IGF-1 LR3

Also known as: Long R3 IGF-1, IGF-1 Long Arginine 3

Evidence: Preclinical

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Overview

IGF-1 analog with Glu3 replaced by Arg plus a 13-residue N-terminal extension, which binds IGF-binding proteins poorly; in animals it is 2 to 3x as potent as IGF-1 at lowering glucose and is cleared faster, not slower.

Long-[Arg3]IGF-I (LR3IGF-I) is a recombinant IGF-1 analog made in E. coli as a fusion protein: Glu3 is replaced by Arg and 13 residues are appended to the N-terminus (Laajoki 2000; King 1992). Both changes cut binding to IGF-binding proteins, and in rat L6 myoblasts the Arg3 substitution alone raised potency for protein and DNA synthesis while slightly lowering type-1 receptor binding, so the gain comes from escaping the binding proteins rather than from better receptor affinity (King 1992). In pigs and marmosets the IGFBP-poor variants were 2 to 3x as potent as IGF-1 at lowering plasma glucose and suppressed glucose for far longer (Tomas 1997). In rats LR3IGF-I was cleared from blood faster than IGF-1 (Shoubridge 2003). It is a laboratory reagent and a veterinary/cell-culture growth factor; no human study exists.

Benefits

2 to 3x the potency of IGF-1 for glucose lowering (pig, marmoset); increased protein and DNA synthesis in rat L6 myoblasts (in vitro); gut and whole-body growth responses in rats and pigs. No muscle hypertrophy study and no human data.

Dosing reference

Research dose: No human data; research-community range 20 to 100 mcg daily. Animal studies dosed by weight (20 to 50 mcg/kg in pigs, 2.6 mcg/kg IV in rats)
Range: 20 to 100 mcg, 1x daily
Reconstitution: 1 mL bacteriostatic water
Common vial sizes: 0.1 mg, 1 mg

Subcutaneous in research use; no human dosing protocol has been published. Site-injection for local growth is not established, and the compound is systemically active. In pigs and marmosets, IGFBP-poor IGF-1 variants lowered plasma glucose 2 to 3x more than IGF-1 and kept it down 4 to 8 times longer by cumulative area, so hypoglycemia is the dose-limiting effect (Tomas 1997).

Mechanism

LR3IGF-I is an 83-residue IGF-1 analog: Glu3 to Arg plus a 13-residue N-terminal extension (MFPAMPLSSLFVN) left over from its methionyl-porcine-GH fusion partner. NMR shows the IGF-1 core is unchanged and only the N-terminal residues are reoriented, which explains the lower affinity for IGF-binding proteins (Laajoki 2000). Because little of the peptide is sequestered by IGFBPs, more is free to activate IGF-1R, and through it PI3K/Akt and mTOR. The analogs bound bovine IGFBP-2 very poorly and the type-1 receptor slightly less well than IGF-1, so reduced IGFBP binding, not receptor affinity, drives the extra potency (King 1992). IGF-1R activation also cross-talks with the insulin receptor, the basis of the hypoglycemia seen in pigs and marmosets (Tomas 1997).

Evidence

Preclinical: animal or in vitro data only

[Arg3]IGF-I and [Gly3]IGF-I were more potent than IGF-1 at stimulating protein and DNA synthesis in rat L6 myoblasts, bound IGFBP-2 very poorly and bound the type-1 receptor slightly less well than IGF-1 (King et al., 1992)
In pigs (20 and 50 mcg/kg) and marmosets (42 to 270 mcg/kg), hypoglycemic potency ran IGF-1 < long-IGF-1 < R3IGF-I = LR3IGF-I < des(1-3)IGF-1, with 2 to 3x the nadir effect and 4 to 8x the cumulative glucose suppression of IGF-1 (Tomas et al., 1997)
Solution NMR of long-[Arg3]IGF-I showed an unchanged IGF-1 fold with a reoriented N-terminus, consistent with its weak IGFBP binding (Laajoki et al., 2000)
After IV bolus in preweaning and adult rats, LR3IGF-I left the circulation faster than IGF-1 and reached gut tissue at a roughly 2:1 ratio (Shoubridge and Read, 2003)
In pigs of different ages, IGF analogs with poor IGFBP affinity produced metabolic and growth effects distinct from IGF-1 (Walton et al., 1995)
Human-trial status: none. No clinical trial of LR3IGF-I has been published or registered; all data are in vitro, rodent, pig and marmoset

References

Side effects

Hypoglycemia is the documented risk: in pigs and marmosets, IGFBP-poor IGF-1 variants lowered plasma glucose 2 to 3x more than IGF-1 at the same dose and kept it suppressed several times longer (Tomas 1997). No human trial and no human safety data exist. IGF-1R signaling is proliferative, which is why IGF-1 analogs are studied with caution in malignancy. Injection-site reactions and jaw pain are commonly reported (anecdotal).

Storage

Storage: Refrigerate 2-8°C (36-46°F)
Lyophilized: 2+ years at room temp, 3+ years refrigerated
Reconstituted: 28-30 days refrigerated

Pharmacology

Half-life: Not measured; cleared from plasma faster than IGF-1 after IV bolus in rats (Shoubridge 2003). The 20 to 30 h figure is community lore and is the wrong direction
Molecular weight: 9111.4 Da
Sequence: MFPAMPLSSLFVN-GP[R]TLCGAELVDALQFVCGDRGFYFNKPTGYGSSSRRAPQTGIVDECCFRSCDLRRLEMYCAPLKPAKSA (83 aa; [R] = Arg for Glu3)

Stacks with

BPC-157