insulin-like growth factor 1

**Synthesis and regulation** - Produced mainly by hepatocytes, with local (paracrine/autocrine) production in bone, cartilage, and muscle. - GH binds the GH receptor, which signals through JAK2/STAT5 (the JAK/STAT pathway) and induces IGF-1 transcription. - Circulates bound to IGF-binding proteins (mainly IGFBP-3 with the acid-labile subunit), giving it a half-life of about 12-15 hours. This is why serum levels are stable, unlike GH, which is pulsatile. - Levels are reduced by malnutrition, liver disease, hypothyroidism, poorly controlled diabetes, and GH deficiency or insensitivity. Levels vary with age: they peak during puberty and fall with aging.

**Receptor and actions** - The IGF-1 receptor is a receptor tyrosine kinase, structurally related to the insulin receptor. It signals through the PI3K/Akt and Ras/MAPK pathways. - Actions: chondrocyte proliferation at the epiphyseal growth plate (linear bone growth), protein synthesis, and increased lean body mass. It also has mild insulin-like effects (increased glucose uptake, hypoglycemic effect). - **Negative feedback:** IGF-1 inhibits GH release from the pituitary and stimulates somatostatin from the hypothalamus.

**GH vs IGF-1 metabolic effects** - GH is diabetogenic (raises blood glucose, causes insulin resistance, and promotes lipolysis). - IGF-1 has insulin-like effects (lowers blood glucose).

**Clinical significance** - **Acromegaly/gigantism:** GH-secreting pituitary adenoma causes elevated IGF-1. Screen with serum IGF-1. Confirm with failure of GH suppression after an oral glucose tolerance test (OGTT), then do pituitary MRI. Treatment is transsphenoidal surgery. Medical options are octreotide/lanreotide (somatostatin analogs), pegvisomant (GH receptor antagonist; monitor IGF-1 levels, not GH), and cabergoline (dopamine agonist). - **GH deficiency:** Low IGF-1 (and low IGFBP-3 in children) suggests GH deficiency. Confirm with a provocative test (insulin tolerance test, arginine, or macimorelin). - **Laron syndrome (GH insensitivity):** AR GH receptor mutation. Phenotype is short stature with HIGH GH and LOW IGF-1. Treated with recombinant IGF-1 (mecasermin). - **Constitutional growth delay / malnutrition:** Low IGF-1 from decreased hepatic production. - **Tumor-induced hypoglycemia:** Non-islet cell tumors (e.g., mesenchymal tumors) secrete "big IGF-2", which causes hypoglycemia with low insulin and low C-peptide. - **Cancer:** IGF-1R signaling promotes proliferation and inhibits apoptosis. High IGF-1 is associated with increased risk of some cancers (breast, prostate, colorectal). - **Pregnancy/fetal growth:** IGF-1 and IGF-2 are key in fetal growth, with IGF-2 especially important (imprinted gene).

**High-yield pearls** - Best screening test for acromegaly = serum IGF-1 (not random GH). - Best confirmatory test for acromegaly = failure of GH suppression on OGTT. - Also called somatomedin C. - Acromegaly findings: enlarged hands/feet, coarse facial features, prognathism, macroglossia, carpal tunnel, hypertension, cardiomyopathy, glucose intolerance, and increased colon polyps. - Mecasermin = recombinant IGF-1, used for severe primary IGF-1 deficiency (Laron). - GH = anti-insulin; IGF-1 = insulin-like.