IGF-1 levels can be measured in the blood in 10-1000 ng/ml amounts. As levels do not fluctuate greatly throughout the day for an individual person, IGF-1 is used by physicians as a is_associated_with::screening test for is_associated_with::growth hormone deficiency and excess in is_associated_with::acromegaly and is_associated_with::gigantism.

Interpretation of IGF-1 levels is complicated by the wide normal ranges, and marked variations by age, sex, and pubertal stage. Clinically significant conditions and changes may be masked by the wide normal ranges. Sequential management over time is often useful for the management of several types of pituitary disease, undernutrition, and growth problems.

As a therapeutic agent
Patients with severe primary insulin-like growth factor-1 deficiency (IGFD) may be treated with either IGF-1 alone or in combination with is_associated_with::IGFBP-3. is_associated_with::Mecasermin (brand name Increlex) is a synthetic analog of IGF-1 which is approved for the treatment of is_associated_with::growth failure. IGF-1 has been manufactured recombinantly on a large scale using both yeast and E. coli.

Aging
Signaling through the is_associated_with::insulin/IGF-1-like receptor pathway is a significant contributor to is_associated_with::biological aging in many organisms. is_associated_with::Cynthia Kenyon showed that mutations in the is_associated_with::daf-2 is_associated_with::gene double the lifespan of the roundworm, C. elegans. Daf-2 encodes the worm's unified is_associated_with::insulin/IGF-1-like receptor. Despite the impact of IGF1-like on C. elegans longevity, direct application to mammalian aging is not as clear as mammals lack dauer developmental stages. It is also inconsistent with evidence in humans.

There are mixed reports that IGF-1 signaling modulates the aging process in humans and about whether the direction of its effect is positive or negative.

Neuropathy
Therapeutic administration of neurotrophic proteins (IGF I) is associated with potential reversal of degeneration of spinal cord motor neuron axons in certain peripheral neuropathies.

Cancer
The IGF signaling pathway is implicated in some cancers. People with is_associated_with::Laron syndrome have a lessened risk of developing cancer. Dietary interventions and modifications such as vegan diets shown to down regulate IGF-1 activity, has been associated with lower risk of cancer. However, despite considerable research, perturbations specific to cancer are incompletely delineated and clinical trials have been unsuccessful.

Stroke
IGF-1 has also been shown to be effective in animal models of stroke when combined with is_associated_with::erythropoietin. Both behavioural and cellular improvements were found.

Recombinant protein
Several companies have evaluated IGF-1 in clinical trials for a variety of indications, including is_associated_with::type 1 diabetes, is_associated_with::type 2 diabetes, is_associated_with::amyotrophic lateral sclerosis (ALS aka "Lou Gehrig's Disease"), severe burn injury and myotonic muscular dystrophy (MMD). Results of clinical trials evaluating the efficacy of IGF-1 in type 1 diabetes and type 2 diabetes showed great promise in reducing hemoglobin A1C levels, as well as daily insulin consumption. However, the sponsor, is_associated_with::Genentech, discontinued the program due to an exacerbation of is_associated_with::diabetic retinopathy in patients coupled with a shift in corporate focus towards is_associated_with::oncology. Cephalon and Chiron conducted two pivotal clinical studies of IGF-1 for ALS, and although one study demonstrated efficacy, the second was equivocal, and the product has never been approved by the FDA.

Small molecules that upregulate IGF-1
In a clinical trial of an investigational compound is_associated_with::ibutamoren, which raises IGF-1 in patients, did not result in an improvement in patients' Alzheimer's symptoms. Another clinical demonstrated that Cephalon's IGF-1 does not slow the progression of weakness in ALS patients, but other studies shown strong beneficial effects of IGF-I replacement therapy in ALS patients, and therefore IGF-I may have the potential to be an effective and safe medicine against ALS, however other studies had conflicting results.

Society and culture
Insmed was found to infringe on patents licensed by Tercica, which then sought to get a U.S. district court judge to ban sales of Iplex. To settle patent infringement charges and resolve all litigation between the two companies, in March 2007 Insmed agreed to withdraw Iplex from the U.S. market, leaving Tercica's Increlex as the sole version of IGF-1 available in the United States.

Numerous sources have claimed that is_associated_with::Deer Antler Spray, purportedly extracted from cervid sources, contains IGF-1. Credence to this claim comes from the fact that deer's antlers grow extremely rapidly and that the associated cellular factors can similarly aid in skeletal healing in humans. IGF-1 is currently banned by various sporting bodies. However, sprays and pills claiming to be 'deer antler velvet extracts' are freely available on the market. As IGF-1 is a protein, it cannot be absorbed orally since it is rapidly broken down in the is_associated_with::gastrointestinal tract. In September 2013, the headquarters of SWATS, an infamous distributor of deer antler spray and other controversial products, was raided and ordered to shut down by is_associated_with::Alabama's attorney general citing "numerous serious and willful violations of Alabama’s deceptive trade practices act".