What is IGF-1 and How Does it Work

[01dragonslayer]

What is IGF-1?​

Insulin-like Growth Factor-1 (IGF-1), also known as Somatomedin-C, is a polypeptide growth factor that is a member of the insulin family of peptides. IGF-1 includes 70 amino acids with a molecular weight of 7649 Daltons. Similar to insulin, which has 51 amino acids, IGF-1 has an A and B chain connected by 3 disulfide bonds in a single chain. The main source of IGF-1 for adults is the liver. The Insulin-like growth factors (IGFs) are mitogenic polypeptides that stimulate the proliferation and survival of various cell types including muscle, bone, and cartilage tissue.



In recent years, new technologies have enabled many advances in the growth hormone (GH) axis (Fig 1). The secretion of GH from the anterior pituitary is regulated by GH releasing hormone (GHRH), somatostatin (GH secretion inhibiting hormone) and other hypothalamic peptides called GH secretagogues, including ghrelin. GH induces the generation of IGF-1 in the liver and regulates the production of IGF-1 in many other tissues. IGF-1 uses autocrine and paracrine signaling mechanisms to interact with its target tissues. IGF-1 then stimulates systemic body growth, producing growth-promoting effects on almost every cell in the body, including skeletal muscle, cartilage, bone, liver, kidney, nervous, skin, hematopoietic cells and lung tissue.

There are many studies reporting the anabolic and chondrogenic effects of IGF-1 on the cartilage tissue by increasing the type 2 collagen mRNA expression and proteoglycan synthesis. IGF-1 plays a critical role in the responses of muscle and bone to physical stress and is required for myocyte hypertrophy, proliferation of satellite cells, osteoblast survival, and elaboration of bone in response to tissue damage. IGF -1 promotes fat metabolism in muscle tissue while simultaneously conserving glucose and up-regulating protein synthesis in individual myocytes, with the net result being muscle hypertrophy (enlargement due to increase in cell size).



Fig 1: Metabolic effects of IGF-1. GH, and insulin under physiological conditions on their target organs. The figure summarizes schematically some of the metabolic effects that IGF-1 (blue continuous line), GH (red discontinuous line), and insulin (green dotted line) exert on the kidney (upper left), brain (upper center), skeletal muscle (left), liver (center), adipose tissue (right), and pancreas (bottom). GH growth hormone, GHRH growth hormone releasing hormone, FFA free fatty acid, IR insulin receptor substrate, IGF-1 insulin- like growth factor 1, IGFBP-1 insulin-like growth factor binding protein 1.

The effects of IGF-1 are modulated by a family of binding proteins (IGFBPs) that carry the ligand in the circulation and extracellular fluids. In the plasma, 99% of IGFs are complexed to a family of binding proteins, which modulate the availability of free IGF-1 to the tissues. There are six binding proteins, with 80-90% of IGF-1 in humans carried by IGFBP-3. IGFPB-1 is regulated by insulin and IGF-1 and IGFBP-3 is regulated mainly by GH but also to some degree by IGF-1.

Insulin-like growth factor 1 receptor (IGF-1R) and other tyrosine kinase growth factor receptors signal through multiple pathways, including mitogen-activated protein (MAP) and P13K. A key pathway is regulated by phosphatidylinositol-3 kinase (PI3K) and its downstream partner, the mammalian target of rapamycin (mTOR). Rapamycin’s complex with FKBPP12 to inhibit the mTORC1 complex. mTORC2 remains unaffected and responds by upregulating Akt, driving signals through the inhibited mTORC1 (Figure 2).

What have Research Studies Shown?​

Scientific research has revealed that IGF-1 can do the following:

• Conditions requiring anabolic enhancement

• Sports/athletic injury recovery

• Soft tissue repair

• Tendon/ligament/muscle repair

• Athletic or exercise performance enhancement (note this product is banned by WADA)

• Anti-aging support

• Cardiovascular conditions, including heart failure (CHF)

• Bone density improvement

• Brain/CNS issues

• Type 1 and Type 2 diabetes, Insulin resistance

• Adjunct to weight loss program; MetS

• Chronic liver disease

• Growth disorders – Acromegaly

• Helps improve connective tissue healing

• Improves brain neurogenesis, development and maturation, myelination

• Improves brain cell survival and resistance to injury

• Improves cellular repair

• Improves antioxidant system

IGF-1 in Research (Expanded)​

Aging/Inflammation

IGF-1 levels decline as we age, and this phenomenon has been termed “somatopause” (Figure 3). Only low levels are generally detected after age 60. Improving IGF-1 levels is reported beneficial for “anti-aging” benefits. Higher IGF-1 levels are reported to improve muscle strength and mobility in older women. IGF-1 is reported to increase glutathione peroxidase, thereby improving the antioxidant defense system.



The IGF-axis helps maintain normal glucose homeostasis and keeps inflammation regulated. When IGF-1 levels are low, inflammation is high. Low levels of IGF-1 and IGFBP-3 have been associated with increased markers of inflammation, including C-reactive protein (CRP) and Interleukin-6 (IL-6). Improved IGF-1 levels are reported to decrease inflammation and decrease autoimmunity. Laboratory and human studies report inflammatory conditions, including autoimmunity, inflammatory bowel disease, multiple sclerosis, contact dermatitis, rheumatoid arthritis and lupus, are decreased when IGF-1 is administered. Immune cells, in particular macrophages, also produce IGF-1 and contribute to local tissue homeostasis. Studies have reported that lymphocyte-derived growth hormone is involved in the production of more lymphocytes and that these, in turn, can actually produce IGF-1 within the immune system.



Brain and Aging

IGF-1 is widely expressed in the central nervous system (CNS), where it promotes proliferation, survival, and differentiation of neuronal and non-neuronal cells. Microglial derived IGF-1 promotes neuronal survival. Further, IGF-1 is a potent neurotrophic factor, rescuing neurons from apoptosis and enhancing neuronal growth and myelination and prolonging survival and resistance to injury. IGF1 signaling is key in promoting organized adult hippocampal neurogenesis.

Low-dose IGF1 treatment triggered a small increase in the differentiation of neuronal progenitors into neurons. IGF1 not only promotes adult neurogenesis through increased stem cell proliferation, but also through organized cell migration Reduced IGF1 signaling is linked to cognitive dysfunction. Studies in humans found a significant correlation between better perceptual motor performance, information processing speed and fluid intelligence and higher circulating IGF1 levels. This is contradictory with some studies reporting that reduced IGF1 signaling is neuroprotective, while others claim that reduced IGF1 signaling with age contributes to brain aging. IGF1 appears to act in concert with BDNF and other neurotrophic factors to promote neurogenesis and remodeling in the brain.



Muscle Growth/Healing

Advancing age is associated with a progressive loss of skeletal muscle mass and function. IGF-1 appears to be of particular importance for the muscle regeneration process. IGF-I stimulates myoblasts proliferation and differentiation, and is implicated in the regulation of muscle growth.

In a mouse model, direct injections of human recombinant IGF-I at two, five, and seven days after injury enhanced muscle healing in lacerated, contused, and strain-injured muscles. Although IGF-I has been reported to improve muscle healing, a study reported that histology of the injected muscle revealed fibrosis within the lacerated site, despite high levels of IGF-I production.



Diabetes

Although the growth hormone (GH)-IGF-1 axis principally regulates tissue growth

and differentiation, insulin exerts its primary effects on fuel metabolism. However, these two endocrine systems interact at multiple levels and in Type 1 Diabetes, the GH-IGF-1 axis is very imbalanced, leading to increased secretion of GH, reduced plasma levels of IGF-1, and complex tissue-specific changes in IGF binding proteins (IGFBPs).

Individuals with type 1 diabetes exhibit abnormalities of the growth GH/ IGF/IGFBPs axis, including GH hypersecretion, reduced circulating levels of IGF-1 and IGFBP-3, and elevated levels of IGFBP-1. IGF-1 can promote glucose uptake in certain peripheral tissues in the magnitude of 4-7% from that of insulin. Administration of IGF-1 to patients with type 1 and 2 diabetes, insulin sensitivity is significantly improved, insulin requirements are reduced, and glycemic control of dyslipidemia is generally improved in short-term studies.



Obesity/Metabolic Syndrome (MetS)

IGF-1 signaling has been implicated in the differentiation and metabolic regulation of adipocytes. In the absence of IGF1, pre-adipocytes differentiation is prevented in vitro. This can be overcome by addition of insulin, which at sufficient concentration will activate the IGF-1 receptor. In addition, IGF-1 also can regulate adipocyte metabolism, suppressing lipolysis in a manner similar to insulin. Given that obesity is associated with adipocyte stress and death, local production of IGF-1 adipose tissue plays a critical role in response to the development of obesity.



Cardiovascular

IGF-1 is reported to have anti-inflammatory and antioxidant effects on blood

vessels, stabilizing existing plaque and reducing additional plaque accumulation. Cardiovascular disease (coronary artery disease, fatal ischemic heart disease, ischemic stroke, congestive heart failure, as well as slower recovery after a heart attack) are all associated with reduced levels of IGF-1. Low levels of IGF-I are associated with increased risk of ischemic heart disease (IHD), cardiovascular mortality, and diabetes mellitus.

Of particular note is a 2011 meta-analysis (n=12 clinical studies and 14,906 participants), reported the risk of dying from all causes was increased in subjects with low as well as high IGF-1 levels. Individuals with low IGF-1 have a 1.27 x increased risk of dying from all causes, while those with higher levels were at a 1.18 x increased risk.





Bone Density

IGF-1 and GH (growth hormone) are an essential part of skeletal growth during puberty and essential for bone health throughout life. Higher IGF-1 levels are associated with greater bone mineral density in older women. A review of clinical studies using IGF-1 administration for improving bone health reported that IGF-1 has significant anabolic activity and bone protective effects.





IGF-1 LR3

• Recombinant form of IGF-1

• 83 amino acids, molecular weight 9,111 Daltons

• IGF-1 LR3 is modified from the base IGF-1 peptide by replacing the glutamic acid at position 3 with arginine (R) – hence the R3.

• The L stands for long, as an additional 13 amino acids were added, again reducing binding, while improving metabolic stability.

• Increased half-life to 20-30 hours vs. IGF-1

• Reduced affinity for IGF binding proteins, therefore increased potency

• 3 x potency vs. IGF-1.

• IGF-1 LR3 is not recommended to use for more than 10 days consecutively.





References:

Kawai M, Rosen CJ. The IGF-I regulatory system and its impact on skeletal and energy homeostasis. J Cell Biochem. 2010;111(1):14-19.

Jonsson KB, Wiberg K, Ljunghall S, Ljunggren O. Insulin-like growth factor I does not stimulate bone resorption in cultured neonatal mouse calvarial bones. Calcif Tissue Int. 1996;59(5):366-370.

Tsukazaki T, Usa T, Matsumoto T, Enomoto H, Ohtsuru A, Nam- ba H, et al. Effect of transforming growth factor-beta on the insulin-like growth factor- autocrine / paracrine axis in cultured rat articular chondrocytes. Exp Cell Res. 1994;215(1):9-16.

Musaro A, McCullagh KJ, Naya FJ, Olson EN, Rosenthal N. IGF-1 induces skeletal myocyte hypertrophy through calcineuri in association with GATA-2 and NFATc1. Nature 1999;400:581-585.

Lu H, Huang D, Saederup N, Charo IF, Ransohoff RM, Zhou L. Macrophages recruited via CCR2 produce insulin-like growth factor-1 to repair acute skeletal muscle injury. FASEB J 2011;25:358-369.

Aguirre GA, Rodriguez J, de la Garza RG, et al. Insulin-like growth factor-1 deficiency and metabolic syndrome. J Transl Med.2016;14:3.

Higashi Y, Pandey A, Goodwin B, et al. Insulin-Like Growth Factor-1 Regulates Glutathione Peroxidase Expression and Activity in Vascular Endothelial Cells: Implications for Atheroprotective Actions of Insulin-Like Growth Factor-1. Biochem Biophys Acta. 2013;1832(3):391-399.

Clemmons DR. Role of insulin-like growth factor in maintaining normal glucose homeostasis, Horm. Res. 2004;62(Suppl.1):77– 82.

K. Kaushal, A.H. Heald, K.W. Siddals, M.S. Sandhu, D.B. Dunger, J.M. Gibson, N.J. Wareham, The impact of abnormal- ities in IGF and inflammatory systems on the metabolic syn- drome, Diabetes Care 27: (2004) 2682–2688.

Rajpathak SN, McGinn AP, Strickler H, et al. Insulin-like growth factor (IGF) axis, inflammation and glucose tolerance among older adults. Growth Horm IGF Res. 2008;18(2):166-173.

Rajpathak SN, McGinn AP, Strickler H, et al. Insulin-like growth factor (IGF) axis, inflammation and glucose tolerance among older adults. Growth Horm IGF Res. 2008;18(2):166-173.

Rom WN, Basset P, Fells GA, Nukiwa T, Trapnell BC, Crysal RG. Alveolar macrophages release an insulin-like growth factor I-type molecule. J Clin Investig 1988;82:1685-1693.

Lalancette-Hebert M, Gowing G, Simard A, Weng YC, Kriz J. Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci 2007;27:2596-2605.

Wrigley S, Arafa D, Tropea D. Insulin-like growth factor 1: at the crossroads of brain development and aging. Front Cell Neurosci. 2017;11:14.

 

[Augustwest]

Good post. Seems peptides are getting big again and my knowledge sure is rusty!!

Why is it advised not to go longer than 10 day cycles?

 

[01dragonslayer]

Good post. Seems peptides are getting big again and my knowledge sure is rusty!!

Why is it advised not to go longer than 10 day cycles?

Depending where you research the 10 day cycle can vary. Desensitization can after a certain time of use making IGF less effective.

 

[kragon]

so ya'll think IGF-1 Des is best for spot enahncement lagging parts or would it have to go through the whole process and basically would just start a cascading event for growth throughout the body?

 

[01dragonslayer]

so ya'll think IGF-1 Des is best for spot enahncement lagging parts or would it have to go through the whole process and basically would just start a cascading event for growth throughout the body?

This is what I've read and researched. DES needs to be injected right prior to strength training because of its short half-life.

 

[Augustwest]

What is the advised dosage timing? I know certain GH peptides effect insulin and glucose. And I know IGF is typically advised pre or post workout. How should I structure it around meals?

Is it better to eat before or after?

Also what about actual dosage? I remember somewhere around 50mcg is a good start.

 

[01dragonslayer]

What is the advised dosage timing? I know certain GH peptides effect insulin and glucose. And I know IGF is typically advised pre or post workout. How should I structure it around meals?

Is it better to eat before or after?

Also what about actual dosage? I remember somewhere around 50mcg is a good start.

Dosages are as follows for IGF-1 LR3: No more than approximately 40 – 50mcg per day should be used by men, and no more than 20mcg per day for females. Because of its long active half-life in the body, the LR3 variant should only be administered once and no more than twice per day. On training/workout days, the IGF-1 dosage should be administered either just before the workout or just after the workout. It is up to the user’s preference, as either before or after is perfectly fine (as is pre-workout only, or post-workout only). If administered twice per day, the full daily dosage can be split in half between the two (e.g. 20mcg pre-workout, and 20mcg post-workout for a total of 40mcg per day). On non-training days, it can be administered at any time of the day.

Dosages are as follows for IGF-1 DES: There is a little bit more variation when it comes to the dosage of the DES variant compared to LR3. For IGF-1 DES, the dosage range is upwards of 50 – 150mcg per day. Because of its much shorter half-life than the LR3 variant, higher dosages can be utilized without as much of the risk for long term effects on the body, though caution should still be utilized. It can be used in the same pre/post-workout manner as IGF-1 LR3, and is in fact commonly used in this manner because of its short half-life.


IGF-1 LR3 1mg Injectable
Either form of IGF-1 can be administered intramuscularly, or subcutaneously. Use of either form should not exceed cycle lengths of 30 days’ total before taking a minimum of 2 weeks off, though longer breaks than 2 weeks between IGF-1 cycles are recommended. This is not only because of the risk of health effects in the long term, but also to ensure IGF-1 receptors return to proper working order following a cycle.

Both variants of IGF-1 will be packaged in a lyophilized powder format (a dehydrated/dried out powder) that will need to be reconstituted either with bacteriostatic water, or – commonly in the case of LR3 – a small amount of acetic acid diluted into bacteriostatic water. It is the user’s responsibility to calculate how much water he or she will have to add to the lyophilized powder in order to reconstitute it properly to form a desired concentration. Most IGF-1 preparations (both LR3 and DES variants) usually come as a standard 1mg total of lyophilized powder. As an example, if 2ml of bacteriostatic water is added to the powder, this will yield the user 50mcg per 10iu (or 0.10ml) of water. Concentrations can and will vary depending on the product purchased, and how the user wishes to reconstitute the product with any desired amount of water. It is imperative that anyone wishing to use any form of IGF-1 understands the proper basic mathematical calculations before reconstituting.

 

[01dragonslayer]

What is the advised dosage timing? I know certain GH peptides effect insulin and glucose. And I know IGF is typically advised pre or post workout. How should I structure it around meals?

Is it better to eat before or after?

Also what about actual dosage? I remember somewhere around 50mcg is a good start.

Here is another good read........ https://johndoebodybuilding.com/20-week-hghigf-1insulin-blast/

 

[01dragonslayer]

What is the advised dosage timing? I know certain GH peptides effect insulin and glucose. And I know IGF is typically advised pre or post workout. How should I structure it around meals?

Is it better to eat before or after?

Also what about actual dosage? I remember somewhere around 50mcg is a good start.

Another....... https://muscleandbrawn.com/peptides/igf-1-lr3/

 

[Augustwest]

Thank you for that. Seems to me like timing the dose around meals isnt critical with IGF but please correct me if im wrong. Just trying to avoid getting lightheaded.

My typical routine is to lift in the AM. So id consume a banana and protein shake, lift, then do dextrose and protein immediately PWO. Id probably do the igf PWO as well. So does it matter which comes first the igf or the shake?

 

[kragon]

I used to make acetic acid reconstitution liquid with benzyl alcohol, back in the day it was thought that the acidic acid would help keep the IGF from degrading.. looking back, does that make any sense at all?