INSULIN LIKE GROWTH FACTOR

INSULIN LIKE GROWTH FACTOR

BY

ARIRAJ ASHRA

ASWATH RAJAN

VALIANTZ-08

CONTENTS

IGF-2IGF-1

INTRODUCTION1 IGF1/GH Axis2 IGF Receptors3 Organs and tissues affected by IGF-14 IGF-Binding Proteins5 Diseases affected by IGF

INSULIN LIKE GROWTH FACTOR-11 Synthesis and circulation2 Mechanism of action3 Receptors4 Related growth factors5 Regulation of aging6 Factors influencing the levels in the circulation7 Diseases of deficiency and resistance8 Use as a diagnostic test9 As a therapeutic agent10 Interactions11cancer and IGF-1

INSULIN LIKE GROWTH FACTOR-21 Gene structure2 Protein structure3 Function4 Diseases5 Interactions

IGF ROLE IN BODY BUILDINGABSTRACT FUNCTION OF IGFSIGNS AND SYMPTOMS OF IGF EXCESS/DEFICITTEST FOR IGF

INSULIN-LIKE GROWTH FACTOR

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 (GH). 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). Insulin-like growth factor 2 (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. 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 intake.

IGF-I has an involvement in regulating neural development including neurogenesis, myelination, synaptogenesis, and dendritic branching and neuroprotection after neuronal damage. Increased serum levels of IGF-I in children link to higher IQ.[1]

IGF-1 shape the development of the cochlea through controlling apoptosis. Its deficit can cause hearing loss. Serum level of it also underlies a correlation between short height and reduced hearing abilities particularly around 3–5 years of age, and at age 18 (late puberty).[2]

IGF receptorsThe IGF's are known to bind the IGF-1 receptor, the insulin receptor, the IGF-2 receptor, the insulin-related receptor and possibly other receptors. The IGF-1 receptor is the "physiologic" receptor - IGF-1 binds to it 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 tyrosine. The IGF-2 receptor only binds IGF-2 and acts as a "clearance receptor" - it activates no intracellular signaling pathways, functioning only as an IGF-2 sequestering agent and preventing IGF-2 signaling.

Organs and tissues affected by IGF-1

Since many distinct tissue types express the IGF-1 receptor, IGF-1's effects are diverse. It acts as a neurotrophic factor, inducing the survival of neurons. It causes skeletal muscle hypertrophy, by inducing protein synthesis, and by blocking muscle atrophy. It is protective for cartilage cells, and is associated with activation of osteocytes, and thus may be an anabolic factor for bone. Since at high concentrations it is capable of activating the insulin receptor, it can also complement for the effects of insulin.

IGF-Binding ProteinsIGF-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 aging .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 smaller 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 less crosstalk. On the other hand, simpler organisms typically have fewer receptors

(only 1 known in the nematode) and the roles of these other insulin are unknown. Furthermore these 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. Researchers are not in complete agreement about the degree of cancer risk that IGF-1 poses

INSULIN-LIKE GROWTH FACTOR1

Identifiers

Symbols IGF1; IGFI

External IDs

OMIM: 147440 MGI: 96432 HomoloGene: 515 GeneCards: IGF1 Gene

Insulin-like growth factor 1 (IGF-1) also known as somatomedin C or mechano growth factor 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 7649 daltons.

SYNTHESIS AND CIRCULATION

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

cient humans, who are categorized as having Larobinds to IGFBP-3 in a 1:1 molar ratio.

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.

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 defin syndrome, or Laron's dwarfism, are treated with recombinant IGF-1.

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 IGF-1 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 II 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.

Regulation of aging

The daf-2 gene encodes an insulin-like receptor in the worm C. elegans. Mutations in daf-2 have been shown by

Cynthia Kenyon to double the lifespan of the worms. The gene is known to regulate reproductive development, aging, resistance to oxidative stress, thermotolerance, resistance to hypoxia, and also resistance to bacterial pathogens.

DAF-2 is the only insulin/IGF-1 like receptor in the worm. Insulin/IGF-1-like signaling is conserved from worms to humans. DAF-2 acts to negatively regulate the forkhead transcription factor DAF-16 through a phosphorylation cascade. Genetic analysis reveals that DAF-16 is required for daf-2-dependent lifespan extension and dauer formation. When not phosphorylated, DAF-16 is active and present in the nucleus.

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.Diseases of deficiency and resistanceRare 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.The IGF signaling pathway appears to play a crucial role in cancer. Several studies have shown that increased levels of IGF lead to an increased risk of cancer. Studies done on lung cancer cells show that drugs inhibiting such signaling can be of potential interest in cancer therapy.[9]

Use as a 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 screening test for growth hormone deficiency and excess in acromegaly and gigantism.

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.

As a therapeutic agent

3-d model of IGF-1

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.[11] 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.[12]

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. Previous shorter 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

Cancer and insulin-like growth factor-I

A potential mechanism linking the environment with cancer risk Insulin-like growth factor-I acts as an important mediator between growth hormone and growth throughout fetal and childhood development. Its effects

and those of the other insulin-like growth factors are modulated by at least six different binding proteins. The role of insulin-like growth factor-I in promoting cancer has been investigated for many years, but recently the quality and quantity of evidence has increased.1 In particular, a number of prospective studies using stored blood collected up to 14 years before the onset of disease have shown associations between insulin-like growth factor-I and prostate cancer, premenopausal breast cancer, and colon cancer.

The risk of cancer is higher among people with raised concentrations of insulin-like growth factor-I, and it is lower among those with high concentrations of insulin-like growth factor binding protein-3 (the main binding protein). The associations are similar when people whose blood samples were taken soon before diagnosis are excluded from analyses, suggesting that the observed relations are not due to the release of the growth factor by preclinical cancer.

INSULIN-LIKE GROWTH FACTOR 2

Identifiers

Symbols

IGF2; C11orf43; FLJ22066; FLJ44734; INSIGF; pp9974

External IDs

OMIM: 147470 MGI: 96434 HomoloGene: 510 GeneCards: IGF2 Gene

RNA expression pattern

Orthologs

Species Human Mouse

Entrez 3481 16002

Ensembl

ENSG00000167244

ENSMUSG00000048583

UniProt P01344 P09535

RefSeq (mRNA)

NM_000612 NM_010514

RefSeq (protein)

NP_000603 NP_034644

Location (UCSC)

Chr 11:2.11 - 2.13 Mb

Chr 7:142.46 - 142.47 Mb

PubMed search

[1] [2]

Insulin-like growth factor 2 (IGF-2) is one of three protein hormones that share structural similarity to insulin.

Gene structure

In humans, the IGF2 gene is located on chromosome 11p15.5, a region which contains numerous imprinted genes. In mice this homologous region is found at distal chromosome 7. In both organisms, Igf2 is imprinted, with expression

resulting favourably from the paternally inherited allele.

The protein CTCF is involved in repressing expression of the gene, by binding to the H19 imprinting control region (ICR) along with Differentially-methylated Region-1 (DMR1) and Matrix Attachment Region -3 (MAR3). These three DNA sequences bind to CTCF in a way that limits downstream enhancer access to the Igf2 region. The mechanism in which CTCF binds to these regions is currently unknown, but could include either a direct DNA-CTCF interaction or it could possibly be mediated by other proteins

Protein structure

IGF-2 exerts its effects by binding to the IGF-1 receptor. IGF2 may also bind to the IGF-2 receptor (also called the cation-independent mannose 6-phosphate receptor), which acts as a signalling antagonist; that is, to prevent IGF2 responses.

Function

The major role of IGF2 is as a growth promoting hormone during gestation.

In the process of Folliculogenesis, IGF2 is created by Theca 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 Progesteron 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.

Diseases

It is sometimes produced in excess in islet cell tumours, causing hypoglycemia. Doege-Potter syndrome is a paraneoplastic syndrome [1] 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 tumours seen in Beckwith-Wiedeman syndrome

IGF-1 and Bodybuilding

IGF-1 LR3, Long R3 IGF-1, IGF-1- Insulin-like Growth Factor – is an experimental drug that represents the next generation in performance enhancing in bodybuilding athletes. This peptide hormone also has the promise of becoming the ultimate fountain of youth.

As the world has finally caught on to the fact that world-class athletes from all sports have been using steroids and other performance enhancing drugs (PEDs), the athletes themselves have moved on to the next generation of substances.

Long R3 IGF-1 is mainly secreted by the liver as a result of stimulation by Human Growth Hormone (HGH). Almost every cell in the human body is affected by IGF-I,

especially cells in muscle, cartilage, bone, liver, kidney, nerves, skin, and lungs. In addition to the insulin-like effects, IGF-I can also regulate cell growth and development, especially in nerve cells, as well as cellular DNA synthesis.

IGF-1 LR3 Benefits:

Stimulates muscle growth and has been shown to benefit the heart (a muscle).

Encourages the absorption of Chondroitin Sulfate and Glucosamine Sulfate (also found in Velvet Antler).

Regenerates nerve tissue Helps burn fat, increase protein transport into cells,

and reduce protein breakdown Improves the production of white blood cells Decreases LDL Cholesterol

IGF-1 LR3 is a hormone just like HGH, but IGF-1 is the most important growth factor that the body produces. IGF-1 is much more powerful than HGH.

Currently the license to conduct human trials using IGF-1 is held by biopharmaceutical company Tercica and is limited to the study of children suffering from growth failure due to IGF-1 deficiency.

Even though the human study of IGF-1 LR3 is extremely narrow and limited to kids, the fact that this substance has been studied on rats and humans and is in the hands of people in labs means that the genie is out of the bottle.

IGF-1 has been used in lab studies since at least the late 1990s; so many people have had access to this drug for quite a long time. And there are people with tons of money who would love to get their hands on this stuff.

IGF-1 LR3 has produced some amazing results in lab rats. Now before you get all over me for talking about success with lab rats, you have to realize that this success with lab rats did lead to the human trials. And the results of the tests with lab rats have been astounding.

The benefits from IGF-1 are so astounding – and offer such promise to humans – that back in 2002, H. Lee Sweeney, Ph.D., Professor and Chairman of Physiology at the University of Pennsylvania and a recognized expert on the subject of the genetic enhancement of skeletal muscle, spoke to the World Anti-Doping Association with regard to the muscle building and regenerating properties of IGF-1.

In 2002, speaking before The President’s Counsel On Bioethics, Dr. Sweeney was of the opinion that the advent of genetically engineered athletes was not imminent and that studies needed to be done in order to determine the safety and long-term effects of IGF-1.

To think that using IGF-1 LR3 to build a better athlete is off in the future, and that this hormone won’t be used until human safety studies can be done, is to ignore the history of how these drugs have been used by athletes. Dr. Sweeney’s position is one of wishful thinking. And I mean no offense to the doctor in any way.

Going back to the HGH situation, bodybuilders were using this hormone in the mid-’80s well before people totally understood how and what this drug really could do. To this day there are many unknowns that are associated with the use of HGH, including the debate as to its safety, yet the use of this hormone is widespread in

bodybuilding, in real sports, and in the general population.

Here are some of the reasons why IGF-1 will revolutionize the world of performance enhancing substances, and why athletes will risk – are risking – their health to use it.

IGF-1 has been shown to increase the rate and extent of muscle repair after injury and increase the rate of muscle growth from training. And not only are existing muscle fibers repaired quicker, IGF-1 is responsible for hyperplasia, which is an increase in the amount of muscle fibers.

Hyperplasia is the Holy Grail of performance enhancing benefits, and occurs when muscle fibers actually split, therefore creating more muscle fibers. Hypertrophy is simply an increase in the size of the existing muscle cells, and occurs from weight training and from steroid use. Hyperplasia plus hypertrophy equals a new breed of amazing athlete.

But wait, there’s more:

Rats that were given IGF-1 and did nothing were bigger and stronger than rats that weren’t given IGF-1 but exercised. And I’ll bet you guessed that rats that were given IGF-1 and exercised were the biggest, strongest rats in the house. The positive effects of IGF-1 on the rats continued for months after the rats stopped getting the supplemental hormone, whereas the exercising rats immediately lost size and strength as soon as they stopped exercising.

In another study the muscle fibers of 27-month old rats – old age for rats – that were given IGF-1 during middle

age, exhibited no deterioration of muscle fibers that indicate the classic and inevitable signs of aging. These rats did not lose any fast twitch muscle fibers – the fibers responsible for power and speed – and had the same speed and power output that they had when they were six months of age.

To quote Dr. Sweeney, “So we were able to conclude that IGF-1 could prevent all of the hallmarks of age-related atrophy and loss of skeletal muscle function in mammalian aging, at least based on the rodent model, and now we’re hoping to pursue this in larger animal models.”

Dr. Sweeney also says that IGF-1 could be used as an

instant muscle builder for members of the general population.

And here’s the final and most compelling reason why IGF-1 is being used right now, and why the demand for this hormone will increase exponentially as time goes by: IGF-1 is undetectable by both blood and urine testing. Because IGF-1 can be injected directly into the muscle, it never enters the blood stream. Therefore, a muscle biopsy is the only way to determine if a person has used IGF-1. And the anti-doping forces will never, ever be allowed to take muscle biopsies from athletes.

In a January 18th, 2004 New York Times Magazine cover story by Michael Sokolove, Dr. Sweeney says (page 30) that after presenting his IGF-1 info at an American Society for Cell Biology conference he was contacted by a high school football coach from Pennsylvania who wanted Dr. Sweeney to treat his entire team. Do you think by

now world-class athletes – with world-class money – are interested in IGF-1?

Included in this article (page 28) were additional details with regard to the results of studies, in which rodents given IGF-1 before birth and at four weeks of age experienced a 35% increase in strength in targeted muscles, did not lose any size and strength as they aged and did not lose any of these gains when they stopped training.

Later on in the article Dr. Sweeney admits that athletes could already be using IGF-1. Elisabeth Barton, an assistant professor who was involved with Dr. Sweeney’s studies, says that creating a human athlete along the lines of these super mice “is easy.”

She goes on to explain, “It’s a routine method that’s published. Anyone who can clone a gene and work with cells could do it. It’s not a mystery.”

Dr. Sweeney added that there’s no limit to what can be done with IGF-1 and gene therapy with regards to building a better athlete. To make a sprinter faster Sweeney said, “I’d put the whole leg on bypass. I would put (IGF-1) in through the blood. It would be more efficient than injections (directly into the muscle), which you would need a lot of because you’re dealing with large muscles. But this is nothing a vascular surgeon couldn’t do.”

So to recap, IGF-1 provides almost permanent muscle-creating, muscle-repairing, and anti-aging benefits and is totally undetectable. Do you think

athletes are chomping at the bit to get their hands on this stuff?

The legitimate scientific world is following the proper protocols with regards to IGF-1, but the underground world is not bound by the same rules. Legitimate science – rightly so – is nowhere near ready to allow “us” to start using this stuff. But this isn’t the point.

The point is that there is a substance out there that scientists are cautiously touting as an instant muscle builder and a fountain of youth, and for some people this is all that they need to hear. These people aren’t going to wait – haven’t waited – for legit science to bless the use of IGF-1 LR3 for human consumption before they go out and inject themselves with it. Adverse side affects? Please.

In 2004 the leading experts on the subject admitted that this gene therapy could already be in use, and that the technology and knowledge is such that the process to deliver it isn’t complicated. Two and a half years later this circle of knowledge, and use, is that much larger.

Knowing how HGH was purloined by people who were too impatient to wait for legit science to do it’s thing, bodybuilders and real athletes did what they had to do to get it and use it, danger be damned. There’s no reason to think that the same situation isn’t occurring right now.

Bodybuilding web sites, bulletin boards, and chat rooms are awash with discussions about IGF-1, what it can do, how to use it, and what drugs to stack with it. There’s talk that underground labs are synthesizing IGF-1, HGH, and a host of other substances.

According to Chemical Muscle Enhancement, a well-known underground PED guidebook written by Internet steroid guru L. Rea and available via download or through Amazon, IGF-1 has even been altered to increase its effectiveness, making IGF-1 ten times more potent (pages 134-136 of Chemical Muscle Enhancement). Several websites make reference to this altered form of IGF-1 – known as DES (1-3) IGF-1. This version of IGF-1, Insulin-like Growth Factor is also refereed to as Lr3IGF-1 (Note: Lr3IGF-1 is 2-3x more potent than regular IGF-1).

IGF-1 is being synthesized and altered in underground labs and is being sold on the black market. Bodybuilders are using IGF-1 and it is illogical and naive to think that some athletes at the highest level of sport are not using IGF-1 right now. People who you’ve probably never even heard of are using it just as there are well-known athletes who have already benefited from the use of IGF-1.

People did crazy things to get their hands on HGH 20 years ago, did crazy things to get their hands on whatever the next-generation drug was 30 years ago, and it’s no different today.

While in some sense the public has finally caught on to “steroids,” the high-tech, high-minded athletes have moved on, light years ahead of what the public can conceive of and comprehend. “Steroids” is the Model-T Ford; IGF-1 is the USS Enterprise or the Millennium Falcon.

With each advance in the field of PEDs the underground has been responsible for the spread of knowledge and supply of these drugs. Advances in technology and today’s free flow of information have made it possible for

underground labs to synthesize, alter, and deliver into the body drugs of all types.

With money, fame, and even a kind of immortality involved, there’s no telling what some people will do. The mindset of the PED user is that IGF-1 can deliver all three of these.

The use of PEDs up until this point has pretty much been a black and white issue, but with this next generation of substances now available the debate will get much more complicated. PEDs are NOT going to be eradicated, their use will become more widespread as the benefits that they provide become more and more attractive to potential users.

Tips for maximizing your Insulin-like growth factor, IGF-1 LR3:

If you are not using ZMA currently, you should start it up before starting the IGF-1. Zinc plays a very crucial role in enzyme activation of IGF-1. It also increases blood plasma levels of total and free IGF-1. A deficiency actually hinders IGF-1 formation.

Since IGF-1 LR3 is such a new peptide, there are no long term studies about the IGF-1 side effects.

The insulin-like growth factor-1 pathway mediator genes: SHC1 Met300Val shows a protective effect in breast cancer

AbstractThe insulin-like growth factor 1 (IGF-1) pathway plays an important role in regulating cell proliferation,

differentiation and apoptosis. IRS1, IRS2 and SHC1 are the key mediators for the downstream pathway processes. Genetic variation within these genes may lead to altered signalling. We screened IRS1, IRS2 and SHC1 for published coding region polymorphisms and choose five of them, IRS1 Ala804Ala and Gly972Arg, IRS2 Cys816Cys and Gly1057Asp and SHC1 Met300Val, for further analysis. the association of the polymorphisms with breast cancer risk using a case–control design with Polish familial breast cancer cases and respective controls. For the polymorphisms in IRS1 and IRS2 no differences in the allele, genotype or haplotype distributions could be detected between the case and control subjects. Carriers of the variant allele of the SHC1 polymorphism were at decreased risk of breast cancer (OR 0.54, 95% CI 0.32–0.90, P = 0.016). A non-significant trend for a protective effect of the SHC1 Val300 allele was also seen in an independent population consisting of German familial breast cancer cases and matched controls. The joint analysis after Mantel–Haenzsel adjustment of the two populations gave an OR of 0.62 (95% CI 0.41–0.93, P = 0.02) for the SHC1 Val300 carriers. A stronger effect was detected in women diagnosed below the age of 50 (OR 0.54, 95% CI 0.32–0.89, P = 0.01). A genotype combination analysis of the non-synonymous polymorphisms in the IRS1, IRS2 and SHC1 genes did not show any effect on breast cancer risk.

BACKGROUND: Milk and dietary calcium may have antiproliferative effects against colorectal cancer, but milk intake also raises serum levels of insulin-like growth factor-I (IGF-I). A high ratio of IGF-I to IGF-binding protein-3 (IGFBP-3) has been linked to an increased risk of colorectal cancer.

METHODS: In a case-control study nested in the Physicians' Health Study, plasma samples were collected from the period 1982 through 1983 from 14 916 men, aged 40-84 years, who also answered dietary questionnaires. Circulating levels of IGF-I and IGFBP-3 were assayed among 193 men who developed colorectal cancer during 13 years of follow-up and 318 age- and smoking-matched cancer-free control men. Conditional logistic regression was used to assess relative risks (RRs) of colorectal cancer for tertiles of IGF-I/IGFBP-3 and dietary factors. Statistical tests were two-sided.

RESULTS: Overall, there was a moderate but statistically nonsignificant inverse association between intake of low-fat milk or calcium from dairy food and colorectal cancer risk. Intake of dairy food (especially low-fat milk) was also positively and moderately associated with plasma levels of IGF-I, IGFBP-3, and IGF-I/IGFBP-3 among control men. We observed a statistically significant interaction between low-fat milk intake and IGF-I/IGFBP-3 in association with risk of colorectal cancer (P(interaction) =.03). Nondrinkers with IGF-I/IGFBP-3 in the highest tertile had a threefold higher risk than nondrinkers with IGF-I/IGFBP-3 in the lowest tertile (RR =

3.05; 95% confidence interval [CI] = 1.29 to 7.24), but no such increase was seen among frequent low-fat milk drinkers (RR = 1.05; 95% CI = 0.41 to 2.69). Conversely, among men with high IGF-I/IGFBP-3, frequent low-fat milk drinkers had a 60% lower risk (95% CI = 0.17 to 0.87; P(trend) =.02) than nondrinkers.

Intake of dairy products was associated with a modest increase in circulating IGF-I levels, but intake of low-fat milk was associated with lower risk of colorectal cancer, particularly among individuals with high IGF-I/IGFBP-3. This subpopulation, which is at increased risk of colorectal cancer, might benefit the most from specific dietary intervention.

Signs and symptoms of IGH excess and deficit

1.  What signs and symptoms are seen with deficient GH and IGF-1?

In children, the following may indicate GH and/or IGF-1 deficiency: Slowed growth rate in early childhood relative to group norms

Shorter stature than others of the same chronological age

Delayed puberty

x-rays showing delayed bone development.In adults, abnormally low levels of GH and/or IGF-1 may cause subtle, nonspecific symptoms such as:

Decreased bone density

Fatigue

Adverse lipid changes

Reduced exercise tolerance.

2.  What signs and symptoms are seen with excess GH and IGF-1 production?

In a child, it is unusual tallness that is often first noticed. With an adult, it may be more subtle: a larger nose, thicker lips, a more prominent jaw, or rings and shoes that no longer fit. Other signs and symptoms may include: Deepened, husky voice

Enlarged organs - liver, heart, kidneys, and spleen

Enlarged tongue

Erectile dysfunction

Fatigue

Headaches and visual disturbances

Joint pain and swelling

Menstrual cycle irregularities

Muscle weakness

Snoring

Sweating and body odor

Thickening of the skin, skin tags

Trapped nerves (Carpal tunnel syndrome)

3.  How long do I have to be monitored?

As long as you are considered to have abnormal (low or high) GH production or are receiving GH replacement therapy, your IGF-1 will need to be monitored.

IGF-1 TESTS:

Why Get Tested?

To identify diseases and conditions caused by deficiencies and overproduction of growth hormone (GH), to evaluate pituitary function, and to monitor the effectiveness of GH treatment

When to Get Tested?As part of an evaluation of pituitary function; when you have symptoms of slow growth, short stature, and delayed development (in children) or decreased bone density, reduced muscle strength, and increased lipids (in adults) that suggest insufficient GH and IGF-1 production; when you have symptoms of gigantism (in children) or acromegaly (in adults) that suggest excess GH and IGF-1

production; during and after treatment for GH abnormalitiesSample Required?A blood sample drawn from a vein in your arm or by a fingerstick (in children)

The Test Sample

What is being tested?

The insulin-like growth factor-1 (IGF-1) test is an indirect measure of the average amount of growth hormone (GH) being produced by the body. IGF-1 and GH are peptide hormones, small proteins that are vital for normal bone and tissue growth and development. GH is produced by the pituitary gland, a grape-sized gland located at the base of the brain behind the bridge of your nose. GH is secreted into the bloodstream in pulses throughout the day and night with peaks that occur mostly during the night. IGF-1 is produced by the liver and to a lesser degree by skeletal muscles, primarily in response to GH stimulation. It mediates many of the actions of GH, stimulating the growth of bones and other tissues and promoting the production of lean muscle mass. IGF-1 mirrors GH excesses and deficiencies, but its level is stable throughout the day, making it a useful indicator of average GH levels.

Like GH, IGF-1 levels are normally low in early childhood, increase gradually during childhood, peak during puberty, and then decline in adult life. Deficiencies in GH and IGF-1 may be caused by conditions such as hypopituitarism or by the presence of a non-GH-producing pituitary tumor that damages hormone-producing cells. Deficiencies in IGF-1 also occur where there is a lack of responsiveness to GH. This insensitivity may be primary (genetic) or

secondary to conditions such as malnutrition and chronic diseases.

Deficiencies early in life can inhibit bone growth and overall development and can result in a child with a shorter than normal stature. In adults, decreased production can lead to low bone densities, less muscle mass, and altered lipids.

Excess GH and IGF-1 can cause abnormal growth of the skeleton and other signs and symptoms characteristic of gigantism and acromegaly. In children, gigantism causes bones to grow longer, resulting in a very tall person with large feet and hands. In adults, acromegaly causes bones to thicken and soft tissues, such as the nose, to swell. Both conditions can lead to enlarged organs, such as the heart, and to other complications such as type 2 diabetes, increased cardiovascular disease risk, high blood pressure, arthritis, and a decreased life span. The most common reason for the pituitary to secrete excessive amounts of GH is a GH-producing pituitary tumor (usually benign). Frequently, the tumor can be surgically removed and/or treated with drugs or radiation. In most cases, this will cause GH and IGF-1 levels to return to normal or near normal levels.

How is the sample collected for testing?A blood sample is obtained by inserting a needle into a vein in your arm or by a fingerstick (in children).Is any test preparation needed to ensure the quality of the sample?

In general, no test preparation is needed; however, since this test may be performed at the same time as others, fasting for at least 12 hours may be required.

How is it used?

IGF-1 is measured to help diagnose the cause of growth abnormalities and to evaluate pituitary function. It is not diagnostic of GH deficiency but may be ordered along with GH stimulation tests to offer additional information. IGF-1 levels and the measurement of GH can also provide information related to GH insensitivity.

IGF-1 may be ordered with other pituitary hormone tests, such as adrenocorticotropic hormone (ACTH), to help diagnose hypopituitarism. It may be used to monitor the effectiveness of treatment for growth hormone deficiencies and growth hormone insensitivity.

IGF-1 testing and a GH suppression test can be used to detect a GH-producing pituitary tumor. Its presence is then confirmed with imaging scans that help identify and locate the tumor. If surgery is necessary, GH and IGF-1 levels are measured after the tumor's removal to determine whether or not all of it was successfully removed. Drug and/or radiation therapy may be used in addition to (or sometimes instead of) surgery to try to decrease GH production and return IGF-1 to normal or near normal concentrations. IGF-1 may be used to monitor the effectiveness of this therapy at regular intervals for years afterward to monitor GH production and to detect tumor recurrence.

When is it ordered?

IGF-1 testing may be ordered, along with a GH stimulation test, when a child has symptoms of GH deficiency, such as a slowed growth rate and short stature. They also may be ordered when adults have symptoms that the doctor suspects may be due to a GH deficiency. An IGF-1 also may be ordered when a doctor

suspects that a person has an underactive pituitary gland and at intervals to monitor patients on GH therapy.

IGF-1 testing may be ordered, along with a GH suppression test, when a child has symptoms of gigantism, an adult shows signs of acromegaly, and/or when a doctor suspects that a patient has hyperpituitarism.

When a GH-producing pituitary tumor is found, GH and IGF-1 are ordered after the tumor is surgically removed to determine whether all of the tumor has been extracted. IGF-1 also is ordered at regular intervals when a patient is undergoing the drug and/or radiation therapy that frequently follow tumor surgery.

IGF-1 levels may be ordered at regular intervals for many years to monitor a patient's GH production and to watch for pituitary tumor recurrence.

What does the test result mean?

Normal concentrations of IGF-1 must be considered in context. Some patients can have a GH deficiency and still have a normal IGF-1 concentration.

Decreased IGF-1If IGF-1 concentrations are decreased, then it is likely that there is a deficiency of GH (GH Deficiency; GHD) or an insensitivity to GH. If this is in a child, the GH deficiency may have already caused short stature and delayed development and may be treated with GH supplementation. Adults will have an age-related decrease in production, but lower than expected concentrations may reflect a GH deficiency or insensitivity.

If a decrease in IGF-1 is due to a more general decrease in pituitary function (hypopituitarism), then several of the patient’s pituitary hormones will need to be evaluated and may be supplemented to bring them up to normal levels. Reduced pituitary function may be due to inherited defects or can rise as a result of pituitary damage following conditions such as trauma, infections, and inflammation.

Decreased levels of IGF-1 also may be seen with nutritional deficiencies (including anorexia nervosa), chronic kidney or liver disease, inactive/ineffective forms of GH, and with high doses of estrogen.

Increased IGF-1Elevated levels of IGF-1 usually indicate an increased production of GH. Since GH levels vary throughout the day, IGF-1 concentrations are a reflection of average GH production, not of the actual amount of GH in the blood. This is accurate up to the point at which the liver’s capacity to produce IGF-1 is reached. With severely increased GH production, IGF-1 levels will stabilize at an elevated maximum concentration.

Increased concentrations of GH and IGF-1 are normal during puberty and pregnancy but otherwise are most frequently due to pituitary tumors (usually benign). If other pituitary hormones are also abnormal, then the patient may have a condition causing general hyperpituitarism.

If IGF-1 is still elevated after the surgical removal of a pituitary tumor, then the surgery may not have been fully effective. Decreasing IGF-1 concentrations during subsequent drug and/or radiation therapies indicate that the treatment is lowering GH production. If levels of IGF-1

become “normalized,” then the patient is no longer producing excess amounts of GH. When a patient is undergoing long term monitoring, an increase in IGF-1 levels may indicate a recurrence of the pituitary tumor.

If an IGF-1 level is normal and the doctor still strongly suspects a GH deficiency, then he may order another test, an IGF BP 2 or IGF BP 3 (insulin-like growth factor binding protein 2 or 3), to help confirm the GH deficiency.

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Comments :discussion involving oestrogen etc can be minimized. Anabolic effects can be put under a separate heading. Studies may be given in a separate heading. Qns and ans may be put in a separate heading. Clinical correlation is nicely done. Discussion of diagnostics tests very nice. Pl put it under a separate heading. References can be quoted at the end. Content page to be prepared.

Cover page to be planned.summary can be provided in the end.

Overall idea : students have presented a complex topic in easily understandable manner.congrats.