What is insulin‑like growth factor (IGF)?

What is Insulin-Like Growth Factor (IGF)?

Insulin-like growth factor (IGF-1) is a critical anabolic hormone that mediates growth hormone effects throughout the body by stimulating cell growth, proliferation, and survival while also regulating glucose metabolism through transmembrane IGF-1 receptors. 1, 2

Molecular Structure and Production

• IGF-1 consists of 70 amino acids in a single polypeptide chain with three intramolecular disulfide bridges and a molecular weight of 7,649 Da 2
• The hormone is structurally similar to insulin, which explains its metabolic effects 3
• Under normal circumstances, growth hormone binds to its receptor in the liver and other tissues, stimulating the synthesis and secretion of IGF-1 2
• IGF-1 is produced not only by the liver but also by local tissues—for example, cardiac fibroblasts serve as an important source of IGF-1 production in the heart 1

Mechanism of Action

• IGF-1 acts through the Type 1 IGF-1 receptor, which is homologous to the insulin receptor, leading to intracellular signaling that stimulates multiple growth processes 2
• The hormone activates both the mitogen-activated protein (MAP) kinase and PI3K signaling pathways in almost every tissue in the body 4
• IGF-1 receptors are present on most cell types and tissues, allowing widespread mitogenic activities that increase cell numbers throughout the body 2

Binding Proteins and Bioavailability

• In blood, approximately 98% of circulating IGF-1 is bound to six distinct IGF binding proteins (IGFBPs), with over 80% bound as a complex with IGFBP-3 and an acid-labile subunit 2, 5
• These IGFBPs bind IGF-1 with an affinity equal to or greater than that of the IGF-1 receptor itself, serving as carrier proteins that modulate IGF-1 bioavailability 5
• IGFBP-3 levels are greatly reduced in subjects with severe primary IGF-1 deficiency, resulting in increased clearance of IGF-1 in these patients 2

Physiological Functions

Growth and Development

• Skeletal growth: IGF-1 controls growth at the cartilage growth plates of bone epiphyses, where stem cells divide to produce chondrocytes that eventually calcify into new bone, allowing bones to lengthen until growth plates fuse at puberty 2
• IGF-1 is a bone trophic factor that enhances proliferation of periodontal ligament cells and bone precursor cells 1
• The hormone plays a crucial role in promoting cell growth and differentiation in childhood and continues to have anabolic effects in adults 5

Cardiac Effects

• IGF-1 is a major regulator of "adaptive" or "physiological" cardiac hypertrophy and promotes survival of cardiac myocytes 1

Metabolic Actions

• IGF-1 suppresses hepatic glucose production and stimulates peripheral glucose utilization, giving it hypoglycemic potential 2
• The metabolic actions of IGF-1 are directed at stimulating the uptake of glucose, fatty acids, and amino acids to support growing tissues 2
• Unlike growth hormone (which causes insulin resistance and hyperglycemia), IGF-1 has insulin-like effects that reduce blood glucose levels 3
• IGF-1 has inhibitory effects on insulin secretion 2

Clinical Significance

Aging and Longevity

• Reduced IGF-1 signaling is associated with increased lifespan and reduced risk of aging-related diseases 1
• Polymorphic variants causing reduced IGF-1 signaling confer health and lifespan benefits in humans, with female Ashkenazi Jewish centenarians showing overrepresentation of loss-of-function mutations in the IGF-1 receptor 1
• Overall growth hormone and IGF-1 signaling falls with age, though paradoxically, mutations that reduce IGF-1 signaling can dramatically extend lifespan 4

Disease States

• People with acromegaly (elevated growth hormone and IGF-1) have a two- to threefold increase in mortality, primarily from vascular disease 1
• IGF-1 expression levels vary in numerous clinical conditions, providing crucial information about an individual's health state 5
• In hepatocellular carcinoma, IGF-1R and IGF-II expression is increased, making this pathway a target for therapeutic intervention 6

Therapeutic Considerations

• Recombinant human IGF-1 (mecasermin) is used to treat severe primary IGF-1 deficiency, with a terminal half-life of approximately 5.8 hours after subcutaneous administration 2
• Growth hormone therapy to increase IGF-1 is expensive and associated with undesirable side effects including salt and water retention and impaired glucose metabolism 1
• Oral estrogen suppresses hepatic IGF-1 production through first-pass liver metabolism, which is particularly problematic in amenorrheic athletes who already have low endogenous IGF-1 concentrations 1

Important Caveats

• The existence of IGFBPs significantly reduces the levels of immunoreactive IGF-1 in samples, requiring multiple pre-treatment steps that reduce reproducibility and complicate interpretation of IGF-1 assay results 5
• Clearance of IGF-1 is inversely proportional to IGFBP-3 levels, with clearance estimated at 0.04 L/hr/kg at low IGFBP-3 levels versus 0.01 L/hr/kg at normal IGFBP-3 levels 2
• IGF-1 has featured in many high-profile doping cases in sports due to its anabolic properties 5