WHAT IS YOUR TAKE ON IGF DES (1-3).. HAS ANYONE TRIED THIS? IF SO CAN YOU PLEASE TELL ME A LITTLE BIT ABOUT IT, AND THE RESULTS, SIDE EFFECTS OF IT.. THANKS!
IGF1LR3 is MUCH better in my op. MUCH better gains i have have.
here is info for you:
Insulin-like growth factor 1
edit
Insulin-like growth factor 1
(somatomedin C)
PDB rendering based on 1bqt.
[show]Available structures
Identifiers
Symbols
IGF1; IGFI
External IDs OMIM: 147440 MGI: 96432 HomoloGene: 515 GeneCards: IGF1 Gene
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez
3479
16000
Ensembl
ENSG00000017427
ENSMUSG00000020053
UniProt
P01343
Q4VJC0
RefSeq (mRNA) NM_000618
NM_010512
RefSeq (protein) NP_000609
NP_034642
Location (UCSC) Chr 12:
101.31 - 101.4 Mb
Chr 10:
87.29 - 87.36 Mb
PubMed search [1]
[2]
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.[1][2] IGF-1 has also been referred to as a "sulfation factor"[3] 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.[4]
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.
Contents
[hide]
• 1 Synthesis and circulation
• 2 Mechanism of action
• 3 Receptors
• 4 Related growth factors
• 5 Regulation of aging
• 6 Factors influencing the levels in the circulation
• 7 Diseases of deficiency and resistance
• 8 Use as a diagnostic test
• 9 As a therapeutic agent
• 10 Interactions
• 11 References
• 12 Further reading
• 13 External links
[edit] 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 binds 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.[5]
[edit] 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.[6]
[edit] 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.
[edit] 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.
[edit] 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.[7] The gene is known to regulate reproductive development, aging, resistance to oxidative stress, thermotolerance, resistance to hypoxia, and also resistance to bacterial pathogens.[8]
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.
[edit] Factors influencing the levels in the circulation
3-d model of IGF-1
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.[9] 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.
[edit] Diseases of deficiency and resistance
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.
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.[citation needed] Studies done on lung cancer cells show that drugs inhibiting such signaling can be of potential interest in cancer therapy.[10]
[edit] Use as a diagnostic test
Reference ranges for IGF-1[11]
(in ng/mL)
Age Females Males
2.5th
centile
97.5th
centile 2.5th
centile 97.5th
centile
20 111 423 156 385
25 102 360 119 343
30 94 309 97 306
35 86 271 84 275
40 79 246 76 251
45 73 232 71 233
50 68 228 66 221
55 64 231 61 214
60 61 237 55 211
65 59 241 49 209
70 57 237 46 207
75 55 219 48 202
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.
[edit] As a therapeutic agent
Mecasermin (brand name Increlex) is a synthetic analog of IGF-1 which is approved for the treatment of growth failure.[12] 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[citation needed] 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.[13] 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.[14]
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[citation needed]. 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[citation needed]. 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.[15] Another clinical demonstrated that Cephalon's IGF-1 does not slow the progression of weakness in ALS patients. Previous shorter studies had conflicting results.[16]
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.[17]
[edit] 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,[18][19][20][21][22][23] IGFBP4,[24][25] and IGFBP7.[26][27]
[edit] References
1. ^ Höppener JW, de Pagter-Holthuizen P, Geurts van Kessel AH, Jansen M, Kittur SD, Antonarakis SE, Lips CJ, Sussenbach JS (1985). "The human gene encoding insulin-like growth factor I is located on chromosome 12". Hum. Genet. 69 (2): 157–60. doi:10.1007/BF00293288. PMID 2982726.
2. ^ Jansen M, van Schaik FM, Ricker AT, Bullock B, Woods DE, Gabbay KH, Nussbaum AL, Sussenbach JS, Van den Brande JL (1983). "Sequence of cDNA encoding human insulin-like growth factor I precursor". Nature 306 (5943): 609–11. doi:10.1038/306609a0. PMID 6358902.
3. ^ Salmon W, Daughaday W (1957). "A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro". J Lab Clin Med 49 (6): 825–36. PMID 13429201.
4. ^ Keating GM (2008). "Mecasermin". BioDrugs 22 (3): 177–88. doi:10.2165/00063030-200822030-00004. PMID 18481900.
5. ^ Miura, Y.; Kato, H.; Noguchi, T. (2007). "Effect of dietary proteins on insulin-like growth factor-1 (IGF-1) messenger ribonucleic acid content in rat liver". British Journal of Nutrition 67 (2): 257. doi:10.1079/BJN19920029. PMID 1596498. edit
6. ^ Yilmaz A, Davis ME, RCM Simmen RCM (1999). "Reproductive performance of bulls divergently selected on the basis of blood serum insulin-like growth factor I concentration". J Anim Sci 77 (4): 835–9.
7. ^ See publications documenting series of experiments at Cynthia Kenyon lab, in particular, Dorman JB, Albinder B, Shroyer T, Kenyon C (December 1995). "The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans". Genetics 141 (4): 1399–406. PMC 1206875. PMID 8601482.; and Apfeld J, Kenyon C (October 1998). "Cell nonautonomy of C. elegans daf-2 function in the regulation of diapause and life span". Cell 95 (2): 199–210. doi:10.1016/S0092-8674(00)81751-1. PMID 9790527.
8. ^ Minaxi S Gami and Catherine A Wolkow (2006). "Studies of Caenorhabditis elegans DAF-2/insulin signaling reveal targets for pharmacological manipulation of lifespan". Aging Cell 5 (1): 31. doi:10.1111/j.1474-9726.2006.00188.x. PMC 1413578. PMID 16441841.
9. ^ Scarth J (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. doi:10.1080/00498250600621627. PMID 16702112.
10. ^ Velcheti V, Govindan R (2006). "Insulin-like growth factor and lung cancer". Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 1 (7): 607–10. PMID 17409926.
11. ^ Ranges estimated from quantile regression as shown in table 4 in: Friedrich, N; Alte, D; Volzke, H; Spilckeliss, E; Ludemann, J; Lerch, M; Kohlmann, T; Nauck, M et al. (2008). "Reference ranges of serum IGF-1 and IGFBP-3 levels in a general adult population: Results of the Study of Health in Pomerania (SHIP)". Growth Hormone & IGF Research 18 (3): 228–237. doi:10.1016/j.ghir.2007.09.005. PMID 17997337. edit
12. ^ Rosenbloom AL (August 2007). "The role of recombinant insulin-like growth factor I in the treatment of the short child". Curr. Opin. Pediatr. 19 (4): 458–64. doi:10.1097/MOP.0b013e3282094126. PMID 17630612.
13. ^ Pollack A (2007-02-17). "Growth Drug Is Caught Up in Patent Fight". The New York Times. Retrieved 2010-03-28.
14. ^ Pollack A (2007-03-07). "To Settle Suit, Maker Agrees to Withdraw Growth Drug". The New York Times. Retrieved 2010-03-28.
15. ^ Sevigny JJ, Ryan JM, van Dyck CH, Peng Y, Lines CR, Nessly ML (November 2008). "Growth hormone secretagogue MK-677: no clinical effect on AD progression in a