IGF-1 DES, the Neglected, but Potentially Superior, Insulin-Like Growth Factor Analog

IGF-1 DES, or more scientifically correct, Des(1-3)IGF-1 (also labeled -3N:IGF-1 in some literature), is a naturally occurring IGF-1 analog, presumably produced post-translationally1,2,3 via removal of a 3-amino acid sequence (Gly-Pro-Glu) from the N-terminal domain. It’s one of two commonly purchased lyophilized IGF-1 variants, sitting side-by-side w/ IGF-LR3 (LongR3IGF-1) in “research chemical” catalogs, though it’s largely eclipsed by the LR3 variant, probably due to being perceived as being comparatively too short-acting of a compound to get meaningful effects as it pertains to muscular hypertrophy & more. It accordingly is often described as the IGF-1 peptide that is ideal for site-growth, though there is no scientific literature that suggests this to be true. In other words, it’s simply broscience. Indeed, articles & comments written about both IGF LR3 & IGF DES on bodybuilding & biohacking platforms seem to inundated with misinformation. This article will progressively inch its way towards attacking that, beginning with critical background information on Des(1-3)IGF-1, and ending with a more jarring comparison with its more popular cousin, LongR3IGF-1. As a forewarning, many studies referenced throughout this article involve experiments done on mammalian species outside of humans, as no results of any study on metabolism & elimination kinetics in humans following IGF-1 analog administration were ever published, due likely to IGF-1 analogs never having received marketing authorization8.

Naturally Occurring Across Several Mammalian Species

While IGF-LR3 tends to steal the spotlight in bodybuilding & bio-hacking societies, it, at the end of the day, is not a naturally occurring IGF-1 analog. It’s a product of laboratory-based synthesis. The same cannot be written of Des(1-3)IGF-1, which has been isolated & purified from human2, bovine3 (think cattle), & porcine4 (think pigs) tissues & excretions. With all other variables controlled for, preference for an exogenous agent, in this case an IGF-1 analog, should always be lent to substances that the body is familiar with, and according to this principle, the naturally occurring Des(1-3)IGF-1 clearly holds the advantage over the synthetically produced LongR3IGF-1.

Decreased Sequestration by Binding Proteins (IGF-BP’s)

A critical reason why both IGF-1 LR3 & IGF-1 DES exhibit such exaggerated biological activity relative to IGF-1 is due to their apparent incapacity of being bound by the IGF-1-binding proteins (IGF-BP’s) that otherwise serve to sequester free IGF-1 and render them incapable of binding to the target receptors from which the prominent biological effects will precipitate. In the case of Des(1-3)IGF-1, it is specifically the loss of the glutamate (Glu) amino acid in the N-terminal domain that grants it this almost total loss of ability to bind to IGF-BP’s, and both Bagley et. al. & Ballard et. al. conclude that this is one possible explanation for why Des(1-3)IGF-1 exhibits such pronounced biological activity.

Bagley CJ et. al.
[5]
Ballard FJ et. al.
[6]
[6]

Enhanced Biological Activity Relative to IGF-1 & IGF-2

In an in vitro study carried out by Francis et. al. on rat L6 myoblasts (muscle progenitor cells, or baby cells, if you will), Des(1-3)IGF-1 was found to be 3.5-fold more active w/ regards the stimulation of DNA synthesis (a surrogate for mitogenic, or mitosis-inducing, activity). Des(1-3)IGF-1 also achieved equivalent inhibition of protein degradation and stimulation of protein synthesis as IGF-1 concentrations that were 8-fold & 8.4-fold greater, respectively, demonstrating its profoundly exaggerated capacity for biological activity at much lower concentrations/doses. The gaps were even more exaggerated when Des(1-3)IGF-1 was compared to IGF-2.

Francis GL et. al.
[1]

Sara et. al., having isolated & purified Des(1-3)IGF-1 in human fetal brain tissue, found again that this truncated version was more potent than either IGF-1 or IGF-2 in stimulating brain DNA synthesis (and thus, proliferation);

[2]

Ogasawara et. al., having isolated Des(1-3)IGF-1 from porcine uterus, applied the IGF-1 analog to both human MCF-7 breast cancer cells and mouse Balb/c 3T3 fibroblasts in an in vitro experiment that found that Des(1-3)IGF-1 was 30-100x more potent at stimulating proliferation than IGF-1;

[4]

Bioavailability, Half-Life, & the Related

In an in vivo experiment carried out by Ballard et. al that saw intravenous (i.v.) infusions of either IGF-1, IGF-2, or Des(1-3)IGF-1, it was found that Des(1-3)IGF-1 demonstrated rapid clearance from plasma, w/ clearance rates that are 3-4x higher than IGF-1 & IGF-26. This is a result that is consistent with other IGF-1 analogs that bind poorly to IGF-BP’s, leading authors to infer that IGF-BP’s likely enhance the durability (half-life) of IGF-1 in the body. So it’s a double-edged sword as far as the binding proteins go; while they limit the potency of IGF-1 peptides, they concomitantly also amplify their half-lives, and thereby extend their presence in the body. With that written and accounted for, however, in the same experiment by Ballard et. al., i.v. infused Des(1-3)IGF-1 was still recoverable intact (undegraded) in the plasma (the clear, yellowish fluid portion of blood) at 10-19% of initial values 5hrs post-infusion. When reconciling this remnant percentage of active peptide with the exaggerated potency of the peptide (see previous sections of this article), it’s easy to speculate that biological activity could still be notable even 5hrs post-infusion. Unfortunately, this particular study did not test for biological activity, so we can’t infer as much from Ballard et. al.’s setup. However, an in vivo experiment carried out on pigs by Walton et. al. did find that a single intravenous injection of Des(1-3)IGF-1 produced not only a more profound, but also a longer-lasting, metabolic effect (hypoglycemic response) than an injection of IGF-1, IGF-1 LR3, or any other IGF-1 analog;

[7]

Now consider that almost all experiments carried out by individuals purchasing IGF-DES or IGF-LR3 will involve either intramuscular (IM) or subcutaneous (SQ) injections, and not an intravenous (i.v.) infusion, meaning that the effective entry & clearance dynamics for most experiments will shift considerably compared to these aforementioned studies, as absorption dynamics of IM or SQ injections are obviously markedly delayed compared to direct intravenous infusion. With that in mind, it becomes easy to speculate that Des(1-3)IGF-1 might exhibit not only a much more profound biological impact, but also a much longer durability in the body than most bodybuilding/biohacking forums & articles will lead you to believe.

Surprisingly Superior Durability, and Prolonged Detectability, Relative to IGF-LR3

I began this article referencing the commonly-espoused belief amongst those in the bodybuilding & biohacking communities that IGF-1 DES is a short-acting analog compared to LR3, and that this reason alone may be the key reason why most individuals devote their attention almost exclusively towards LongR3IGF-1. How fitting, then, to end the article on this particular note. So far, with a reference to an experiment done in pigs by Walton et. al. in particular, it was delineated how Des(1-3)IGF-1 can produce both a more exaggerated & prolonged biological response than LongR3IGF-1, at least when metabolism is in question. To add, a very recent study by Mongongu et. al. (2021) that was designed to delineate ways to optimize detection of IGF-1 analogs for anti-doping purposes found that, while intramuscularly injected Des(1-3)IGF-1 was detectable in its native, undegraded, & unoxidized form through 24hrs post-injection in a rat model, the native form of LongR3IGF-1 was only detectable through the 4hr mark. This discrepancy in duration will undoubtedly come as a surprise to many a reader. In addition to these observations, it was found that LongR3IGF-1 degraded rapidly into a series of metabolites, an outcome that was subsequently replicated in an in vitro experiment that saw the peptides incubated overnight in human blood (human matrices). The study authors suggest that passive proteolysis could be responsible for IGF-LR3’s degradation into these metabolites, probably due to the action of circulating human peptidases that do not require metabolism in cells. We do not know what the biological impacts of IGF-LR3’s metabolites are, and this is cause for concern, if for no other reason than these degradation products simply not possessing the capacity to elicit the mitogenic or anabolic impacts of an intact LongR3IGF-1 peptide. Oppositely, however, Des(1-3)IGF-1 rendered no degradation products in vivo or in vitro. What was detected at 24hrs post-injection, was what was injected originally: the same native form.

Mongongu et. al.
[8]
[8]
[8]
[8]
[8]

This is totally at odds with what you’d typically read on bodybuilding/biohacking websites & forums, wherein IGF-LR3 is typically celebrated as a long-acting & durable IGF-1 analog. This discrepancy lends credence to the notion that a typical reader has to take all the information available to them with several grains of salt. All in all, IGF-DES > IGF-LR3 in many more ways than one, and I expect LR3 to eventually be phased out of production over the coming decades as some of the details outlined above become more mainstream.

References

  1. Francis GL, Upton FM, Ballard FJ, McNeil KA, Wallace JC. Insulin-like growth factors 1 and 2 in bovine colostrum. Sequences and biological activities compared with those of a potent truncated form. Biochem J. 1988 Apr 1;251(1):95-103. doi: 10.1042/bj2510095. PMID: 3390164; PMCID: PMC1148968.
  2. Sara VR, Carlsson-Skwirut C, Andersson C, Hall E, Sjögren B, Holmgren A, Jörnvall H. Characterization of somatomedins from human fetal brain: identification of a variant form of insulin-like growth factor I. Proc Natl Acad Sci U S A. 1986 Jul;83(13):4904-7. doi: 10.1073/pnas.83.13.4904. PMID: 3460078; PMCID: PMC323852.
  3. Francis GL, Read LC, Ballard FJ, Bagley CJ, Upton FM, Gravestock PM, Wallace JC. Purification and partial sequence analysis of insulin-like growth factor-1 from bovine colostrum. Biochem J. 1986 Jan 1;233(1):207-13. doi: 10.1042/bj2330207. PMID: 3954725; PMCID: PMC1153005.
  4. Ogasawara M, Karey KP, Marquardt H, Sirbasku DA. Identification and purification of truncated insulin-like growth factor I from porcine uterus. Evidence for high biological potency. Biochemistry. 1989 Mar 21;28(6):2710-21. doi: 10.1021/bi00432a052. PMID: 2730884.
  5. Bagley CJ, May BL, Szabo L, McNamara PJ, Ross M, Francis GL, Ballard FJ, Wallace JC. A key functional role for the insulin-like growth factor 1 N-terminal pentapeptide. Biochem J. 1989 May 1;259(3):665-71. doi: 10.1042/bj2590665. PMID: 2730580; PMCID: PMC1138570.
  6. Ballard FJ, Knowles SE, Walton PE, Edson K, Owens PC, Mohler MA, Ferraiolo BL. Plasma clearance and tissue distribution of labelled insulin-like growth factor-I (IGF-I), IGF-II and des(1-3)IGF-I in rats. J Endocrinol. 1991 Feb;128(2):197-204. doi: 10.1677/joe.0.1280197. PMID: 2005410.
  7. Walton PE, Dunshea FR, Ballard FJ. In vivo actions of IGF analogues with poor affinities for IGFBPs: metabolic and growth effects in pigs of different ages and GH responsiveness. Prog Growth Factor Res. 1995;6(2-4):385-95. doi: 10.1016/0955-2235(95)00007-0. PMID: 8817682.
  8. Mongongu C, Coudoré F, Domergue V, Ericsson M, Buisson C, Marchand A. Detection of LongR3 -IGF-I, Des(1-3)-IGF-I, and R3 -IGF-I using immunopurification and high resolution mass spectrometry for antidoping purposes. Drug Test Anal. 2021 Jul;13(7):1256-1269. doi: 10.1002/dta.3016. Epub 2021 Feb 22. PMID: 33587816.