Insulin-like growth factors

1. Introduction

• Insulin-like growth factors are peptide hormones structurally related to insulin, consisting mainly of IGF-1 and IGF-2.

• Produced primarily in the liver under the regulation of growth hormone (GH), but also synthesized locally in many tissues for autocrine and paracrine actions.

• Play a central role in growth, development, and metabolic regulation, especially during childhood and adolescence.

• Mediate many of the growth-promoting effects of GH, including cell proliferation, differentiation, and survival.

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2. Types and Structure

• IGF-1

  • Single-chain polypeptide with 70 amino acids.

  • Highest serum levels during puberty.

  • Strongly regulated by GH secretion and nutritional status.

• IGF-2

  • 67-amino acid polypeptide.

  • Important for fetal growth; less GH-dependent in adults.

• Both bind to IGF binding proteins (IGFBPs) in the circulation, which modulate their stability, half-life, and bioavailability.

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3. Mechanism of Action

• Bind to IGF-1 receptor (IGF1R), a transmembrane tyrosine kinase receptor.

• Activate intracellular signaling pathways:

  • PI3K-Akt pathway → promotes cell survival and protein synthesis.

  • MAPK pathway → stimulates cell proliferation and differentiation.

• Cross-reactivity with insulin receptor possible, especially at high concentrations.

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4. Physiological Roles

• Growth and Development

  • Stimulate skeletal growth and organ development.

  • Increase protein synthesis and reduce protein breakdown.

• Metabolism

  • Enhance glucose uptake in muscle and fat (insulin-like effect).

  • Reduce hepatic glucose production.

• Tissue Repair

  • Promote regeneration in muscle, nerve, and connective tissue.

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5. Pharmacological Preparations and Uses

• Mecasermin – recombinant human IGF-1, used for growth failure in children with severe primary IGF-1 deficiency or GH gene deletion with neutralizing antibodies.

• Mecasermin rinfabate – complex of recombinant IGF-1 with IGFBP-3, prolonging half-life.

• Investigational uses include muscle wasting disorders, neurological injury recovery, and diabetic wound healing.

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6. Pharmacokinetics

• Absorption: Subcutaneous injection; bioavailability influenced by binding proteins.

• Distribution: Circulates bound to IGFBPs (mainly IGFBP-3) and acid-labile subunit (ALS) complex, increasing stability.

• Metabolism: Proteolytic degradation in tissues and circulation.

• Half-life:

  • Free IGF-1: ~10–30 minutes.

  • IGF-1 bound to IGFBP-3/ALS: ~12–15 hours.

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7. Indications

• Severe primary IGF-1 deficiency (e.g., mutations in GH receptor gene).

• GH gene deletion with antibodies to GH.

• Investigational: sarcopenia, burns, chronic kidney disease-related catabolism.

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8. Contraindications

• Known hypersensitivity to drug components.

• Active or suspected neoplasia (due to mitogenic potential).

• Closed epiphyses in children (risk of disproportionate growth).

• Hypoglycemia unawareness in patients at risk.

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9. Adverse Effects

Common

• Hypoglycemia (especially if meal not consumed shortly after dosing).

• Injection site reactions.

• Headache, dizziness.

Less Common but Important

• Tonsillar/adenoidal hypertrophy → snoring, sleep apnea.

• Intracranial hypertension.

• Joint pain, myalgia.

• Edema.

Rare/Serious

• Benign intracranial hypertension with papilledema.

• Potential tumor promotion in predisposed individuals.

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10. Drug Interactions

• Insulin and other hypoglycemic agents – additive risk of hypoglycemia.

• Glucocorticoids – may antagonize growth-promoting effects by inhibiting GH-IGF axis.

• Oral estrogens – can lower circulating IGF-1 levels via hepatic effects.

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11. Monitoring

• Growth velocity and height in pediatric patients.

• Blood glucose (pre- and post-dose).

• Signs of intracranial hypertension.

• ENT evaluation for adenotonsillar hypertrophy during long-term therapy.

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12. Advantages

• Directly addresses growth failure in cases where GH therapy is ineffective due to GH resistance.

• Potent anabolic and mitogenic effects beneficial in selected conditions.

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13. Limitations

• Requires subcutaneous injection; long-term therapy often needed.

• Hypoglycemia risk mandates careful meal timing.

• Theoretical and observed potential for stimulating neoplastic growth limits use in cancer-prone patients.