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IGF-1 LR3 (Insulin-Like Growth Factor-1 Long Arg3) Information
by IGF1LR3

Introduction to the Insulin-Like Growth Factors
IGFs are hormones that play prominent roles in cellular communication by allowing cells to interact with their external physiologic environments. The IGF system of communication is frequently referred to as the IGF axis and consists of cell-surface receptors (IGF-1R and IGF2R), ligands (IGF-1 and IGF2 as well as their derivatives) and a family of six IGF-binding proteins (IGFBP-1 to IGFBP-6). Proteases, a separate contingency of enzymes, remove IGFBPs from circulation to control the body's response to IGFs. The family of insulin-like growth factors (IGFs) are potent growth factors and mitogens (encouraging cell division) that share sequence similarities to the protein insulin. They have prominent physiologic roles in everything from cancer development to physiologic growth and development. IGF-1 and its derivatives, such as IGF-1 LR3, have been of special interest bodybuilders and anti-aging communities.

IGF-1 LR3 is a Potent Derivative of IGF-1
Part of the push to develop anti-cancer protein drugs based off of the properties of IGF-1 has led to the development of synthetic derivatives of the polypeptide hormone. The most potent of these derivatives is referred to IGF-1 LR3 or alternatively as IGF-1 Long Arg3. IGF-1 LR3 has been modified to include 13 additional amino acids on its N-terminal end and has had its third glutamine residue converted to the amino acid arginine. The availability of IGF-1 is almost exclusively controlled by the IGFBPs. The result of the amino acid manipulations in IGF-1 is that IGF-1-LR3 does not bind as strongly to the IGFBPs. Meaning the protein hormone remains in circulation for longer periods of time before being degraded and thus has a longer period of action .

By resisting IGFBP-binding, IGF-1 LR3 has a greater physiologic effect than IGF-1 does, particularly in tissues with high IGFBPs. IGF1 LR3 is, in essence, more potent than IGF-1 because its duration of action is longer. The longer duration of action allows for smaller doses to be administrated with the same effects. Some IGF-1 derivatives, such as the GPE derivative, made up of just the last three N-terminal amino acids of the IGF1 protein, have been shown to have therapeutic effects in neurological injuries. Most studies concerning the effects of IGF-1 derivatives have been carried out in animal models, with little data available for humans. Because IGF-1 is binds to the insulin receptor, it can result in hypoglycemia or low blood sugar.

The Function of Insulin-Like Growth Factor-1
The IGF-1/Growth Hormone (GH) axis is separate from, but affected by, the Insulin-Like Growth Factor (IGF) axis. IGF-1, made primarily by the liver, is produced in response to GH and serves to regulate normal processes of cell proliferation and programmed cell death (apoptosis). IGF-1 plays a very prominent role in cell division by actively encouraging cells to divide, a process that is linked with both growth and development. IGF1 also inhibits apoptosis, thereby preventing cell death and encouraging maximal cell growth, another process linked to normal growth and development. Simply put, many of the effects of growth hormone are mediated through the actions of IGF-1.

Insulin Like Growth Factor Receptors
IGF-1 Long R3 binds to at least two cell surface receptors: IGF-1R and the insulin receptor. The IGF-1 receptor is referred to as the physiologic receptor because IGF-1 binds to it with significantly higher affinity (~100x higher) than it does to the insulin receptor. By binding to IGF-1R, IGF-1 can affect metabolism, cell growth, differentiation (cell division), cell death, normal development, and even malignant growth. IGF-1R has been implicated in several different types of cancer include breast, prostate, and lung cancer. IGF-1 also binds to the insulin receptor and activates it, thereby encouraging cells to take up glucose from the blood stream. In severe cases, excess IGF-1 can lead to hypoglycemia (low blood sugar).

IGF-1 and Cancer
IGF-1 has been implicated in the development of several cancers, but efforts to block the hormone as a means of treatment have been met with little success. It appears that the role of IGF-1 in cancer development is not direct, despite the fact that the hormone is known to reduce cell death. It is currently thought that IGF-1 is a major factor in the development of resistance to anti-cancer therapies. Studies show that increased expression of IGF-1R on cancer cells increases their rate of growth in animal models. Studies also indicate that IGF-1 deficient mice have a reduced capacity to support tumor growth and metastasis. In other words, IGF signaling appears to be a factor in allowing cancer cells to survive long enough to mutate and become resistant to cancer treatment. Unfortunately, it is not clear if the role of IGF-1 in normal tissue is dispensable such that the signaling pathway can be manipulated to reduce tumor growth without having substantial effect throughout the body.

Approved Uses of IGF-1
The primary use of IGF-1 is in research, particularly animal research aimed at uncovering the subtleties of IGF-1 signaling pathways. Active areas of research also include the effects of IGF-1 on muscle, bone, skin, cartilage, the liver, the heart, and the kidneys. The use of IGF-1 as an anti-tumor agent, despite previous research suggesting no effect, is also an active area of investigation.

Recombinant human IGF-1 (rhIGF-1) is currently used, in conjunction with growth hormone, to treat dwarfism and other growth disorders. In such settings, the polypeptide hormone is administered at dosages between 80-120 micrograms per kilogram (mcg/kg) and can impact growth by increasing final height an average of 12-15 cm. Though recombinant growth hormone has been available and used in the treatment of dwarfism in GH-deficient patients since the 1980s, rhIGF-1 has only been available since approximately 2007. The short availability means that long-term data on its effectiveness and side effects are lacking.

The Anabolic Effects of IGF-1 LR3
Currently IGF-1 is not recommended for use as an anabolic agent and, indeed, the recombinant form of the hormone is tightly regulated against such use. Nevertheless, IGF-1 is popular among bodybuilders. The hormone has become so popular, in fact, that a number of different research groups are working to develop methods of detecting IGF-1 misuse among athletes. Growth hormone is easily detected via blood assay, but there is no internationally recognized test for detecting IGF-1 LR3 even though there are standard laboratory assays.

The benefits of IGF-1 on muscle cells are three-fold. The first benefit is on growth. IGF-1 encourages hyperplasia, or an increase in the number of muscle cells. This means that rather than making individual cells larger, IGF-1 encourages more muscle cells to develop. When combined with other forms of supplementation that encourage hypertrophy (increase in the size of cells), IGF-1 can substantially increase strength. The second benefit of IGF-1 on skeletal muscle is in regards to the life span of satellite cells. Satellite support muscle cells, providing them with needed nutrients and helping them to operate efficiently. By increasing the lifespan of these cells, IGF-1 helps to increase their number with muscle tissue. Finally, IGF-1 encourages differentiation of myoblasts, which is to say that it encourages the conversion of stem cell progeny from nonspecific stem cells into dedicated muscle tissue. In this way, IGF-1 actually increases the rate of muscle development by increasing the rate at which cells are converted to muscle cells.

The draw of IGF-1 for anabolic use also is enhanced by its lipolytic or fat-burning properties. The hormone not only increases muscle growth, it increased fat-burning as well. This leads to greater muscle definition. An interesting caveat to the use of IGF-1 and its derivatives for muscle growth is that the effects appear to be transient. Research in rats indicates that losses in strength and size and muscles occur quickly after cessation of hormone injections. These findings would suggest that IGF-1 is not only necessary to build muscle and tissue, but that it is necessary to maintain tissue as well. This has profound implications for health as the risk of serious side effects increases with prolonged use.

IGF-1 and The Prevention of Aging
The decline in IGF-1 levels as an individual ages has been speculated to account for the wide-ranging physiologic manifestations of age including muscle atrophy, cartilage deterioration, and even mental decline. Studies investigating the use of IGF-1 as a supplement to counteract the effects of aging have shown potential benefit and neuroprotective effects in a limited number of settings. Though test subjects with low IGF-1 levels have the highest mortality rates in numerous studies, this does not, as discussed, translate into improved longevity with IGF-1 supplementation. Though the pathway is straightforward in worms and other lower organisms, it is substantially more complicated in mammals. In fact, research has been dramatically contradictory regarding IGF-1. It is worth noting that interference with IGF-1 signaling via calorie restriction increases lifespan, an effect that is in direct opposition to the theory that IGF-1 supplementation will improve lifespan.
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