What is the role and origin of Insulin-like Growth Factor 1 (IGF1) and Insulin-like Growth Factor Binding Protein 3 (IGFBP3)?

Role and Origin of IGF1 and IGFBP3

Insulin-like Growth Factor 1 (IGF1) and Insulin-like Growth Factor Binding Protein 3 (IGFBP3) are critical components of the growth hormone axis, with IGF1 primarily produced by the liver in response to growth hormone stimulation, while IGFBP3 serves as the main carrier protein for IGF1 in circulation, extending its half-life and regulating its bioavailability.

Origin of IGF1 and IGFBP3

IGF1

• Primary source: Liver (hepatic production) in response to growth hormone (GH) stimulation 1
• Secondary sources: Local production in an autocrine/paracrine manner by target tissues such as bone 1
• Regulation: Controlled by the GH/IGF1 axis, with GH stimulating hepatic IGF1 production

IGFBP3

• Primary source: Liver
• Secondary sources: Various tissues including fibroblasts
• Regulation: GH-dependent, with levels correlating with IGF1 levels

Structure and Complex Formation

IGF1, IGFBP3, and acid-labile subunit (ALS) form a ternary complex in circulation:

• This "parachute-like" ternary complex extends the serum half-life of IGF1 2
• Approximately 75% of circulating IGF1 is bound in this ternary complex 3
• The complex is too large to pass through renal glomeruli, preventing IGF1 clearance 3
• IGFBP3 binds IGF1 with high affinity, regulating its bioavailability to tissues 2

Physiological Roles

IGF1

1. Growth and development:

   • Critical mediator of GH effects on linear growth
   • Stimulates cell growth and cell proliferation 1
   • Essential for normal bone development and growth
   • Important for pubertal development

2. Metabolic regulation:

   • Glucose homeostasis
   • Insulin-like effects on peripheral tissues
   • Protein anabolism

3. Cell survival and proliferation:

   • Activates signaling pathways including PI3K/Akt/mTOR and Ras/Raf/MEK/ERK 1
   • Anti-apoptotic effects in various cell types

IGFBP3

1. IGF-dependent functions:

   • Primary carrier protein for IGF1 in circulation
   • Extends IGF1 half-life from minutes to hours
   • Regulates IGF1 bioavailability to tissues
   • Modulates IGF1 interaction with its receptors

2. IGF-independent functions:

   • Direct anti-proliferative effects
   • Pro-apoptotic activities independent of IGF1 binding 4
   • Binds to cell surface receptors to mediate direct cellular effects
   • Can inhibit cell division induced by other growth factors like EGF 4

Clinical Significance

Growth Disorders

• Low IGF1 levels are associated with growth failure in children 1
• IGF1 is used as a diagnostic marker for GH deficiency and resistance
• Recombinant IGF1 therapy is used for severe primary IGF1 deficiency

Chronic Kidney Disease (CKD)

• CKD is associated with GH resistance and functional IGF1 deficiency 1
• While IGF1 and IGFBP3 levels may remain relatively stable in CKD, ALS levels decrease with declining renal function 3
• GH therapy in children with CKD helps overcome GH resistance and improves growth 1

Female Athlete Triad

• Low energy availability leads to decreased IGF1 levels 1
• IGF1 is a bone trophic factor important for bone health
• Low IGF1 contributes to low bone mineral density in amenorrheic athletes 1

Cancer

• IGFBP3 can have tumor-suppressive effects by:
  • Sequestering IGF1 and limiting its mitogenic effects
  • Direct IGF-independent pro-apoptotic actions 5, 4
• IGFBP3 expression is decreased in some cisplatin-resistant lung cancer cells 5
• Overexpression of IGFBP3 can enhance cisplatin response in lung cancer cells 5

Cardiovascular Disease

• The relationship between IGF1/IGFBP3 levels and coronary artery disease remains unclear
• Some studies suggest no significant association between circulating IGF1 or IGFBP3 levels and risk of coronary artery disease 6

Pathological Alterations

Disruptions in IGF1/IGFBP3 System

• Growth hormone deficiency: Low IGF1 and IGFBP3 levels
• Growth hormone resistance: Low IGF1 despite normal/high GH levels
• Nutritional deficiencies: Energy deficiency leads to GH resistance and low IGF1 1
• Chronic diseases: Altered IGF1 bioavailability due to changes in IGFBP3 levels

Aging

• IGF1 and IGFBP3 levels decrease with increasing age 3
• Reduced IGF1 signaling is associated with longevity in some experimental models 1

Clinical Considerations

• IGF1 and IGFBP3 measurements are useful diagnostic tools for growth disorders
• IGF1 levels can be falsely normal or low in severe hypothyroidism, malnutrition, or severe infection 1
• IGF1 levels can be falsely elevated in poorly controlled diabetes mellitus, hepatic and/or renal failure 1
• Oral estrogens can reduce hepatic IGF1 generation, potentially confounding test results 1

Therapeutic Applications

• Recombinant human IGF1 therapy for severe primary IGF1 deficiency
• GH therapy in CKD to overcome GH resistance and improve growth 1
• Potential therapeutic target in certain cancers due to IGFBP3's tumor-suppressive properties 5