des(1-3)IGF-1
IGF-1 DES, DES(1-3)IGF-1, des-(1-3)-IGF-I, truncated IGF-1, brain IGF-1, IGF-1 DES(1,3)
des(1-3)IGF-1 is human IGF-1 with the first three amino acids clipped off. It occurs naturally in brain and in bovine colostrum, and the truncation sharply weakens its grip on IGF binding proteins, which makes it more potent than intact IGF-1 in systems where those binding proteins are present. It has been studied in rats since the late 1980s and never once administered in a registered human trial.
Mechanism
The N-terminal tripeptide of mature IGF-1 is Gly-Pro-Glu. Removing it produces a 67-residue peptide that retains the full A, B, C and D domains, the three native disulfide bridges and the receptor-binding surface, but loses a critical contact with the IGF binding proteins. Reported reductions in IGFBP affinity vary by assay and by which binding protein is measured, but the direction is consistent. Ballard's tracer work makes the functional consequence concrete: when radiolabelled peptides were incubated with rat plasma, association with 150 kDa and smaller IGFBP complexes was substantial for IGF-1 and IGF-2 and 'essentially absent' for des(1-3)IGF-1, and after intravenous injection most des(1-3)IGF-1 radioactivity remained free. The practical consequence is that des(1-3)IGF-1 is not efficiently loaded into the ternary IGFBP-3/acid-labile-subunit complex that normally reservoirs IGF-1 in plasma.
At the receptor, des(1-3)IGF-1 behaves like IGF-1. It is an agonist at the type 1 IGF receptor with intrinsic affinity close to that of the intact hormone, and it signals through the same two pathways: IRS-1 to PI3K to AKT to mTORC1 (raising translational capacity and suppressing FoxO-driven proteolysis), and Shc to Ras to ERK1/2 (proliferation). Higher free concentrations also permit cross-activation of the insulin receptor and of IGF-1R/insulin-receptor hybrids.
Unlike Long R3 IGF-1, des(1-3)IGF-1 is not purely a laboratory invention. It is generated endogenously, having been isolated from bovine and human brain and detected in colostrum, and it can be produced from intact IGF-1 by acid-activated proteases in tissue. Whether it serves a distinct physiological function in the brain, or is simply a degradation product with residual activity, has never been settled. That ambiguity is worth holding onto: the fact that a molecule occurs naturally does not tell you that injecting it is either safe or useful.
What the research shows
des(1-3)IGF-1 was worked out mainly by the same Adelaide group that produced Long R3 IGF-1, and the two compounds share a literature. In growth-hormone-deficient lit/lit mice, truncated IGF-1 showed enhanced potency relative to intact IGF-1. In rats with reduced renal mass, after gut resection, and in streptozotocin-diabetic animals, des(1-3)IGF-1 and IGF-1 both improved weight gain, nitrogen retention and muscle protein synthesis. Tomas and colleagues found that in diabetic rats, des(1-3)IGF-1 at 1.08 mg/kg per day, or IGF-1 at a 2.5-fold higher dose, produced effects roughly 70% of those obtained with insulin on weight and nitrogen balance, and did so without the substantial carcass fat accumulation that insulin produced. Their stated conclusion was measured: des(1-3)IGF-1 is 'at least as potent as' full-length IGF-1, which is a weaker claim than the marketing shorthand suggests. That dissociation between lean and fat accretion is genuinely interesting, and has never been followed up in humans.
Ballard's clearance work is the single most useful and least-cited finding for anyone evaluating this compound. Measured directly in rats, des(1-3)IGF-1 was cleared from plasma roughly four times faster than intact IGF-1 and distributed into a volume nearly three times larger. This directly contradicts the widespread marketing claim that the truncation makes the molecule longer-acting. It is worth reporting the authors' own inference honestly: they proposed that binding proteins inhibit transfer of growth factors to tissue sites of action, and that rapidly cleared analogues may therefore have greater biological potency in vivo. Faster clearance and greater tissue delivery are not contradictory. What is not supported is the claim of longer duration in the blood.
On the human side there is nothing. ClinicalTrials.gov has no interventional study of des(1-3)IGF-1. No published trial has administered it to people. The compound peaked as a research tool in the early 1990s, and by Ballard's own 1996 review it had settled into the literature as an instructive probe of IGFBP biology rather than a drug candidate. Almost all of the primary studies are more than thirty years old, were conducted in catabolic-illness and growth-failure models rather than in healthy adults, and used continuous infusion in animals of a few hundred grams. None of that translates cleanly to a trained adult human.
Evidence assessment
Preclinical only
Every surviving citation is rodent, mouse or in vitro work, or a narrative review of that work; no registered human trial or published human administration study of des(1-3)IGF-1 exists.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Des(1-3)IGF-I: a truncated form of insulin-like growth factor-I Preclinical only
Consolidates the evidence that the enhanced potency of des(1-3)IGF-1 arises from reduced IGF binding protein affinity rather than from altered receptor binding.
Plasma clearance and tissue distribution of labelled insulin-like growth factor-I (IGF-I), IGF-II and des(1-3)IGF-I in rats Preclinical only
Mean total plasma clearances were 4.59, 1.20 and 1.34 mL/min per kg for des(1-3)IGF-1, IGF-1 and IGF-2 respectively, with steady-state volumes of distribution of 461, 167 and 181 mL/kg; association with plasma IGFBP complexes was essentially absent for des(1-3)IGF-1.
Increased weight gain, nitrogen retention and muscle protein synthesis following treatment of diabetic rats with insulin-like growth factor (IGF)-I and des(1-3)IGF-I Preclinical only
des(1-3)IGF-1 at 1.08 mg/kg per day, or IGF-1 at a 2.5-fold higher dose, produced approximately 70% of insulin's effect on body weight and nitrogen retention, without the substantial carcass fat increase seen with insulin; the IGF peptides did not correct glucosuria.
IGF-I and the truncated analogue des-(1-3)IGF-I enhance growth in rats after gut resection Preclinical only
Both IGF-1 and des(1-3)IGF-1 enhanced growth in rats after gut resection.
Enhanced potency of truncated insulin-like growth factor-I (des(1-3)IGF-I) relative to IGF-I in lit/lit mice Preclinical only
des(1-3)IGF-1 showed enhanced growth-promoting potency relative to intact IGF-1 in a growth-hormone-deficient mouse model.
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 Preclinical only
In IGFBP-secreting cell lines, des(1-3)IGF-I ranked alongside Long [Arg3]-IGF-I as the most potent analogue tested, confirming that potency differences track IGFBP affinity rather than receptor affinity.
Safety
No human safety data exist for des(1-3)IGF-1. The predictable risks follow from its pharmacology and from what is documented for licensed recombinant IGF-1 (mecasermin): hypoglycaemia, which is the dominant acute hazard and is amplified rather than reduced by loss of IGFBP buffering; hypersensitivity and injection-site reactions; lymphoid and tonsillar hypertrophy on sustained exposure; and raised intracranial pressure. The rapid plasma clearance seen in rats does not make it safer; it means any given dose delivers a sharper, higher free-IGF peak.
The longer-term concern is the same one that applies to any sustained supraphysiological IGF-1 receptor agonism. IGF-1R signalling is mitogenic and suppresses apoptosis; higher circulating IGF-1 is associated in observational and Mendelian randomisation studies with modestly elevated risk of several common cancers. Nothing about the N-terminal truncation changes that receptor biology.
A specific problem for des(1-3)IGF-1 as sold: it is genuinely difficult to manufacture correctly. Getting three disulfide bonds to form in the right pattern in a 67-residue peptide expressed in bacteria is non-trivial, and misfolded disulfide isomers are biologically inactive or aberrantly active and are not detected by the simple purity assays that unregulated vendors report. There is no independent published survey of what is actually in products sold as 'IGF-1 DES', which is itself the finding: the composition of what people are injecting is unknown.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | No MHRA marketing authorisation. IGF-1 products are prescription-only medicines, and supplying an unlicensed medicinal product for human use breaches the Human Medicines Regulations 2012. Not controlled under the Misuse of Drugs Act 1971. Supply as a laboratory reagent is lawful only where it is genuinely not offered or intended for human administration. |
| United States | Not approved by FDA for any indication, and no investigational new drug programme is active. It is not a dietary supplement, and marketing it for human use makes it an unapproved new drug and misbranded under the Federal Food, Drug, and Cosmetic Act. Sold by research-chemical vendors under a 'for research use only' label. Mecasermin, recombinant human IGF-1, is the only approved IGF-1 product in the US and is a different molecule. Not DEA-scheduled. |
| WADA (sport) | Prohibited at all times. The WADA Prohibited List, section S2.3, prohibits 'Insulin-like Growth Factor-1 (IGF-1) and its analogues'; des(1-3)IGF-1 is squarely an IGF-1 analogue. Class S2 substances are non-Specified Substances. Detection is complicated by the fact that des(1-3)IGF-1 also occurs endogenously, which is an analytical problem rather than a defence. |
Questions
Both are IGF-1 variants engineered or selected to escape IGF binding proteins, but they do it differently. DES(1-3)IGF-1 removes the first three residues from the natural 70-residue chain, giving a 67-residue peptide that also occurs naturally in brain and colostrum. LR3 adds a 13-residue foreign extension and swaps glutamate 3 for arginine, giving an 83-residue wholly synthetic construct. In the original head-to-head cell work the two ranked similarly for potency. Neither has been tested in a human trial.
In rats, yes, substantially shorter. Ballard and colleagues measured plasma clearance of 4.59 mL/min per kg for des(1-3)IGF-1 against 1.20 for intact IGF-1, roughly four-fold faster, with a volume of distribution of 461 versus 167 mL/kg. The reason is exactly the property it is sold for: because it is not loaded into the IGFBP-3 and acid-labile-subunit reservoir, it does not linger in plasma. The frequent claim that the truncation makes it longer-acting is not supported by the primary literature.
Yes, in the sense that it is found in bovine and human brain and in colostrum, and can be generated from intact IGF-1 by tissue proteases. Whether that endogenous form serves a distinct physiological purpose or is a partially active breakdown product has never been resolved. Either way, natural occurrence tells you nothing about the safety of injecting a manufactured version at supraphysiological doses.
It was developed as a research probe rather than a drug candidate, at a time when recombinant IGF-1 itself was the commercial priority. The clinical problem it addressed, restoring growth and nitrogen balance in catabolic states, proved hard to translate, and IGF-1's narrow window between anabolism and hypoglycaemia discouraged development of analogues that widened free-hormone exposure further. Interest faded in the mid-1990s. There is no registered trial and no published human administration study.