Understanding Insulin-like Growth Factor-1 (IGF-1) in Research
What is IGF-1?
Insulin-like Growth Factor-1 (IGF-1), also known as Somatomedin-C, is a crucial polypeptide growth factor that belongs to the insulin family of peptides. It consists of 70 amino acids and has a molecular weight of 7649 Daltons. IGF-1 shares structural similarities with insulin, which comprises 51 amino acids, with both having A and B chains connected by three disulfide bonds in a single chain. In adults, the liver serves as the main generator of IGF-1. Mitogenic polypeptides called insulin-like growth factors (IGFs) promote the growth and survival of many cell types, such as muscle, bone, and cartilage tissue.
The Growth Hormone Axis
In recent years, advancements in technology have significantly enhanced our understanding of the growth hormone (GH) axis. GH secretion inhibitory hormone (somatostatin), GH releasing hormone (GHRH), and other hypothalamic peptides, such as ghrelin, control the anterior pituitary's ability to secrete growth hormone. GH induces the production of IGF-1 in the liver and regulates IGF-1 production in various other tissues. IGF-1 interacts with its target tissues through autocrine and paracrine signaling mechanisms, stimulating systemic body growth and promoting growth effects on almost every cell in the body, including skeletal muscle, cartilage, bone, liver, kidney, nervous system, skin, hematopoietic cells, and lung tissue.
How Does IGF-1 Work?
Numerous studies have documented the anabolic and chondrogenic effects of IGF-1 on cartilage tissue by increasing type 2 collagen mRNA expression and proteoglycan synthesis. IGF-1 is essential for the responses of muscle and bone to physical stress, playing a critical role in myocyte hypertrophy, satellite cell proliferation, osteoblast survival, and bone elaboration in response to tissue damage. IGF-1 promotes fat metabolism in muscle tissue while conserving glucose and upregulating protein synthesis in myocytes, resulting in muscle hypertrophy.
Modulation of IGF-1 Effects
The family of binding proteins known as IGFBPs, which transport the ligand in extracellular fluids and the circulation, regulates the effects of IGF-1. These binding proteins complex with 99 percent of IGFs in the plasma, adjusting the amount of free IGF-1 that is available to tissues. Six binding proteins are present; in humans, IGFBP-3 carries 80–90% of IGF-1. While IGFBP-3 is primarily regulated by GH and is also somewhat regulated by IGF-1, IGFPB-1 is regulated by insulin and IGF-1.
IGF-1 Signaling Pathways
The tyrosine kinase growth factor receptors, such as the IGF-1 receptor (IGF-1R), signal via several pathways, including as the PI3K and mitogen-activated protein (MAP) pathways. Phospholipase III Kinase (PI3K) and its downstream partner, mammalian target of rapamycin (mTOR), regulate a crucial pathway. The mTOR pathway is crucial for regulating cell growth, proliferation, motility, survival, protein synthesis, and transcription.
Research Findings on IGF-1
Aging and Inflammation
IGF-1 levels decline with age, a phenomenon termed "somatopause." After age 60, IGF-1 levels are generally low. Research indicates that improving IGF-1 levels can provide anti-aging benefits, such as enhanced muscle strength and mobility in older adults. IGF-1 also increases glutathione peroxidase, enhancing the antioxidant defense system. The IGF-1 axis helps maintain glucose homeostasis and regulates inflammation. Low IGF-1 levels are associated with increased inflammation markers, such as C-reactive protein (CRP) and Interleukin-6 (IL-6). Studies have shown that improved IGF-1 levels can decrease inflammation and autoimmunity, benefiting conditions like inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis.
Brain Health and Aging
IGF-1 is widely expressed in the central nervous system (CNS), promoting the proliferation, survival, and differentiation of neuronal and non-neuronal cells. Microglial-derived IGF-1 supports neuronal survival, while IGF-1 acts as a potent neurotrophic factor, rescuing neurons from apoptosis and enhancing neuronal growth and myelination. Reduced IGF-1 signaling is linked to cognitive dysfunction, and studies have found a correlation between higher IGF-1 levels and better perceptual motor performance and information processing speed. IGF-1 works in concert with brain-derived neurotrophic factor (BDNF) and other neurotrophic factors to promote neurogenesis and brain remodeling.
Muscle Growth and Healing
As people age, they experience a progressive loss of skeletal muscle mass and function. IGF-1 is crucial for muscle regeneration, stimulating myoblast proliferation and differentiation. Research using mouse models has shown that direct injections of human recombinant IGF-1 enhance muscle healing in lacerated, contused, and strain-injured muscles. Although IGF-1 has been reported to improve muscle healing, some studies have noted fibrosis within the lacerated muscle site despite high levels of IGF-1 production.
Diabetes
The GH-IGF-1 axis primarily regulates tissue growth and differentiation, while insulin primarily affects fuel metabolism. In Type 1 Diabetes, the GH-IGF-1 axis is imbalanced, leading to increased GH secretion, reduced IGF-1 plasma levels, and complex changes in IGF binding proteins (IGFBPs). Individuals with type 1 diabetes exhibit abnormalities in the GH/IGF-1/IGFBP axis, including GH hypersecretion and reduced circulating levels of IGF-1 and IGFBP-3. IGF-1 can promote glucose uptake in certain peripheral tissues. In patients with type 1 and 2 diabetes, IGF-1 administration has been shown to improve insulin sensitivity, reduce insulin requirements, and enhance glycemic control.
Obesity and Metabolic Syndrome
IGF-1 signaling plays a role in adipocyte differentiation and metabolic regulation. In the absence of IGF-1, pre-adipocyte differentiation is hindered. IGF-1 also regulates adipocyte metabolism, suppressing lipolysis similarly to insulin. Local IGF-1 production in adipose tissue is critical in response to obesity-related stress and cell death.
Cardiovascular Health
IGF-1 stabilizes pre-existing plaque and prevents new plaque buildup in blood vessels via having anti-inflammatory and antioxidant properties. Cardiovascular diseases like coronary artery disease, ischemic heart disease, and ischemic stroke, are associated with reduced IGF-1 levels. A 2011 meta-analysis reported that both low and high IGF-1 levels increase the risk of mortality. Individuals with low IGF-1 have a 1.27 times increased risk of dying from all causes, while those with high levels have a 1.18 times increased risk.
Bone Density
IGF-1 and GH are essential for skeletal growth during puberty and bone health throughout life. Higher IGF-1 levels are linked to greater bone mineral density in older women. Clinical studies have shown that IGF-1 administration improves bone health by exerting significant anabolic activity and bone protective effects.
IGF-1 LR3
IGF-1 LR3 is a recombinant form of IGF-1 with enhanced potency and stability. It consists of 83 amino acids with a molecular weight of 9,111 Daltons. The modification involves replacing glutamic acid at position 3 with arginine (R) and adding 13 additional amino acids, improving metabolic stability and reducing binding affinity to IGF binding proteins. IGF-1 LR3 has a half-life of 20-30 hours and is approximately three times more potent than IGF-1. It is not recommended for use beyond 10 consecutive days due to its potency.
Conclusion
Insulin-like Growth Factor-1 (IGF-1) plays a critical role in various physiological processes, including tissue growth, metabolic regulation, and cellular repair. Its broad impact on muscle growth, bone density, brain health, and cardiovascular function makes it a significant focus of research. Continued studies on IGF-1 and its analogs, such as IGF-1 LR3, will provide deeper insights into their potential applications and mechanisms, contributing to advancements in the field of peptide research.