IGF-1 LR3 (Long R3 IGF-1)
Long [Arg3] Insulin-like Growth Factor-1 (Long R3 IGF-1)
A modified IGF-1 analog with reduced IGFBP binding and extended half-life, studied exclusively in animal and in vitro models. Research demonstrates organ growth, cardiomyocyte proliferation, and tissue regeneration effects in fetal sheep, mice, and rats but no human clinical data exists for the LR3 variant (PMID 33427051, PMID 12947030, PMID 41015370).
Last updated: 2026-03-10
Safety Summary
Controlled human safety data for IGF-1 LR3 are absent. In fetal sheep, LR3-IGF-1 lowered plasma insulin and glucose after 1 week and reduced in vivo glucose-stimulated insulin secretion; acute infusion also suppressed insulin during a hyperglycemic clamp (PMID 33938236, PMID 37114757). In growth-restricted fetal sheep, circulating amino acids fell during treatment without a growth benefit (PMID 39679943). By contrast, local controlled release in a rat sciatic-nerve conduit study did not produce systemic toxicity (PMID 41015370). Community sources consistently report hypoglycemia as the primary practical concern, with users maintaining carbohydrate intake during use. The AACE/ACE guidelines for GH deficiency note that IGF-1 levels should be kept within age-related physiological range to minimize side effects (PMID 31760824). All frequency and severity ratings above are extrapolated and community reports; no controlled human safety data exists for LR3.
Known Side Effects
Expected (based on mechanism and animal data)
Expected (based on animal data)
Observed in animal models
Community-reported
Community-reported
Theoretical / animal-extrapolated
Who Should NOT Use This
IGF-1 is a potent growth factor implicated in cellular proliferation and tumor growth. Elevated IGF-1 levels have been epidemiologically associated with increased cancer risk in review literature (PMID 33557137, PMID 29626053). IGF-1R signaling promotes cell survival and inhibits apoptosis. No LR3-specific cancer data exists but the mechanism applies to all IGF-1R agonists.
IGF-1 has insulin-like glucose-lowering effects (PMID 33557137). LR3 IGF-1 suppresses endogenous insulin secretion (PMID 33938236, PMID 37114757). Combined with insulin or hypoglycemic agents, risk of severe hypoglycemia is substantially increased.
IGF-1 LR3 alters fetal growth patterns, organ development, and insulin secretion in fetal sheep models (PMID 33427051, PMID 33938236). Effects on human pregnancy are unknown but potentially harmful.
IGF-1 promotes bone growth via effects on osteoblasts and growth plates (PMID 29626053). Exogenous IGF-1R agonists could theoretically cause disproportionate growth. This is mechanism-based; no LR3-specific pediatric data exists.
Talk to Your Doctor
Before considering IGF-1 LR3 (Long R3 IGF-1), discuss it with your healthcare provider. Ask about potential interactions with your current medications, whether it is appropriate for your health conditions, and what monitoring may be needed.
Sources: [1-16]
Evidence Assessment
Tier 5: Animal/in vitro data only for the LR3 variant. The most rigorous evidence comes from fetal sheep infusion studies (PMID 33427051, PMID 33938236, PMID 32573852, PMID 39679943, PMID 37114757, PMID 36091374) and animal models of nerve regeneration (PMID 41015370) and Alzheimer's disease (PMID 39610283). Multiple in vitro studies document receptor activation and cell proliferation effects (PMID 12947030, PMID 11566722, PMID 22227200). No registered human clinical trials for IGF-1 LR3 exist on ClinicalTrials.gov. Native IGF-1 (mecasermin/Increlex) has FDA approval for primary IGF-1 deficiency, but that evidence does not transfer to the LR3 analog due to substantially different pharmacokinetic properties. Phase A and Phase B independently agreed on tier 5.
1Extracellular signal-regulated kinase and phosphoinositol-3 kinase mediate IGF-1 induced proliferation of fetal sheep cardiomyocytesPMID 12947030
Sundgren NC et al. - American Journal of Physiology - Regulatory, Integrative and Comparative Physiology (2003) - animal study (in vivo + in vitro) - Fetal sheep (gestational day ~135); cell cultures
In vivo LR3 IGF-1 did not stimulate cardiomyocyte hypertrophy but decreased the percentage of binucleated cells (suggesting proliferation rather than maturation). In culture, LR3 IGF-1 increased myocyte BrdU uptake 3-5 fold. Blockade of either ERK or PI3K completely abolished LR3 IGF-1-stimulated proliferation. IGF-1 through IGF1R stimulates cardiomyocyte hyperplasia, not hypertrophy.
Limitations: Fetal sheep model. Focused on cardiomyocytes, not skeletal muscle. Relevance to adult human physiology unclear.
2IGF-1 infusion to fetal sheep increases organ growth but not by stimulating nutrient transfer to the fetusPMID 33427051
Stremming J et al. - American Journal of Physiology - Endocrinology and Metabolism (2021) - animal study - 16 catheterized late-gestation fetal sheep (LR3 IGF-1 n=8, saline n=8)
LR3 IGF-1 infusion for 1 week increased heart, adrenal gland, and spleen weights (P<0.05). Fetal insulin was lower (P<0.05). Umbilical amino acid uptake rates and fetal amino acid concentrations were lower (P<0.05). Skeletal muscle showed higher myoblast proliferation (P<0.05). Total fetal weight was not significantly different (P=0.15).
Limitations: Fetal sheep model. Short 1-week infusion. Fetal weights not statistically different. Relevance to adult muscle growth uncertain.
3Coronary vascular growth matches IGF-1-stimulated cardiac growth in fetal sheepPMID 32573852
Jonker SS et al. - FASEB Journal (2020) - animal study - Near-term fetal sheep, 127-134 days gestation
IGF-1 LR3 treatment increased fetal heart mass. Coronary conductance was preserved on a per-gram basis. Adenosine and nitric oxide contributed similarly to vasodilation in both groups. Coronary vascular growth matched cardiac growth.
Limitations: Fetal sheep model. Short treatment period. No long-term follow-up.
4Reduced glucose-stimulated insulin secretion following a 1-wk IGF-1 infusion in late gestation fetal sheep is due to an intrinsic islet defectPMID 33938236
White A et al. - American Journal of Physiology - Endocrinology and Metabolism (2021) - animal study with ex vivo islets - IGF-1 LR3 n=8, vehicle n=9; clamp n=8 vs 7; isolated islets n=8 vs 7
Plasma insulin and glucose were lower (P=0.0135 and P=0.0012). Hyperglycemic clamp GSIS was lower (P=0.0453). Isolated islet GSIS remained lower (P=0.). indicating an intrinsic islet defect. No differences in pancreatic insulin content.
Limitations: Fetal sheep model. Effect may be specific to developing pancreas. Relevance to adult beta-cell function unknown.
5Attenuated glucose-stimulated insulin secretion during an acute IGF-1 LR3 infusion into fetal sheep does not persist in isolated isletsPMID 37114757
White A et al. - Journal of Developmental Origins of Health and Disease (2023) - animal study with ex vivo islets - 10 fetal sheep (crossover); isolated islets n=6 vs 6
Acute 90-min LR3 infusion decreased fetal plasma insulin (P<0.05). Clamp insulin concentrations were 66% lower (P<0.0001). However, isolated islets showed no persistent secretory impairment, indicating beta-cells can recover after acute exposure.
Limitations: Fetal sheep model. Acute exposure only. Crossover design may have carryover effects.
6IGF-1 LR3 does not promote growth in late-gestation growth-restricted fetal sheepPMID 39679943
White A et al. - American Journal of Physiology - Endocrinology and Metabolism (2025) - animal study - 14 FGR fetal sheep (LR3 n=7, vehicle n=7)
At lower dose (1.17 mcg/kg/h for 1 week), LR3 did NOT improve fetal body weight, insulin, glucose, oxygen, or GSIS. Amino acid concentrations decreased (P=0.). notably BCAAs. Negative result may be dose-dependent.
Limitations: FGR model. Lower dose than prior studies. Short duration. Negative result.
7Sheep recombinant IGF-1 promotes organ-specific growth in fetal sheepPMID 36091374
Stremming J et al. - Frontiers in Physiology (2022) - animal study (in vitro + in vivo) - Fetal sheep, 1-week infusion, oIGF-1 vs saline
Ovine-specific recombinant IGF-1 stimulated myoblast proliferation in vitro and increased heart, kidney, spleen, and adrenal growth and myoblast proliferation in vivo without increasing muscle mass or protein synthetic rate. Results similar to prior LR3 studies.
Limitations: oIGF-1 vs saline comparison, not direct head-to-head with LR3. Fetal sheep model.
8Intranasal long R3 insulin-like growth factor-1 treatment promotes amyloid plaque remodeling in cerebral cortex but fails to preserve cognitive function in male 5XFAD micePMID 39610283
Engel MG et al. - Journal of Alzheimer's Disease (2025) - animal study with in vitro support - WT and 5XFAD male mice, n=19-27/group, 7 months treatment
Intranasal LR3 improved body composition but did NOT preserve cognition. In cortex, reduced filamentous plaques, increased inert plaques, reduced low MW Abeta oligomers. In vitro, enhanced microglial Abeta uptake. Does not support monotherapy for AD but warrants investigation in combinations.
Limitations: Aggressive mouse AD model. Male mice only. Failed primary cognitive endpoint.
9Revolutionary decellularized Alstroemeria stem-based nerve conduit integrated with GelMA and controlled IGF-1 LR3 release for enhanced rat sciatic nerve regenerationPMID 41015370
Yavuz E et al. - International Journal of Biological Macromolecules (2025) - animal study - 30 rats in 6 groups (n=5/group), 1 cm sciatic nerve defect
IGF-1 LR3 controlled-release conduit significantly improved axonal regeneration, comparable to autologous nerve grafts. No systemic toxicity observed. First plant-based biomaterial nerve conduit with IGF-1 LR3.
Limitations: Rat model. Small sample size. Novel platform needs replication. LR3 is a device component, not standalone therapy.
10Insulin-Like Growth Factor-1 (IGF-1) and Its Monitoring in Medical Diagnostic and in SportsPMID 33557137
Bailes J, Soloviev M - Biomolecules (2021) - review - N/A
Comprehensive review of IGF-1 network including recombinant variants like LR3. Describes ~98% of circulating IGF-1 bound by six IGFBPs. LR3 has reduced IGFBP affinity and increased potency. Reviews mecasermin FDA/EMA approval. Discusses IGF-1 as doping agent.
Limitations: Narrative review. Does not present original LR3 data.
11Interactions between follicle-stimulating hormone and growth factors in modulating secretion of steroids and inhibin-related peptides by nonluteinized bovine granulosa cellsPMID 11566722
Glister C et al. - Biology of Reproduction (2001) - in vitro - Bovine granulosa cells from 4-6 mm follicles
LR3 IGF-I alone markedly increased inhibin A (8-fold), activin A (41-fold), follistatin (12-fold), and estradiol (18-fold). Modest increases in progesterone and cell number. Demonstrates potent LR3 bioactivity on reproductive tissues.
Limitations: Bovine granulosa cells. In vitro only. Reproductive physiology context.
12Na+ transport across rumen epithelium of hay-fed sheep is acutely stimulated by the peptide IGF-1 in vitroPMID 22227200
Shen Z et al. - Experimental Physiology (2012) - animal study (in vitro + ex vivo) - Rumen epithelium from hay-fed sheep; cultured rumen epithelial cells
Serosal LR3 IGF-1 at 20 mcg/L rapidly (within 30 min) stimulated net Na+ flux by ~60% (P<0.05). Effect inhibited by amiloride. Mechanism involves NHE activation.
Limitations: Rumen physiology study. Relevance to human tissues uncertain.
13Insulin-like growth factors: actions on the skeletonPMID 29626053
Yakar S et al. - Journal of Molecular Endocrinology (2018) - review - N/A
IGFs regulate bone growth and properties via effects on osteoblasts, osteocytes, and osteoclasts. Decreasing IGF-1 during aging correlates with reduced BMD and increased fracture risk.
Limitations: General IGF-1 review. Does not address LR3 specifically.
14Regulation of the cardiomyocyte population in the developing heartPMID 21147149
Thornburg K et al. - Progress in Biophysics and Molecular Biology (2011) - review - N/A
Reviews growth factors regulating fetal cardiomyocyte proliferation including IGF-1. Provides context for LR3 IGF-1 effects on cardiomyocyte hyperplasia vs hypertrophy.
Limitations: Review article. Not LR3-specific.
15Control of culture environment for improved polyethylenimine-mediated transient production of recombinant monoclonal antibodies by CHO cellsPMID 16739959
Galbraith DJ et al. - Biotechnology Progress (2006) - in vitro (bioprocess) - CHO cell cultures
LR3-IGF addition combined with mild hypothermia synergistically increased recombinant antibody production 11-fold. Demonstrates LR3 IGF-1 bioactivity in cell culture.
Limitations: Bioprocess study, not therapeutic.
16Recombinant expression of IGF-1 and LR3 IGF-1 fused with xylanase in Pichia pastorisPMID 37261455
Lu Z et al. - Applied Microbiology and Biotechnology (2023) - in vitro (production/bioactivity) - N/A
Achieved recombinant expression of LR3 IGF-1 at ~1 g/L in bioreactor. Purified LR3 displayed cell proliferation bioactivity comparable to standard IGF-1.
Limitations: Production study, not therapeutic.