An Analysis Of The Insulin Growth Factor, IGF-1, Part I

The Insulin like Growth Factor (IGF-1) is another one of those pieces in the human growth mechanism that we have to learn and understand for us to build a better knowledge base to work from.

Of course I always try to answer the most obvious question, “What is Insulin like Growth Factor (IGF-1)?”

This time I am just going to copy and paste the entire Wikipedia article below and highlight the important parts (source HERE).  This piece of the puzzle is just as critical to learn as the GH.


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 17,066 daltons.

IGF-1 is produced primarily by the liver as an endocrine hormone as well as in target tissues in a paracrine/autocrine fashion. Production is stimulated by 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 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.

Synthesis and circulation

In rat experiments 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 biologically active recombinant human IGF-I (rhIGF-I) in transgenic rice grains.

Mechanism of action

Its primary action is mediated by binding to its specific receptor, the Insulin-like growth factor 1 receptor, abbreviated as “”IGF1R””, present on many cell types in many tissues. Binding to the IGF1R, a receptor tyrosine kinase, initiates intracellular signaling; 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.

IGF-1 is a primary mediator of the effects of growth hormone (GH). Growth hormone is made in the anterior pituitary gland, 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.

Deficiency of either growth hormone or IGF-1 therefore results in diminished stature. GH-deficient children are given recombinant GH to increase their size. IGF-1 deficient humans, who are categorized as having Laron syndrome, or Laron’s dwarfism, are treated with recombinant IGF-1. In beef cattle, circulating IGF-I concentrations are related to reproductive performance.

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.

Receptors

IGF-1 binds to at least two cell surface receptors: the IGF-1 receptor (IGF1R), and the insulin receptor. The 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 tyrosine kinase – meaning it signals by causing the addition of a phosphate molecule on particular tyrosines. IGF-1 activates the insulin receptor at approximately 0.1x 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 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.

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

Contribution to ageing

It is now widely accepted that signaling through the insulin/IGF-1-like receptor pathway is a significant contributor to the biological aging process in many organisms. This avenue of research first achieved prominence with the work of Cynthia Kenyon, who showed that mutations in the daf-2 gene could double the lifespan of the roundworm C. elegans. daf-2 encodes the worm’s unified insulin/IGF-1-like receptor.

Insulin/IGF-1-like signaling is conserved from worms to humans. In vitro experiments show that mutations that reduce insulin/IGF-1 signaling have been shown to decelerate the degenerative aging process and extend lifespan in a wide range of organisms, including Drosophila melanogaster, mice, and possibly humans. Reduced IGF-1 signaling is also thought to contribute to the “anti-aging” effects of Calorie restriction.

Nevertheless the situation in vivo is evidently different, Anabolic deficiency in men with chronic heart failure is prevalent and could have an associated detrimental impact on survival. Deficiency of anabolic hormones identifies groups with a higher mortality.

Factors influencing the levels in the circulation

Factors that are known to cause variation in the levels of growth hormone (GH) and IGF-1 in the circulation include: 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 xenobiotic intake. 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.

Neuropathy

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

Dwarfism

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 -3SD. 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 [diabetes].

IGF-I and Cancer

The IGF signaling pathway has a pathogenic role in cancer. Studies have shown that increased levels of IGF lead to increased growth of existing cancer cells. People with Laron syndrome have also recently been shown to be of much less risk to develop cancer.

Use as a diagnostic test

Interpretation of IGF-1 levels is complicated by the wide normal ranges, and 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.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 screening test for growth hormone deficiency and excess in acromegaly and gigantism.

As a therapeutic agent

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.

Several companies have evaluated IGF-1 in clinical trials for a variety of additional indications, including type 1 diabetes, type 2 diabetes, 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, Genentech, discontinued the program due to an exacerbation of diabetic retinopathy in patients coupled with a shift in corporate focus towards 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.

However, in the last few years, two additional companies Tercica and Insmed compiled enough clinical trial data to seek FDA approval in the United States. In August 2005, the FDA approved Tercica’s IGF-1 drug, Increlex, as replacement therapy for severe primary IGF-1 deficiency based on clinical trial data from 71 patients. In December 2005, the FDA also approved Iplex, Insmed’s IGF-1/IGFBP-3 complex. The Insmed drug is injected once a day versus the twice-a-day version that Tercica sells.

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.[26] To settle patent infringement charges and resolve all litigation between the two companies, Insmed in March 2007 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.

By delivering Iplex in a complex, patients might get the same efficacy with regard to growth rates but experience fewer side effects with less severe hypoglycemia. This medication might emulate IGF-1’s endogenous complexing, as in the human body 97–99% of IGF-1 is bound to one of six IGF binding proteins. IGFBP-3 is the most abundant of these binding proteins, accounting for approximately 80% of IGF-1 binding.

In a clinical trial of an investigational compound MK-677, 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.

IGFBP-3 is a carrier for IGF-1, meaning that IGF-1 binds IGFBP-3, creating a complex whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life in serum. Without binding to IGFBP-3, IGF-1 is cleared rapidly through the kidney, due to its low molecular weight. But when bound to IGFBP-3, IGF-1 evades renal clearance. Also, since IGFBP-3 has a lower affinity for IGF-1 than IGF-1 has for its receptor, IGFR, its binding does not interfere with IGF-1 function. For these reasons, an IGF-1/IGFBP-3 combination approach was approved for human treatment… brought forward by a small company called Insmed. However, Insmed fell afoul patent issues, and was ordered to desist in this approach.

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

Interactions

Insulin-like growth factor 1 has been shown to bind and interact with all the IGF-1 Binding Proteins (IGFBPs), of which there are six (IGFBP1-6).

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

Me: What the main takeaways from the wikipedia article are is that the IGF-1 is that IGF-1 is a primary mediator of the effects of growth hormone (GH). Growth hormone is made in the anterior pituitary gland, 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. deficiency of IGF-1 receptors is Laron Syndrome. The IGF-1 is very similar to insulin but only binds to insulin receptors at 1/10th the rate of the IGF-1 receptors. The IGF-1 receptors is tyrosine kinase activated, which tursn on the AKT signaling pathway. What is shown in others studies is that the IGF-1 signaling pathway also is a significant contributor to the aging process and well as increased levels of cancer. There are ways to produce synthetic IGF using yeast and E-coli and the IGF are processed and can be used only a a very specific group of people who suffer from IGF-1 deficiency. 

In the broader scheme of things this could be mean for some people that there is a strong correlation between height and aging and cancer. People who may be genetically prone to tallness may be prone to age faster than their shorter counterparts and be more likely to develop cancer.

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