IGF-1
IGF-1 is an endogenous 70-amino acid polypeptide structurally similar to insulin that mediates most of growth hormone's anabolic effects. It plays critical roles in growth, tissue repair, muscle hypertrophy, and neuroprotection, with a complex relationship to cancer risk and longevity.
Insulin-Like Growth Factor 1 (IGF-1), also known as Somatomedin C, is a 70-amino acid endogenous polypeptide with structural homology to proinsulin. It is the primary mediator of growth hormone's (GH) anabolic and growth-promoting effects and plays fundamental roles in growth, development, tissue repair, and metabolism throughout life.
Overview
IGF-1 is produced primarily in the liver (~75% of circulating IGF-1) in response to GH stimulation, though virtually all tissues produce IGF-1 locally in an autocrine/paracrine manner. It circulates in blood predominantly bound to IGF binding proteins (IGFBPs), particularly IGFBP-3, which forms a ternary complex with the acid-labile subunit (ALS) that extends IGF-1's effective half-life from minutes to hours.
IGF-1 signaling peaks during puberty (driving the adolescent growth spurt) and declines progressively with age, paralleling GH decline. This decline contributes to age-related changes in body composition, bone density, cognitive function, and tissue repair capacity. However, the IGF-1 axis also plays a central role in the biology of aging and cancer — creating a fundamental tension in IGF-1-related interventions.
Mechanism of Action
Insulin-like Growth Factor 1 (IGF-1) is a 70-amino acid peptide hormone primarily produced by the liver in response to growth hormone (GH) stimulation, though it is also synthesized locally in many tissues for autocrine and paracrine signaling. IGF-1 binds with high affinity to the IGF-1 receptor (IGF-1R), a transmembrane receptor tyrosine kinase structurally similar to the insulin receptor. Ligand binding induces receptor autophosphorylation of intracellular tyrosine residues, creating docking sites for insulin receptor substrate (IRS-1 and IRS-2) adaptor proteins, which initiate two major downstream signaling cascades.
The PI3K/Akt/mTOR pathway is the primary mediator of IGF-1's anabolic and survival effects. IRS-1 recruits and activates phosphoinositide 3-kinase (PI3K), which generates phosphatidylinositol-3,4,5-trisphosphate (PIP3), recruiting Akt (protein kinase B) to the membrane for activation. Activated Akt has multiple critical targets: it activates mTOR complex 1 (mTORC1), which phosphorylates p70S6 kinase and 4E-BP1 to drive ribosomal biogenesis and cap-dependent mRNA translation -- the molecular basis of muscle protein synthesis and hypertrophy. Akt also phosphorylates and inactivates pro-apoptotic proteins BAD and caspase-9, while stimulating NF-kB survival signaling, providing potent anti-apoptotic protection that promotes cell survival and tissue maintenance. Additionally, Akt promotes glucose uptake via GLUT4 translocation, contributing to IGF-1's insulin-like metabolic effects.
The Ras/MAPK/ERK pathway drives cell proliferation and differentiation. IGF-1R activation recruits Grb2/SOS adaptor proteins to activate Ras GTPase, initiating the Raf/MEK/ERK kinase cascade. Activated ERK1/2 translocates to the nucleus and phosphorylates transcription factors (Elk-1, c-Fos, c-Myc) that drive gene expression for cell cycle progression, proliferation, and tissue remodeling. In circulation, IGF-1 bioavailability is tightly regulated by six IGF-binding proteins (IGFBPs), with IGFBP-3 carrying approximately 75% of circulating IGF-1 in a ternary complex with acid-labile subunit (ALS), extending its half-life from minutes to hours and controlling tissue-specific delivery.
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IGF-1
**Insulin-Like Growth Factor 1 (IGF-1)**, also known as Somatomedin C, is a 70-a
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Research
Neuroprotection and Cognitive Function
IGF-1 is neuroprotective through multiple mechanisms: promoting neuronal survival via Akt signaling, stimulating neurogenesis in the hippocampus, enhancing synaptic plasticity, and promoting myelination. IGF-1 crosses the blood-brain barrier and is also produced locally by brain astrocytes and neurons.
Age-related IGF-1 decline correlates with cognitive decline, and IGF-1 administration improves cognitive outcomes in animal models of aging, Alzheimer's disease, and traumatic brain injury (Dyer et al., 2016). However, human trials of IGF-1 for neurodegenerative disease have been disappointing, suggesting that timing, dose, and delivery route are critical.
Bone Metabolism
IGF-1 stimulates osteoblast proliferation and differentiation, promoting bone formation. It mediates GH's effects on longitudinal bone growth during development and maintains bone density in adults. Low IGF-1 levels are associated with osteoporosis risk, and GH/IGF-1 axis decline contributes to age-related bone loss (Giustina et al., 2008).
The Longevity Paradox
Model organism research consistently shows that reduced IGF-1/insulin signaling extends lifespan:
- C. elegans: daf-2 (insulin/IGF receptor) mutants live 2-3x longer.
- Drosophila: Insulin receptor substrate mutations extend lifespan.
- Mice: GH receptor knockout mice (Laron dwarf) live ~40% longer. IGFBP-3 overexpression extends lifespan.
- Humans: Centenarians and their offspring show lower IGF-1 levels and reduced IGF-1R signaling (Suh et al., 2008).
This creates a fundamental paradox: IGF-1 promotes tissue repair, muscle mass, bone density, and neuroprotection in the short/medium term, but reduced IGF-1 signaling is associated with longevity. The resolution may involve context-dependent effects, tissue-specific signaling, and the difference between pulsatile and tonic IGF-1 exposure.
Anabolic Effects and Muscle Growth
IGF-1 is a potent anabolic hormone that promotes skeletal muscle hypertrophy through mTOR-mediated protein synthesis and satellite cell activation. Locally produced IGF-1 in muscle (mechano-growth factor, MGF) is upregulated by exercise and mechanical loading, mediating exercise-induced muscle adaptation (Goldspink, 2005).
Recombinant IGF-1 administration increases lean body mass and reduces body fat in GH-insensitive states. In severe primary IGF-1 deficiency (Laron syndrome), recombinant IGF-1 (mecasermin/Increlex) is the standard of care, demonstrating that IGF-1 mediates most of GH's growth effects (Laron, 2004).
The Cancer Risk Debate
This is the most controversial aspect of IGF-1 biology. Epidemiological studies consistently show that higher circulating IGF-1 levels are associated with increased risk of several cancers, particularly prostate, breast, and colorectal cancer (Renehan et al., 2004). The mechanisms are clear: IGF-1 promotes cell proliferation, inhibits apoptosis, and activates mTOR — all pro-tumorigenic effects.
However, this relationship is complex:
- Association vs. causation: High IGF-1 is associated with cancer risk, but IGF-1 administration has not been shown to cause cancer in clinical trials.
- The longevity paradox: Low IGF-1 signaling extends lifespan in model organisms (worms, flies, mice). Centenarian populations often have low IGF-1 and IGF-1R activity. Yet low IGF-1 also impairs tissue repair, immune function, and neuroprotection.
- Context-dependency: IGF-1's effects may differ in normal tissue (repair, maintenance) versus pre-malignant tissue (proliferation, survival).
- IGF-1R as drug target: Multiple IGF-1R inhibitors have been developed as cancer therapeutics, though clinical results have been largely disappointing (Pollak, 2012).
Safety Profile
Recombinant IGF-1 (mecasermin) carries significant risks at therapeutic doses: hypoglycemia (most common and dose-limiting), injection site hypertrophy, intracranial hypertension, and tonsillar/adenoid hypertrophy in children. Long-term concerns include the theoretical cancer risk associated with sustained IGF-1 elevation. IGF-1 therapy requires careful glucose monitoring due to insulin-like hypoglycemic effects. The drug is FDA-approved only for severe primary IGF-1 deficiency, reflecting its narrow therapeutic index. Indirect IGF-1 elevation through GH secretagogues (sermorelin, ipamorelin, MK-677) is generally considered safer due to preserved physiological feedback.
Pharmacokinetic Profile
IGF-1 — Pharmacokinetic Curve
Subcutaneous injection (recombinant form)Quick Start
- Route
- Subcutaneous injection (recombinant form)
Molecular Structure
- Formula
- C331H512N94O101S7
- Weight
- 7649 Da
- CAS
- 67763-96-6
- PubChem CID
- 4369
- Exact Mass
- 391.1090 Da
- LogP
- 1.7
- TPSA
- 110 Ų
- H-Bond Donors
- 2
- H-Bond Acceptors
- 6
- Rotatable Bonds
- 6
- Complexity
- 582
Identifiers (SMILES, InChI)
InChI=1S/C19H21NO6S/c21-18(20-22)14-19(10-12-25-13-11-19)27(23,24)17-8-6-16(7-9-17)26-15-4-2-1-3-5-15/h1-9,22H,10-14H2,(H,20,21)
ARIRIZBKMKMEBD-UHFFFAOYSA-NResearch Protocols
subcutaneous Injection
- Routes: Subcutaneous injection (standard), intravenous (research infusion studies).
| Goal | Dose | Frequency | Duration |
|---|---|---|---|
| FDA-approved use | 0.04-0.12 mg | Twice daily | — |
| Research dosing | 20-100 µg, 40-120 µg | Twice daily | — |
intravenous Injection
- Routes: Subcutaneous injection (standard), intravenous (research infusion studies).
| Goal | Dose | Frequency | Duration |
|---|---|---|---|
| General Research Protocol | 0.04-0.12 mg | Twice daily | — |
| General Research Protocol | 20-100 µg | Per protocol | — |
| General Research Protocol | 40-120 µg | Twice daily | — |
Interactions
Peptide Interactions
IGF-1 and insulin share significant structural homology and receptor signaling overlap. IGF-1 can bind insulin receptors (at lower affinity), and hybrid IGF-1R/insulin receptor heterodimers exist. This cross-talk explains IGF-1's effects on glucose metabolism and why insulin resistance and IGF-1 ...
What to Expect
What to Expect
Rapid onset expected; half-life of ~10-15 minutes (free); ~12-15 hours (bound to IGFBP-3/ALS) indicates fast-acting pharmacokinetics
Research studies in adults typically 6 months to 2 years.
Due to short half-life (~10-15 minutes (free); ~12-15 hours (bound to IGFBP-3/ALS)), effects are expected per-dose; consistent daily administration...
Regular administration schedule required; effects are dose-dependent and do not persist between doses
Safety Profile
Common Side Effects
- Dermatological Issues:: Elevated IGF-1 is strongly linked to acne breakouts (zits) through the stimulation of sebaceous glands.
- Cancer Risk:: Concerns exist regarding the potential for high IGF-1 levels to accelerate the growth of existing solid malignancies, such as prostate cancer.
- Insulin Sensitivity:: Chronic pharmacological elevation (via HGH or peptides) can negatively impact glucose metabolism and lead to pre-diabetic states.
Quality Indicators
What to look for
- Multiple peer-reviewed studies available
Red flags
- Potential carcinogenicity concerns
Frequently Asked Questions
References (13)
- [1]Supplementing With Which Form of Creatine (Hydrochloride or Monohydrate) Alongside Resistance Training Can Have More Impacts on Anabolic/Catabolic Hormones, Strength and Body Composition?
→ This study demonstrates that resistance training combined with creatine supplementation significantly increases serum IGF-1 levels, contributing to improved muscle mass and strength.
- [2]Betaine supplement enhances skeletal muscle differentiation in murine myoblasts via IGF-1 signaling activation
→ Research indicates that betaine supplementation improves muscle fiber maturation and hypertrophy by increasing the expression of the IGF-1 receptor and activating its signaling pathways.
- [3]The influence of arginine supplementation on IGF-1: A systematic review and meta-analysis
→ A meta-analysis exploring how arginine intake affects circulating IGF-1 levels, noting its role as a potential secretagogue for the growth hormone/IGF-1 axis.
- [4]Creatine Supplementation and Skeletal Muscle Metabolism for Building Muscle Mass- Review of the Potential Mechanisms of Action
→ This review highlights that creatine increases muscle mass partly by modulating the IGF-1/mTOR pathway, serving as a cellular stressor that triggers protein synthesis.
- [5]The influence of vitamin D supplementation on IGF-1 levels in humans: A systematic review and meta-analysis
→ A large-scale analysis found that Vitamin D supplementation significantly increases circulating IGF-1 concentrations in humans, suggesting a synergistic relationship for bone and muscle health.
- [6]
- [8]Dyer AH et al The role of Insulin-Like Growth Factor 1 (IGF-1) in brain development, maturation and neuroplasticity Neuroscience (2016)
- [9]Giustina A, Mazziotti G, Canalis E Growth hormone, insulin-like growth factors, and the skeleton Endocr Rev (2008)
- [10]Renehan AG et al Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis Lancet (2004)
- [11]Pollak M The insulin and insulin-like growth factor receptor family in neoplasia: an update Nat Rev Cancer (2012)
- [12]Suh Y et al Functionally significant insulin-like growth factor I receptor mutations in centenarians Proc Natl Acad Sci U S A (2008)
- [13]Guevara-Aguirre J et al Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans Sci Transl Med (2011)
- [7]Laron Z Laron syndrome (primary growth hormone resistance or insensitivity): the personal experience 1958-2003 J Clin Endocrinol Metab (2004)
IGF-1 LR3
IGF-1 LR3 is a synthetic modified construct of insulin-like growth factor-1 with an extended half-life that enhances cell division, fat metabolism, and muscle repair through reduced binding to IGF binding proteins.
IGF-2
IGF-2 (Insulin-like Growth Factor 2) is a 67 amino acid peptide hormone critical for fetal growth and development, regulated by genomic imprinting. It signals through IGF-1R, insulin receptor isoform A, and its own IGF-2R (mannose-6-phosphate receptor), with roles in cancer biology, metabolism, and tissue repair.