IGF-1 LR3

IGF-1 LR3: what the published research shows

Compiled by NADA-Labs from the peer-reviewed literature cited below. No own study data.

IGF-1 LR3 — LR3IGF-I or Long [Arg3]-IGF-I in most cited papers — is a recombinant fusion analogue of human IGF-I with the first 11 amino acids of methionyl porcine growth hormone plus Val-Asn at the N-terminus and arginine instead of glutamate at position 3⁸. The research literature attributes its effects mainly to very weak binding to the IGF-binding proteins (IGFBPs) — IGF-I has about 1000-fold higher affinity towards IGFBP-3, IGFBP-4 and rat plasma IGFBPs (Ballard 1993, PMID 7683526) — while binding to the type 1 IGF receptor is only about 3-fold weaker than that of IGF-I². In rats, it therefore circulates mostly as free peptide and is cleared faster than IGF-I⁵, and in cell lines its apparent potency depends on whether the cells secrete IGFBPs⁸. It has been studied in cell assays, rats and pigs^{1,2,3,4,5,6,7,8}; no study in humans was identified.

Evidence base: Animal and in vitro studies only; PubMed searches for the common spellings of the name found no study in which IGF-1 LR3 was given to humans. Cited are one acute study in pigs, whose marmoset arm did not include IGF-1 LR3¹, four controlled rat studies over 3 to 14 days^2,3,4,6, a rat clearance study⁵, an acute haemodynamic study in anaesthetised rats⁷ and the cell-based study that describes the analogue⁸. Most of this work comes from one research consortium and was published between 1992 and 1997; the summaries rely on the abstracts, where group sizes, variability and statistics are largely missing. Further records cover diabetic rats (Tomas 1993, PMID 7683875), injection instead of infusion (Tomas 1996, PMID 8708565), pigs (Dunaiski 1997, PMID 9488001), guinea pigs (Conlon 1995, PMID 7561636) and a 7-month intranasal study in male 5XFAD mice (Engel 2025, PMID 39610283).

Key studies at a glance

Potency of IGF-1 LR3 relative to IGF-I across study models

Effects reported in the studies

• Reduced IGFBP binding and model-dependent potency (in vitro). In L6 rat myoblasts all long analogues stimulated protein and DNA synthesis and inhibited protein breakdown more potently than IGF-I; Long [Arg3]-IGF-I was among the most potent in IGFBP-secreting cell lines but less potent than IGF-I in chicken embryo fibroblasts, which secrete no detectable IGFBPs⁸. IGFBP-3 inhibited IGF-1 LR3-induced phosphorylation of the IGF-I receptor in a dose-dependent manner, in a concentration range similar to IGF-I (Devi 2001, PMID 11735239).
• Anabolic responses in catabolic rats. In dexamethasone-treated rats (7-day infusion), IGF-1 LR3 and des(1-3)IGF-I were about 2.5-fold more potent than IGF-I, although IGF-1 LR3 binds the type 1 IGF receptor 3-fold less well; at the highest IGF-I dose body weight changed by +6 g vs. -19 g with dexamethasone alone, and the gain in carcass weight reflected nitrogen rather than fat². Part of the potency advantage remained with injection instead of infusion, but for reversal of carcass muscle loss IGF-1 LR3 was barely equipotent with IGF-I (Tomas 1996, PMID 8708565).
• Growth in normal and diabetic rats. In growing female rats (14-day infusion), the highest IGF-I dose raised weight gain, N retention and food conversion efficiency by 18-26 %, and a much lower daily amount of IGF-1 LR3 produced similar effects with body proportions maintained³; a companion report gives a 6-fold potency for growth (Ballard 1993, PMID 7683526). In streptozotocin-diabetic rats both variants (IGF-1 LR3 and des(1-3)IGF-I) were 2.5-3 times more potent than IGF-I in restoring growth, but the IGFs did not reduce glucosuria (Tomas 1993, PMID 7683875).
• Intestinal growth. After 3 days of infusion in female rats (n = 5-6/group), IGF-1 LR3 but not IGF-I increased intestinal wet weight by 20 % vs. controls, independent of food intake, and duodenal and ileal crypt length by 13 % and 22 %; thymidine labelling indices rose with both peptides (up to 14 %)⁴. After an intravenous bolus in preweaning and adult rats, labelled IGF-1 LR3 reached 37-50 % higher levels per gram of gastrointestinal tissue than labelled IGF-I (Shoubridge 2003, PMID 12697696).
• Plasma clearance and distribution. After an intravenous bolus, IGF-1 LR3 was cleared more rapidly than IGF-I (metabolic clearance rate 9.84 vs. 0.90 ml/min per kg in virgin rats) and was mostly free peptide, whereas in virgin rat plasma IGF-I was mainly associated with the 150 kDa complex; in pregnant rats (day 18), when plasma IGFBPs are markedly reduced, IGF-I clearance rose to 2.88 while that of IGF-1 LR3 stayed similar (9.19)⁵. More IGF-1 LR3 than IGF-I tracer was found in kidneys, ovaries and adrenals of virgin rats and in ovaries and adrenals of pregnant rats; more IGF-I than IGF-1 LR3 radioactivity was found in caecum, brain, liver and heart of both groups and, in pregnant rats, also in kidneys, placenta, fetus and fetal plasma⁵.
• Plasma glucose in pigs. After a single bolus injection, the IGFBP-poor variants including IGF-1 LR3 were 2- to 3-fold more potent than IGF-I in lowering plasma glucose to the nadir, with an about 4- to 8-fold greater cumulative suppression over 4 h; only IGF-1 LR3 was also more potent than IGF-I in lowering plasma amino acids¹.
• Regional haemodynamics (anaesthetised rats). The gastrocnemius was the only vascular region with a significant increase in blood flow after infusion of IGF-1 LR3 (+308 %) or IGF-I (+58 %); vascular resistance fell compared with vehicle in the brain (-48 % and -60 %) and in skeletal muscle (-77 % and -41 %)⁷.
• Species and model differences. In finisher pigs, a 4-day infusion of IGF-1 LR3 decreased daily gain and food intake, while IGF-I did not (Dunaiski 1997, PMID 9488001); in guinea pigs, IGF-1 LR3 increased the fractional weights of adrenals, gut, kidneys and spleen without stimulating overall growth (Conlon 1995, PMID 7561636). In male 5XFAD mice, 7 months of intranasal IGF-1 LR3 did not significantly alter cognitive measures; in the cortex, the share of filamentous plaques fell, that of inert plaques rose and low-molecular-weight Aβ oligomers were reduced, while percent body fat tended to be lower than with vehicle (Engel 2025, PMID 39610283). After renal ischaemia in rats, the variants showed no potency advantage for growth effects⁶.

Adverse effects and tolerability reported

• No human data. No study in which IGF-1 LR3 was given to humans was identified; the findings below come from rats and pigs^1,6,7.
• Hypoglycaemia. Plasma glucose lowering in pigs was dose-responsive and more prolonged with the IGFBP-poor variants, with an about 4- to 8-fold greater cumulative suppression over 4 h than with IGF-I¹; in finisher pigs, a 4-day infusion left plasma glucose unaffected (Dunaiski 1997, PMID 9488001).
• Renal function after renal ischaemia. Rats given IGF-1 LR3 for 3 days after renal ischaemia showed a significantly greater fall in GFR than controls, lower urinary osmolality, higher fractional sodium excretion and more tubular epithelial calcification; the authors describe a deleterious effect on renal function in the early recovery period⁶.
• Blood pressure. In anaesthetised rats, mean arterial blood pressure fell by 15 % during a 20-min infusion of IGF-1 LR3 and by 25 % of baseline during 60-min infusions of IGF-I or IGF-1 LR3; the authors relate such vascular changes to side-effects reported during IGF-I administration in humans — a statement about IGF-I, not about IGF-1 LR3⁷.
• Endocrine feedback. In finisher pigs, IGF-1 LR3 lowered the mean plasma GH concentration by 23 % and the area under the GH peaks by 60 %, and reduced plasma IGF-I, IGFBP-3 and insulin (Dunaiski 1997, PMID 9488001).
• Organ-selective growth. Gut weight rose by up to 45 % with IGF-I and especially the analogues in dexamethasone-treated rats² and intestinal weight by 20 % within 3 days with IGF-1 LR3 in female rats⁴; the studies report this as an outcome, not as an adverse event.
• Tolerability not systematically reported. The abstracts of the rat infusion studies give no adverse-event counts, clinical signs or drop-outs^2,3,4.

Limitations of the evidence. No human data were identified, and results in cells, rats, pigs, guinea pigs or mice do not predict effects in humans. Most of the cited work comes from one research consortium and was published between 1992 and 1997^{1,2,3,4,5,6,7,8}; independent studies are few (Engel 2025, PMID 39610283; Devi 2001, PMID 11735239), and Dunaiski 1997 (PMID 9488001) also comes from this consortium and shares two authors with Tomas 1997¹. The summaries rely on abstracts without full group sizes, variability or statistics. Doses are stated by mass, not in molar amounts^2,3; most potency comparisons used continuous infusion, and with injection in rats the advantage was much reduced (Tomas 1996, PMID 8708565). Effects differed by species — growth was stimulated in rats but reduced in pigs (Dunaiski 1997, PMID 9488001) — and by model⁶. None of the findings summarised here establish efficacy or safety for any use outside the described research models.

References

1. Tomas FM, Walton PE, Dunshea FR, Ballard FJ (1997). IGF-I variants which bind poorly to IGF-binding proteins show more potent and prolonged hypoglycaemic action than native IGF-I in pigs and marmoset monkeys. Journal of Endocrinology. PMID 9415072 DOI
2. Tomas FM, Knowles SE, Owens PC, Chandler CS, Francis GL, Read LC, Ballard FJ (1992). Insulin-like growth factor-I (IGF-I) and especially IGF-I variants are anabolic in dexamethasone-treated rats. Biochemical Journal. PMID 1371669 DOI
3. Tomas FM, Knowles SE, Chandler CS, Francis GL, Owens PC, Ballard FJ (1993). Anabolic effects of insulin-like growth factor-I (IGF-I) and an IGF-I variant in normal female rats. Journal of Endocrinology. PMID 8371075 DOI
4. Steeb CB, Trahair JF, Read LC (1995). Administration of insulin-like growth factor-I (IGF-I) peptides for three days stimulates proliferation of the small intestinal epithelium in rats. Gut. PMID 8549937 DOI
5. Bastian SE, Walton PE, Wallace JC, Ballard FJ (1993). Plasma clearance and tissue distribution of labelled insulin-like growth factor-I (IGF-I) and an analogue LR3IGF-I in pregnant rats. Journal of Endocrinology. PMID 7693845 DOI
6. Martin AA, Gillespie CM, Moore L, Ballard FJ, Read LC (1994). Effects of insulin-like growth factor-I peptides in rats with acute renal failure. Journal of Endocrinology. PMID 8138750 DOI
7. Gillespie CM, Merkel AL, Martin AA (1997). Effects of insulin-like growth factor-I and LR3IGF-I on regional blood flow in normal rats. Journal of Endocrinology. PMID 9415069 DOI
8. Francis GL, Ross M, Ballard FJ, Milner SJ, Senn C, McNeil KA, Wallace JC, King R, Wells JR (1992). Novel recombinant fusion protein analogues of insulin-like growth factor (IGF)-I indicate the relative importance of IGF-binding protein and receptor binding for enhanced biological potency. Journal of Molecular Endocrinology. PMID 1378742 DOI

This section summarises findings published in the cited peer-reviewed literature for informational purposes. It is not a claim of efficacy or safety, contains no dosing or administration information by design, and does not constitute medical, veterinary or scientific advice. Results in cell cultures or animal models do not predict effects in humans.