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Categories: Anti hair-loss, Anti-aging drugs, Performance enhancement, Recovery, Research peptides. Tags: anabolics, glucose uptake enhancer, growth factors, growth hormone, hair loss, HGH, igf-1, igf-1 lr3, insulin-like growth factor. IGF1 LR3 also known as Long R3 IGF-1 or Insulin-Like Growth Factor-I LR3 is a Human Recombinant, single, non-glycosylated, polypeptide chain containing 83 amino acids and having a molecular mass of 9200 Daltons. IGF-1 LR3 is the primary protein involved in responses of cells to growth hormone (GH): that is, IGF-I is produced in response to GH and then induces cellular activities. The polypeptide Long R3 Insulin-like Growth Factor-I IGF-1 LR3) is an 83 amino acid analog of IGF-I actually comprising the complete IGF-1 sequence but with the substitution of an Arginine (Arg) for the Glutamic Acid (Glu) at position 3, as well as a 13 amino acid extension peptide. Recombinant Human Long-Arg3-Insulin-like Growth Factor-I IGF-1 Long R3 (IGF1-LR3) is a synthetic analog of the naturally existing insulin growth factor (IGF) which is a 93 amino acid residue. The studies on transgenic and knockout mice have shown that it can control its development and growth. IGF-1 is a peptide roughly the same structure and size as insulin, or about 70 amino acids long. Perhaps the most remarkable also strong influence it has on the human body is its ability to cause hyperplasia, which is an definite splitting of cells. Long-R3 IGF-1 (IGF1-LR3) plays an important part in childhood growth and continues to have results in adults. The most common range used during clinical research is typically between 20mcg to 120mcg per day. Although glucose is the major fuel whose oxidation leads to energy-coupled insulin secretion there are other means for stimulated insulin secretion. The pyruvate is oxidized by the PDHc and the resulting acetyl-CoA is oxidized in the TCA cycle. Alterations in Exocrine Pancreatic Function in Diabetes Mellitus - Nils Ewald and Philip D. Hepatocellular carcinoma (HCC), which is a common malignancy worldwide, usually develops in a cirrhotic liver due to hepatitis virus infection. Mechanisms of action of GTCs in the inhibition of metabolic syndrome-related liver carcinogenesis. AcknowledgmentsThis work was supported in part by Grants-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan (No. Insulin glargine is equipotent to human insulin for its action on the insulin receptor, but the altered amino-acid sequence leads to a six-fold higher affinity of insulin glargine for the IGF-1 receptor compared to human insulin. Remarkably few large scale trials have tested the clinical efficacy of insulin glargine compared to NPH insulin in multiple injection regimens in type 1 diabetes. A Cochrane meta-analysis found that the use of insulin glargine was associated with the same HbA1c and (based on only 3 studies) a reduction of hypoglycaemia rates by 16% (figure 3).
Considering the absolute numbers, this is of relatively minor importance for most patients (in fact, up to 70% of users of NPH insulin will not experience any hypoglycaemia at all), but in some individuals hypoglycaemia rates may be considerably higher and use of the more expensive insulin glargine could be warranted. In 2009 a series of studies in the journal Diabetologia drew attention to a possible risk of (breast) cancer associated with the use of insulin glargine. The clinical benefits of glargine are probably limited to a slight reduction in hypoglycaemia rates and the fact that (unlike NPH insulin) it does not have to be resuspended before injection. Though all of us know that glargine is a Novo Nordisk innovation, this is the only document I could obtain from the internet. As you well know, there are 3 macro-nutrients our body needs on a regular basis – fats, carbohydrates, and protein. In a study published this week in Cell Metabolism, researchers equate the risk of high protein intake to that of smoking! The definition of high amount of protein is getting 20% or more of your daily calories from protein. Vitamin b-12 only exists in animal meat so I’m wondering how you get vitamin b-12 without the use of supplements? It is very true that way too much emphasis is put on protein in the Standard American Diet and in several weight loss and fad diets. This formula has been chemically altered to avoid binding to proteins in the human body, and to increase the half life, approximately 20-30 hours. This sequence change causes IGF-1 to avoid binding to proteins and allow it to have a much longer half life, around 20-30 hours. Modifications of the natural form occurred with the substitution of the Arg with Glu at the position 3, giving a code R3, and also an extension of a 13 amino acid at the B-terminus. Hypertrophy is what ensues during weight training; it is an increase in the size of muscle cells.
One important process is referred to as the pyruvate cycle and involves coupling of amino acid metabolism to insulin secretion.
Within β-cells of the pancreas, this process, driven by mitochondrial malic enzyme serves as an important means for the use of amino acid carbon oxidation for the stimulated secretion of insulin.
Metabolic syndrome, which is frequently complicated by obesity and diabetes mellitus, is also a critical risk factor for liver carcinogenesis.
IntroductionHepatocellular carcinoma (HCC) is one of the most common malignancies and results in high mortality; an estimated 748,300 new cases and 695,900 deaths occur worldwide in a single year as a result [1]. The black arrows at the right corner mean the incidence of hepatocellular carcinoma (HCC) is up-regulated.
In human interventional studies, relatively high doses of GTCs seem to be often used to achieve high concentrations of catechins in the blood and tissues. It was made by Novo Nordisk, but because they deemed it unpromising and decided to pursue acylated insulins instead, the analogue was sold to Hoechst (now part of sanofi). Available data suggest that the use of insulin glargine or NPH insulin leads to similar HbA1c. A Cochrane meta-analysis by Horvath and colleagues comparing insulin glargine and NPH insulin in patients with type 2 diabetes found no difference in HbA1c and a slight decrease in hypoglycaemia risk with insulin glargine.In type 2 diabetes several trials have compared the use insulin glargine as a once-daily basal insulin with NPH insulin, both in combination with oral glucose-lowering drugs.
This has led to a torrent of observational studies investigating this matter, with some supporting but others finding no evidence for such an association. These benefits have to be weighed against the higher cost of insulin glargine and the fact that many patients will not suffer from hypoglycaemia when using NPH insulin. People who are trying to lose weight instinctively stay away from fats because each gram of fat has 9 calories, whereas each gram of carb or protein has only 4 grams. They found a 75% increase in mortality and a 4-fold increase in the chances of cancer for people aged 50 to 65 who consumed high amount of protein, especially from animal sources. HOWEVER, let’s not assume a home cooked meal is automatically healthier than a product that comes in a package. It has sure worked for me to cut back on the animal protein and make sure what I do eat is as low in additives and hormones etc as I can.
And I tell them that I get the correct amount everyday from plant based foods and not over the protein about through animal foods.
This analog of IGF-1 has been produced with the purpose of increasing the biological activity of the IGF peptide.” IGF stands for insulin-like growth factor.
When applied to cardiomyocyte cultures, R3 have shown a large increase in proliferating cell nuclear antigen expression and in several cyclins involved in cell progression as well as in bromodeoxyuridien (BrdU) labeling (Kajstura et al. It is a hormone released in the liver as well as in peripheral tissues such as skeletal muscle. In lean tissue, Long-R3 IGF-1 (IGF1-LR3) prevents insulin form carrying glucose across cell membranes, as a result, the cells have to change to burning off fat as a source of energy.
Adult humans have a fixed number of muscle cells, that can become larger with training, however the number of muscle sells does not increase. In most studies, the maximum active length for research studies Long-R3 IGF-1 (IGF1-LR3) is 50 days on also 20-40 days off. This pathway involves a cascade of phosphorylation events that ultimately regulate the nuclear translocation of DAF-16 (Ref. The insulin secreting β-cells, in contrast to the liver, do not express the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) but do express robust levels of the gluconeogenic enzyme pyruvate carboxylase (PC).


Indeed, this process is energetically equal to glucose-stimulated insulin secretion (GSIS).
Green tea catechins (GTCs) may possess potent anticancer and chemopreventive properties for a number of different malignancies, including liver cancer. HCC usually develops in the livers of patients with chronic hepatitis and liver cirrhosis caused by persistent infection with hepatitis viruses, indicating that these patients are at high risk of liver carcinogenesis [2,3]. Therefore, a number of case reports of side effects related to administration of GTCs can be seen; these include excess gas, nausea, heartburn, abdominal pain, dizziness, headache, muscle pain, and hepatotoxicity [75,76]. Originally designated HOE901, it was taken through a clinical development program which led to its launch in 2003.
And while some studies reported a decrease of 20-30% in hypoglycaemia rates, others found no difference. However, the only large randomized trials looking at hard endpoints, most notably the aforementioned ORIGIN trial, found no evidence of an increased cancer risk. Side-effects other than slight irritation at the injection site as a result of the acidity of the solution have not been conclusively demonstrated.
It’s interesting to note that the study found that the opposite was true for people over 65 years old! This means a balance of proteins from plant and animal sources, along with complex carbs (whole grains, fruits, vegetables), and healthy fats. In the China Study and much other research, a low fat and high CARB diet has been proven to be the optimal diet for humans. I think I’m arguing semantics here but I work on a dry powder protein shake with a really long ingredients list.
I am no where near protein deficient, I lost weight, I feel great, and the whole protein thing is an absolute myth. All marks, brands and names belong to the respective companies and manufacturers and are used solely to identify the companies and products.
Among the effects the most positive are increased amino acid transport to cells, increased glucose transport, increased protein synthesis, and decreased protein degradation. Long-R3 IGF-1 (IGF1-LR3) increases satellite cell activity, muscle DNA, muscle protein content, muscle weight and muscle cross sectional area. But, with this preparation use you are able to induce hyperplasia which actually increases the number of muscle cells present in the muscle.
Coupled with the activity of PC is the activity of malic enzyme which together, is the only means for pyruvate cycling in β-cells.
Antioxidant and anti-inflammatory activities are key mechanisms through which GTCs prevent the development of neoplasms, and they also exert cancer chemopreventive effects by modulating several signaling transduction and metabolic pathways. In addition to hepatitis virus infection, metabolic syndrome, which is strongly associated with obesity and diabetes mellitus, has been identified as a major risk factor for the development of HCC [4,5,6]. These adverse reactions appear to be experienced in examinations with supplementation of high doses of GTCs in pills or capsules rather than drinking green tea [77]. Heralded as the first insulin with a peakless action profile and a duration of action beyond 24 hours, it soon became a marketing success, even though it was subsequently shown that it does have a peak action and that its duration of action will vary between individuals. These amino-acids increase the iso-electric point[a] of the insulin to a pH of approximately 7.
Of note, 43% and 75% of patients in the glargine and standard group had no hypoglycaemic episodes during the whole follow-up, again highlighting the necessity to tailor the use of this more expensive insulin to those who demonstrably have frequent hypoglycaemic episodes.
A meal or snack with ample protein will keep you satiated longer than a meal with a low protein count, not to mention the importance of protein in cellular growth. Since 99% of the ingredients are botanicals, protein, grains or grasses I hope the long ingredient list doesn’t scare people away. IGF-1 causes muscle cell hyperplasia, which is an actual splitting and forming of new muscle cells. Other effects it has on cell lines are increased cell survival, inhibition of the apoptotic pathways, culture longevity and increased recombination of protein production (Fang et al. After intense resistance training, the body experiences a surge in GH and IGF, and this is one way that new muscle is built. The importance of Long-R3 IGF-1 (IGF1-LR3) lies in the fact that all of its obvious effects work to induce muscle growth. Research studies show that with weight training the new cells develop faster and become stronger and more dense.
INS-N is an unknown insulin-like peptide, and DAF-2 is its cell-surface receptor, which has tyrosine kinase activity. Cytoplasmic malic enzyme plays an important role in acetyl-CoA transport from the mitochondria to the cytosol for its use in lipid biosynthesis.
Furthermore, GTCs are considered to be useful for the prevention of obesity- and metabolic syndrome-related carcinogenesis by improving metabolic disorders. These findings strongly suggest that cirrhotic patients, especially those who are obese and have diabetes mellitus, are at high risk of developing HCC and, therefore, may be good candidates for chemoprevention strategies [7,8,9].Tea, produced from dried leaves of the plant Camellia sinensis, is one of the most popular beverages worldwide.
Recent literature indicates that green tea extract, including GTCs, may inhibit certain types of microsomal cytochrome P450 (CYP), and may not lead to drug-induced liver injury when a drug and green tea are administered simultaneously [78].A randomized, double-blind, placebo-controlled phase IIa chemoprevention trial demonstrated that GTCs have antioxidant effects in individuals who have several risk factors for HCC, and this may suggest that chemoprevention with GTCs is an effective strategy for diminishing oxidative DNA damage [79].
Moreover, the clinical benefits over conventional NPH insulin are actually limited to a slight reduction in hypoglycaemia rates. Although GH is considered to be highly anabolic, in actuality, IGF-1 is suspected to be responsible for the primary anabolic activities of GH.
Several interventional trials in humans have shown that GTCs may ameliorate metabolic abnormalities and prevent the development of precancerous lesions. The possible beneficial effects of tea polyphenols (catechins), including cancer chemoprevention in humans, have been extensively investigated [10,11,12].
In another study, the application of the LR3 IGF-1 has led to an increase in the myocyte bromodeoxyuridine uptake by three to fivefold.
IP3 is phosphatidylinositol-3,4,5-trisphosphate (for simplicity, it is shown here as part of the pathway, although it is actually a membrane component), which is produced as a result of AGE-1 activity and activates PDK-1.
The role of the mitochondrial malic enzyme is principally to provide the cell with an alternate source of pyruvate under conditions where glycolytic flux in reduced.
The purpose of this article is to review the key mechanisms by which GTCs exert chemopreventive effects in liver carcinogenesis, focusing especially on their ability to inhibit receptor tyrosine kinases and improve metabolic abnormalities. Among tea catechins, green tea catechins (GTCs) have been most extensively studied for their cancer chemopreventive and anti-cancer properties. The possible chemopreventive properties of GTCs in metabolic syndrome-related liver carcinogenesis have also been investigated, and are described later. Mode of prolonged action of insulin glargine (see text for full explanation) to crystallization and micro-precipitation of the insulin; subsequently, insulin glargine is slowly released into the circulation from this depot (Figure 2).
But it has also shown that IGF-1 LR3 actions have been blocked by the ERK and P13K labeling which completely abolished the BrdU uptake. This causes the growth of muscles through both hyperplasia (which is an increase in number of muscle cells) and mitogenesis (which is the actual growth of new muscle fibers). In these circumstances, the pyruvate generated by the actions of mitochondrial malic enzyme comes from fumarate precursors such as glutamine. We also review the evidence for GTCs acting to prevent metabolic syndrome-associated liver carcinogenesis. In addition, the ability of GTCs to improve metabolic abnormalities and reduce body weight has been reported by a number of basic and clinical studies [13,14,15]. The authors found that there were major limitations that needed to be taken into account when interpreting the results of these studies, including an improper comparison of control and treatment groups, possible selection bias, and a lack of randomization.
High amounts of protein in the diet do indeed create a health risk, but nothing on the order of smoking. Furthermore, ut has been shown that in mycocytes, IGF-1 R3 stimulates the cardiomyocyte division in vivo (Sundgren et al. When glutamine is de-aminated by glutaminase the resulting glutamate can also be de-aminated by glutamate dehydrogenase yielding 2-oxoglutarate (α-ketoglutarate) which can then be shunted to malate synthesis in the TCA cycle. These reports indicate that GTCs, which can exert both chemopreventive and anti-metabolic syndrome effects, are promising agents to prevent the development of HCC, especially in obese liver cirrhotic patients with metabolic disorders.In this article, we provide an overview of the clinical characteristics and molecular pathogenesis of HCC, focusing on the role of obesity and its related metabolic abnormalities.


In addition, the dosage and duration of GTC administration varied between studies, and this might have affected the results of these studies. DAF-16 is a forkhead class transcription factor that is homologous to the FOXO class of human transcription factors, and is probably orthologous to human FOXO3A. We also review the evidence that GTCs might prevent obesity- and metabolic syndrome-related liver carcinogenesis.
Therefore, large-scale, randomized, double-blinded, placebo-controlled studies should be conducted to clarify the chemopreventive effects of GTCs on HCC development in chronic liver disease patients, especially those who have metabolic syndrome or are obese. It has also been suggested that IGF-1-Long 3R is more potent than the IGF-1 because of its low binding capacity with all known IGF binding proteins (Tomas et al.
It has a potent effect on lipid (fat) metabolism, and helps the body burn fat at a significantly elevated rate. The target of rapamycin (TOR), JNK and RAS pathways also feed into the insulin-like signalling pathway at the level of DAF-16 regulation. Interestingly, the serum levels of IGF-1, VEGF, and prostate-specific antigen were significantly decreased following the administration of a green tea mixture to prostate cancer patients [81]. If you chow down on big hunks of red meat at every meal and smoke and drink and do not exercise, the first thing you should take on is smoking cessation. In addition, IGF-1 is both a neuroprotector and neuropromotor, which improves mental functions such as reflexes, memory, and learning ability.
TOR is a kinase that responds to intracellular amino acids, especially leucine, among other activities; RAS and JNK are involved in numerous signal-transduction cascades in mammals. Therefore, appropriate biomarkers, including HCC-related tumor markers and several types of growth factors associated with liver carcinogenesis and fibrosis, should be measured when evaluating the chemopreventive effects of GTCs on liver tumorigenesis in future clinical trials. In another investigation, feeding of LR3-IGF-1 in different amounts to investigate the effects on somatotropic axis (plasma levels of IGF-1 and 2, IGFBPs) was done. IGF is also important for production of connective tissue and insuring proper bone density. They have reported that plasma Long-R3 increased when administered subcutaneously but with no such behavior when administered orally. Although IGF-1 is very potent at building muscle and burning fat, the Lr3 IGF-1 version is roughly 2-3x as powerful.
Furthermore, LR3 lowered the levels of native IGF-1 in rbGH-injected in calves, but L-R3 increased the amounts of IGF-II concentrations when administered with L-R3 subcutaneously. Lr3IGF-1 (Long R3 Insulin-like Growth Factor-I or Long R3IGF-I) is an 83 amino acid analog of human IGF-I actually comprising the complete human IGF-1 sequence but with the substitution of an Arg for the Glu at position 3, as well as a 13 amino acid extension peptide at the N-terminus. The parenteral administration of the Long R3 IGF-1 decreased the growth hormone concentration but did not affect the secretory system. This makes Long R3IGF-I significantly more potent (2-3x) than IGF-I in studies, because it has a lower affinity to be rendered inactive by IGF binding proteins, and consequently more potential activity in the body. It was also reported that the somatotrophic acis is basically functioning in neonatal calves and can be influenced by nutrition, growth hormone and Long-R3-IGF-1 (IGF1-LR3). Overweight and obesity increase the risk for liver cancer in patients with liver cirrhosis and long-term oral supplementation with branched-chain amino acid granules inhibits liver carcinogenesis in heavier patients with liver cirrhosis. Molecular Mechanisms for Anti-Cancer Effects of GTCs and Chemopreventive Potential in Liver CarcinogenesisChemopreventive and anti-cancer effects of GTCs in HCC have been reported in several in vitro studies (for more detail, see review [54]).
EGCG inhibits the growth and proliferation of human HCC-derived cells by inducing apoptosis [55,56,57]. Obesity, Metabolic Syndrome, and HCCObesity, a serious healthcare problem worldwide, and its related metabolic disorders, including diabetes mellitus and insulin resistance, which are collectively known as “metabolic syndrome” have been recognized as major risk factors for the development of HCC [4,5,6]. Several meta-analyses have shown a significant association between the risk of liver carcinogenesis and obesity- and diabetes mellitus-related complications [27,28,29]. In the literature, it is shown that the levels of both IGF-1 and IGF-2 in cells and culture media are decreased by treatment with EGCG, while the levels of IGF binding protein-3 are increased. Furthermore, a higher body mass index and diabetes mellitus have been shown to increase the risk of HCC in patients with decompensated cirrhosis [5]. In addition, treatment of HuH7 human HCC cells with EGCG decreases the expression of both phosphorylated and non-phosphorylated vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) proteins [59].
Insulin resistance and hyperleptinemia, both of which are frequently observed in obese individuals, also contribute to the increased risk of HCC recurrence after curative treatment [6,30].
EGCG also inhibits HuH7 cell proliferation and down-regulated the levels of VEGF in culture media, suggesting that EGCG may be able to inhibit cell growth by disrupting the VEGF-VEGFR related autocrine loop existing in HCC cells. These two article, focusing on IGF-1R and VEGFR-2, indicate that certain types of RTKs and their downstream pathways are key targets of GTCs and hence mediators of their chemopreventive and anti-cancer properties. Moreover, EGCG suppresses platelet-derived growth factor (PDGF)-induced cell proliferation in human hepatic stellate cells by inhibiting the phosphorylation of PDGF receptor (PDGFR), another RTK [60]. Along with the direct effects of EGCG on certain types of RTKs at the cell surface, several studies have revealed that EGCG has indirect effects on RTKs by targeting the lipid organization of the plasma membrane, lipid rafts.
EGCG treatment alters the lipid rafts of cancer cells and inhibits binding of the ligand epidermal growth factor (EGF) to the EGF receptor (EGFR), which is an RTK as well, and the subsequent receptor dimerization [61].
EGCG also decreases cell surface EGFR by inducing the internalization of EGFR into endosomal vesicles, leading to inhibiting the activation of the receptor and exerting anti-cancer effects [62].
Although only colon cancer cells are employed in these examinations, the indirect effects on cell surface RTKs appear to be one of the putative mechanisms of GTCs against liver cancer. Administration of EGCG through drinking water also prevented carbon tetrachloride (CCl4)-induced rat hepatic fibrosis by inhibiting IGF-1R and PDGFR-? expression [63]. These findings may be particularly significant because, in addition to HCC cells, GTCs also target several types of RTKs in a variety of other cell types, and this might contribute to the prevention of liver fibrosis progression, a precancerous condition of HCC development.A number of in vivo preclinical studies, including chemically induced models, tumor xenograft models, and spontaneous models, have found that GTCs have chemopreventive effects in liver carcinogenesis [54]. Supplementation with GTCs significantly suppressed the development of glutathione S-transferase placental form (GST-P)-positive (GST-P+) foci, a hepatic preneoplastic lesion, induced by DEN via reduction of oxidative stress [64].
The growth of HCC xenografts was suppressed by administration of EGCG in drinking water, and this was associated with the induction of apoptosis [56]. Furthermore, EGCG administration also reduced the incidence of spontaneous HCC development in mice [65]. The results of these preclinical studies demonstrate that GTCs can potentially prevent the early phase of liver carcinogenesis and inhibit the growth of existing HCC.
Clinical Trial Using GTCs and Future DirectionsSeveral series of preclinical investigations using both cell cultures and rodent models have strongly indicated that GTCs have chemopreventive and therapeutic potential in human cancers. The results from a randomized, double-blinded, placebo-controlled study showed that oral administration of GTCs for 1 year also inhibited the progression of high grade prostate intraepithelial neoplasia to prostate cancer [67]. Moreover, oral administration of mixed tea products significantly decreased the size of leukoplakia, a precancerous lesion of the oral mucosa [68].
These findings suggest that an interventional approach using GTCs may be effective in the prevention of certain types of tumorigenesis, especially in early stages.It is believed that consumption of green tea in its whole form provides greater anti-cancer effect than supplementation with EGCG alone.
Indeed, several reports have indicated that EGCG exerts more significant cancer chemopreventive effect when administered in combination with other tea catechins [69,70,71].
Our findings have also shown that EGCG treatment combined with (?)-epicatechin (EC) results in synergistic inhibition of cell growth in the HT29 human colon cancer cell line [72]. According to the combination assay, the optimal ratio of EGCG to EC for effective anti-cancer activity is 60:7. The ratio reflects the relative concentration of EGCG to EC of Polyphenon E (PolyE), which contains 65% EGCG, 25% other catechins, and 0.6% caffeine, extracted from green tea. PolyE is reported to display anti-cancer effects almost equivalent to that of the same concentration of EGCG alone in in vitro study [72]. Other studies in rodents have also demonstrated greater efficacy from PolyE in inhibiting tumor development compared to GTCs [10,73]. These findings suggest that the anti-cancer effect of GTC may differ depending on its composition or combination with other agents.



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