Insulin-like growth factor 1

IGF-I structure (1).

Structure of IGF-I (2).

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

IGF-1 is a hormone similar in molecular structure to insulin. It plays an important role in child growth (the highest levels occur at puberty, the lowest in childhood and old age), and continues to have anabolic effects in adults.

IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges; its molecular weight is 7649 daltons.

Synthesis and circulation

IGF-1 is a protein released by many tissues and affects virtually every cell in the body. The main synthesizing organs of IGF-1 is the liver, although it is also produced locally in the placenta, heart, lung, kidney, pancreas, spleen, small intestine, testicles, ovaries, intestine thick, brain, bone marrow and pituitary gland. Production is stimulated by growth hormone (GH) and can be retarded by malnutrition, lack of sensitivity to growth hormone, lack of growth hormone receptors, or failure of the post-receptor signaling pathway (second messenger) of GH including SHP2 and STAT5B. Approximately 98% of IGF-1 is always bound to one of 6 binding proteins (IGFBPs). IGFBP3, the most abundant protein, accounts for 80% of all IGF binding. IGF-1 binds to IGFBP-3. in a 1:1 molar ratio. This protein forms a ternary complex of 140,000 daltons with IGF-1 and with an acid-labile subunit.

In experiments with rats, the amount of IGF-1 mRNA in the liver was positively associated with dietary casein and negatively associated with a protein-free diet.

Recently, an efficient plant expression system was developed to produce recombinant biologically active human IGF-I (rhIGF-I) in transgenic rice grains.

Humans produce approximately 30 µg (micrograms) of IGF-1 per day until the age of 30, from which point production decreases with age.

Mechanism of action

Its main action is mediated by binding to its specific receptor, the receptor for insulin-like growth factor 1, abbreviated as IGF1R, present in many types of tissues. Upon binding to IGF1R, a receptor tyrosine kinase, it initiates intracellular signaling; IGF-1 is one of the most potent natural activators of PKB signal transduction, a stimulator of cell growth and proliferation, and a potent inhibitor of programmed cell death.

IGF-1 is a major mediator of the effects of growth hormone (GH). Growth hormone is produced in the anterior pituitary gland and released into the bloodstream, which then stimulates the liver to produce IGF-1. IGF-1 then stimulates the body to grow systemically, and has growth-promoting effects on almost all cells in the body, especially skeletal muscle, cartilage, bone, liver, nerves, skin, hematopoietic cells, and lung. In addition to insulin-like effects, IGF-1 may also regulate cell development and growth, especially in nerve cells, as well as cellular DNA synthesis.

Therefore, deficiency of either growth hormone or IGF-1 would result in decreased height. GH deficient children are given recombinant GH to increase their size. IGF-1 deficient humans, who are classified as having Laron syndrome, or Laron dwarfism, are treated with recombinant IGF-1. In cattle, circulating IGF-1 is related to reproductive performance.

Receivers

IGF-1 binds to at least two cell membrane receptors: the IGF-1 receptor (IGF1R), and the insulin receptor. IGF-1 has a high affinity for the IGF-1 receptor, and a low affinity for the insulin receptor. These receptors are tyrosine kinases (meaning that they signal by causing the addition of a phosphate molecule to certain tyrosines). IGF-1 activates the insulin receptor at approximately 0.1 times the power of insulin.

IGF-1 is produced throughout life. The highest levels occur during puberty growth, the lowest in childhood and old age.

Other IGF-BPs (binding/transporter proteins) are inhibitory. For example, both IGFBP-2 and IGFBP-5 bind IGF-1 with a higher affinity than IGF-1 binds its receptor. Therefore, the increase in the serum levels of these two IGF-BPs would result in a decrease in IGF-1 activity.

Contribution to aging

It is widely accepted that signaling through the insulin receptor/IGF-1 pathway is a significant contributor to the biological aging process in many organisms. This line of research gained importance with the work of Cynthia Kenyon, who showed that mutations in the Daf-2 gene could double the life of a C nematode. elegans. The daf-2 gene encodes the insulin/IGF-1 receptors of this nematode.

Insulin/IGF-1 signaling is conserved from worms to humans. According to studies subsequent to Kenyon's work, mutations that reduce insulin/IGF-1 signaling have been shown to slow the degenerative process of aging and extend lifespan in a wide range of organisms, including Drosophila melanogaster, mice, and possibly humans.

Reduced IGF-1 signaling is also believed to contribute to the "anti-aging" on caloric restriction.

Factors influencing levels in circulation

IGF-1 3D model

Factors that are known to cause variations in circulating growth hormone (GH) and IGF-1 levels include: genetics, time of day, age, gender, exercise, stress levels, nutrition levels and body mass index (BMI), health status, race, estrogen status, and xenobiotic intake. The inclusion of xenobiotic intake as a factor influencing circulating GH-IGF status highlights the fact that the GH-IGF axis IGF is a potential target of certain endocrine disrupting chemicals - see endocrine disruptor.

Deficiency and resistance diseases

Rare diseases have been described due to failures in the production or response to IGF-I, which result in a specific alteration of growth. One of these disorders, Laron syndrome, 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 (IGFD). Affected patients have normal to elevated GH levels, a height below -3 standard deviations (SD), and IGF levels below -3 SD. Severe primary IGF deficiency includes patients with GH receptor mutations, post-receptor mutations, or IGF mutations. As a result for apoptosis, patients do not respond to GH treatment.

The IGF signaling pathway appears to play an important role in cancer. Several studies have shown that high levels of IGF increase the risk of cancer. Studies in lung cancer cells show that drugs that inhibit this signaling could be a powerful therapeutic weapon against cancer in the future.

Clinical utilities

As a diagnostic test

IGF-I levels can be measured in blood, with a normal range of 10 to 1000 ng/ml. Since the levels do not fluctuate much throughout the day for each person, they are used in screening tests to detect GH deficiency and excess.

The interpretation of IGF-I levels is complicated, given the width of the normal range, and its variations by age, sex and pubertal stage. Clinically significant alterations may be masked by such a wide range. The sequential determination of the levels is usually more useful, especially in certain pituitary pathologies, malnutrition and growth problems.

As a therapeutic agent

Mecasermin (trade name Increlex) is a synthetic analogue of IGF-1 that is approved for the treatment of failure to thrive. IGF-1 has been recombinantly manufactured on a large scale using yeast and E.coli.

Clinical trials have been conducted to assess the potential efficacy of recombinant IGF-I in a multitude of pathologies: impaired growth, types 1 and 2 diabetes mellitus, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig"), severe burns, and myotonic muscular dystrophy. Trials show great efficacy in diabetes mellitus, in terms of reducing hemoglobin A1C levels, as well as daily insulin consumption. However, the company sponsoring the trial (Genentech) discontinued the trial due to exacerbation of diabetic retinopathy in certain patients. Regarding its use for ALS, the Cephalon and Chiron laboratories carried out two trials: one demonstrated its therapeutic efficacy and the result of the second was ambiguous, so its use was not approved by the FDA.

However, due to the efforts of the Tercica laboratory, in August 2005 the FDA approved the use of a type of recombinant IGF-I, Increlex, as replacement therapy for patients with severe IGF-I deficiency, after a trial with 71 patients. In December of the same year, the FDA approved Inplex (from the Insmed laboratory), an IGF-I/IGF BP-3 complex. This drug is injected in a single daily dose, compared to the two necessary for Increlex, so the side effects are fewer for the same efficacy.

Insmed was accused of infringing Tercica's patent license and was taken to court with the intention of having Inplex banned from sale. As a result, Increlex is currently the only IGF-I-derived drug on the market. the US market.

In a clinical trial of an investigational compound called MK-677, which elevates patients' IGF-1, it did not result in an improvement in Alzheimer's symptoms. Another trial showed that Cephalon's IGF-1 did not delays the progression of weakness in patients with ALS. Previous studies of shorter duration had conflicting results.

IGFBP-3 is a carrier for IGF-1, meaning that IGF-1 binds to IGFBP-3, creating a complex whose combined molecular weight and binding affinity allows the growth factor to have a longer half-life. increased in serum. Without its binding to IGFBP-3, IGF-1 is rapidly cleared through the kidney, due to its low molecular weight. By being bound to IGFBP-3, IGF-1 evades renal elimination. Also, because IGFBP-3 has a lower affinity for IGF-1 than IGF-1 has for its receptor, insulin-like growth factor receptor 1 (IGFR), its binding to IGFBP-3 does not interfere with its function. For these reasons, an IGF-1/IGFBP-3 combination was approved for human treatment.

IGF-1 has also been shown to be effective in cerebrovascular accidents, in animal models, when it is combined with erythropoietin. Behavioral and cellular improvements were obtained.

Interactions

Insulin-like growth factor 1 has been shown to bind and interact with all six IGF-1 Binding Proteins (IGFBP 1-6).

Specific references are provided for interactions with IGFBP3, IGFBP4, and IGFBP7.

Further reading