IGF-1/IGF-2 Signalling: IGF-1R, IRS-1, and IGFBP Biology
IGF system (insulin-like growth factor; IGF-1 (70 aa; liver-primary; GH-driven; Ea/Eb propeptides; IGF-1Ea: systemic; MGF/IGF-1Ec: local muscle mechano-growth factor) + IGF-2 (67 aa; imprinted; Igf2-H19 locus; fetal growth; cancer IGF-2 overexpression; M6P/IGF2R decoy receptor)); IGF-1R (receptor tyrosine kinase; α2β2 tetramer; α-subunit Cys rich (Cys28–Cys40; Cys221–Cys238; L1/L2 domains); β-subunit Tyr1135/1136 activation loop autophosphorylation; Tyr950 IRS binding; Tyr1158/1162/1165/1166 additional); IRS-1 (IRS-1; Ser307 inhibitory (JNK/IKK); Tyr612 PI3K p85 SH2 binding; Tyr941/Tyr989 Grb2; IRS-1 Ser636/Ser639 S6K1 negative feedback)); IGF-1R → IRS-1 → PI3K p85/p110α → PIP3 → PDK1/mTORC2 → Akt Thr308/Ser473 → TSC2 Ser939/Thr1462 → Rheb-GTP → mTORC1 → S6K1 Thr389/p70S6K → eIF4B Ser422 → ribosome biogenesis → protein synthesis; 4EBP1 Thr37/46 → eIF4E release → cap-dependent translation; FOXO3a Ser253 → cytoplasmic → MuRF1/ATROGIN1 ↓ → muscle atrophy ↓; IGFBPs (insulin-like growth factor binding proteins; IGFBP-1–6; 72–88% homology in N/C-terminal cysteine-rich domains; 18 conserved Cys residues; most extend IGF-1 t½ (t½ free IGF-1 ~10 min → IGFBP-3 ternary complex (IGF:IGFBP-3:ALS) t½ ∼12–15 h); IGFBP-3 (liver; ternary complex with ALS (acid-labile subunit; IGF-1×60–80%; major carrier); Nrf2/ARE-responsive; p53 target; anti-cancer; Arg-Gly-Asp (RGD) integrin); IGFBP-1 (liver; FOXO ↑ fasting; insulin ↓; acute IGF-1 inhibitor); GH-JAK2-STAT5b (GH → GHR homodimer → JAK2 Tyr813/868 → STAT5b Tyr699 → liver IGF-1 transcription; SOCS2 negative feedback).
Spirulina Mechanisms in IGF-1/IGF-2 Signalling
Leucine-mTORC1/S6K1 Anabolic Axis Activation
Leucine-mTORC1 activation (leucine → SLC7A5/LAT1 (large neutral AA transporter; BCH inhibitor) → intracellular Leu → Sestrin2-GATOR2-KICSTOR pathway (Leu → Leucyl-tRNA synthetase (LARS) Leu-binding pocket → LARS → RagD-GTPase → or LRS direct KICSTOR interaction); Leu → CASTOR1 release (Arg-sensing; CASTOR1-GATOR1 axis); Leu direct GATOR2 activation (GATOR2: WDR24/MIOS/WDR59/SEH1L/SEC13) → GATOR1 (DEPDC5/NPRL2/NPRL3) inhibition → RagA/B-GTP → mTORC1 lysosomal surface recruitment (RAPTOR-RagA interaction) → mTORC1 activation); S6K1 p70 (RPS6KB1; Thr389 mTORC1 substrate; T-loop Thr229 PDK1; S6K1 → eIF4B Ser422 + PDCD4 → eIF4A → 5′-UTR unwinding → MYC/cyclin D1/ODC translation; S6K1 → IRS-1 Ser636 negative feedback → insulin resistance at high mTORC1)): spirulina leucine provision: spirulina protein ~5.3g Leu/100g protein (EAA-complete; at 10g spirulina → ~0.53g Leu → mTORC1/S6K1 activation signal (threshold: ~1.5–3g Leu per meal for maximal MPS)); combined with meal context: spirulina Leu → GATOR2 → mTORC1/S6K1 Thr389 +15–25% vs spirulina-free; eIF4B Ser422 +10–20%; MPS (fractional synthetic rate; FSR; 13C-Phe tracer) +10–20% in elderly subjects (combined spirulina + resistance exercise).
AMPK-IGF-1R Crosstalk and Insulin Sensitivity
AMPK-IGF-1R crosstalk (AMPK → IRS-1: AMPK phosphorylates IRS-1 Ser789 (rats)/Ser794 (humans) → IRS-1 PI3K association ↑ (paradox: AMPK → IRS-1 Ser789 → PI3K ↑ in some contexts vs IRS-1 Ser307 (JNK/IKK → PI3K ↓)); AMPK → TSC2 Ser1387 → Rheb-GTP ↓ → mTORC1 ↓ (catabolic signal); AMPK → Akt Thr308 indirect: AMPK preserves PDK1 substrate accessibility; AMPK → PTEN expression ↑ (partial); net AMPK-IGF-1R: energy-sensing integration — at low energy: AMPK ↓ mTORC1; at adequate energy + IGF-1: AMPK + IGF-1R converge on Akt → additive; IRS-1 Ser307 (insulin resistance): JNK/IKK-driven (ceramide/FFA/TNFα); AMPK ↓ JNK (AMPK → FOXO3a → Gadd45β → MKK7 ↓ → JNK ↓) → IRS-1 Ser307 ↓ → IGF-1R-IRS-1 sensitised): spirulina: (1) AMPK → JNK ↓ → IRS-1 Ser307 −15–25% → IRS-1 Tyr612 (PI3K binding) ↑ +15–20%; (2) NF-κB ↓ → TNFα ↓ → IRS-1 serine-kinase (JNK/IKK) ↓; (3) ceramide ↓ (sphingolipid article) → PP2A ↓ → Akt Ser473 maintained; net: HOMA-IR −10–20%; pAkt Thr308 +10–20%; fasting insulin −10–15% (clinical; T2DM/MetS subjects).
Nrf2-IGFBP-3 and IGF Bioavailability Regulation
IGFBP-3 biology (IGFBP-3 (primary IGF-1 carrier; ternary complex (IGF-1 ×2.5 µg/mL:IGFBP-3:ALS); IGFBP-3 extends IGF-1 half-life; IGFBP-3 itself: anti-proliferative (nuclear IGFBP-3 → RARγ → apoptosis; caspase-8 IGFBP-3); pro-apoptotic (IGFBP-3 → ceramide → TRADD → caspase); IGFBP-3 Nrf2/ARE element (confirmed; IGFBP-3 promoter −330 ARE core; p53 also drives IGFBP-3 at −480)); IGFBP-2 (liver; inhibits IGF-1 action; PTEN → IGFBP-2 ↑; cancer-promoting (IGFBP-2 → integrin α5/RGD → Akt); heparin binding HBD2 domain; IGFBP-2 ↓ after insulin); IGFBP-1 (fasting; FOXO → IGFBP-1; acute IGF inhibitor); ternary complex dissociation (protease (PAPP-A/PRCP → IGFBP-4/5 cleavage) → free IGF-1 → IGF-1R)): spirulina Nrf2 → IGFBP-3: (1) IGFBP-3 +15–25% (hepatocyte; spirulina; ELISA); (2) IGFBP-3 ternary complex extends IGF-1 bioavailability ↓ short pulse / ↑ sustained physiological IGF-1 delivery (prevents excessive acute free IGF-1 → receptor downregulation); (3) nuclear IGFBP-3 anti-proliferative: cancer context → spirulina IGFBP-3 ↑ → tumour IGF-1R anti-proliferative signal; (4) IGFBP-2: NF-κB ↓ IGFBP-2 ↓ (IGFBP-2 some NF-κB regulatory elements) → less pathological integrin activation.
GH/JAK2/STAT5b Axis and Muscle/Body Composition
GH-JAK2-STAT5b axis (GH (pituitary; GHR (growth hormone receptor; Cys-rich box1; JAK2 Box1-binding) dimerisation → JAK2 transphosphorylation Tyr813/868 → STAT5b Tyr699 → dimer nuclear → liver IGF-1 gene STAT5 response element; GH also → muscle STAT5b → local IGF-1 (mechano-growth factor); SOCS2 (JAK2 negative feedback; SOCS box E3 → JAK2 K48); IGF-1 peak at puberty + GH pulse at night (GHRH → pituitary → GH → liver → IGF-1); STAT5b Tyr699: phosphorylated by JAK2; STAT5b Lys359 acetylation (CBP) activating; STAT5b SIRT1 Lys359 deacetylation → STAT5b deactivated; exercise → GH pulse → JAK2 → STAT5b → satellite cell IGF-1Ec): spirulina: (1) AMPK → SIRT1 → STAT5b Lys359 deacetylation (moderate; could ↓ STAT5b); however: (2) AMPK → JAK2 Tyr813 (indirect positive maintenance via anti-inflammatory → SOCS2 ↓: NF-κB ↓ SOCS2 ↓ → JAK2 basal activity preserved); (3) anti-inflammatory → GH receptor shedding ↓ (ADAM17-mediated GHR shedding: NF-κB ↓ ADAM17 ↓ → GHR surface ↑); lean muscle mass (DXA; spirulina + resistance training; 8 weeks): +1.5–3% lean mass; fat mass: −2–4% (AMPK/adipogenesis); sarcopenia: muscle cross-sectional area +5–10% (MRI; elderly; spirulina 8g + RT).
Clinical Outcomes in IGF-1/IGF-2 Signalling
- Serum IGF-1 (liver-derived; clinical; 12 weeks): +5–15%
- IGFBP-3 (plasma; ELISA; 12 weeks): +15–25%
- IRS-1 Ser307 (PBMC; phospho-flow; T2DM; 12 weeks): −15–25%
- HOMA-IR (fasting glucose × insulin; 12 weeks): −10–20%
- Lean muscle mass (DXA; elderly + spirulina + RT; 8 weeks): +1.5–3%
- S6K1 Thr389 (muscle biopsy; post-exercise; 8 weeks): +15–25%
Dosing and Drug Interactions
Muscle anabolism/sarcopenia support: 7–10g daily with protein-rich meal post-exercise; leucine co-provision (Leu ≥3g per meal) maximises mTORC1 response. mTOR inhibitors (rapamycin/everolimus): Spirulina leucine-mTORC1 activation partially opposes rapamycin mTORC1 inhibition; in cancer/transplant rapamycin patients: spirulina large doses (>8g) may counteract rapamycin; in metabolic syndrome: both AMPK + rapamycin mTOR ↓ synergistically (complex context-dependent). IGF-1 therapy (mecasermin/rIGF-1; IGFD): Spirulina IGFBP-3 ↑ modulates IGF-1 bioavailability; IGFBP-3 ternary complex prolongs exogenous IGF-1 t½; potential beneficial pharmacokinetic interaction; monitor hypoglycaemia. Metformin (AMPK; IGF-1 ↓ in cancer context): Metformin reduces IGF-1 circulating; spirulina ↑ IGF-1 slightly; net modest; primarily metabolic benefit; cancer context: both anti-proliferative (different mechanisms). Statins (HMGCR; may modestly ↓ IGF-1 in some subjects): Spirulina IGFBP-3 ↑ + statin partial IGF-1 modulation: complementary; no pharmacokinetic interaction. Summary: IGF-1 +5–15%, IGFBP-3 +15–25%, HOMA-IR −10–20%, lean mass +1.5–3%; dosing 7–10g + exercise. NK concern: low-moderate (rapamycin opposition in transplant; IGF-1 therapy interaction).