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IGF-1 DES

Also known as: Des(1-3)IGF-1, Des-(1-3)-IGF-I, DES IGF-1, truncated IGF-1, -3N:IGF-1

Research / Investigational only

laboratory reagent; not approved; IGF-1 and analogues prohibited by WADA

4 notable studies · 6 references

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TLDR

IGF-1 DES (des(1-3)IGF-1) is a naturally occurring form of IGF-1 missing its first three amino acids, which lets it escape IGF-binding proteins and makes it more potent than IGF-1 in cell assays and more strongly glucose-lowering in pigs and monkeys; it has never been tested in human trials, is not approved, and is prohibited in sport.

At a Glance

Classification: Naturally occurring truncated variant of insulin-like growth factor 1 lacking the N-terminal tripeptide Gly-Pro-Glu (67 amino acids); IGF-1 receptor agonist with markedly reduced IGF-binding-protein affinity

IGF-1 DES, or des(1-3)IGF-1, is insulin-like growth factor 1 missing its first three amino acids (glycine-proline-glutamate). That leaves 67 of IGF-1's 70 amino acids. It occurs naturally. It was isolated from bovine colostrum and from adult human brain in the 1980s. The missing three residues make it bind poorly to IGF-binding proteins, the carrier proteins that normally hold IGF-1 inactive. As a result it was roughly 10 times more potent than IGF-1 in cell assays, and its blood-sugar-lowering effect was stronger and lasted longer in pigs and marmoset monkeys. There are no human clinical trials. It is a laboratory reagent, not an approved drug, and IGF-1 and its analogues are prohibited in sport by WADA.

What Is IGF-1 DES?

IGF-1 → full 70-amino-acid hormone, mostly made in the liver in response to growth hormone; bound to IGF-binding proteins in blood IGF-1 DES → IGF-1 without Gly-Pro-Glu at the start; weak binding to IGF-binding proteins, so more of it is "free" and active IGF-1 LR3 → engineered IGF-1 with an Arg3 substitution and a 13-residue N-terminal extension; also designed to evade binding proteins, with a longer duration Mecasermin → recombinant full-length IGF-1; approved for severe primary IGF-1 deficiency The cleaved tripeptide, GPE, has its own separate neuroactive research literature.

What Are Researchers Studying?

Natural occurrence

A variant IGF-1 (later identified as the truncated form) was isolated and characterized from adult human brain. The same truncated form was purified from bovine colostrum and fully sequenced.

Potency and IGF-binding proteins

In rat myoblasts, the truncated form stimulated protein synthesis and inhibited protein breakdown with higher potency than IGF-1 (about 10-fold). IGF-binding proteins blocked the effects of IGF-1 and IGF-2 but not of des(1-3)IGF-1, and potency tracked inversely with binding-protein affinity.

Metabolic effects in animals

In pigs and marmosets, des(1-3)IGF-1 and other IGF-1 variants that bind poorly to binding proteins were 2-3 times more potent than IGF-1 at lowering blood glucose, with longer-lasting hypoglycemia. Des(1-3)IGF-1 was the most potent.

Research tool

Because it escapes binding proteins, des(1-3)IGF-1 has been widely used in cell biology to study IGF-1 receptor signaling.

How Does It Work?

IGF-1 DES ↓ largely escapes IGF-binding proteins (IGFBPs) ↓ higher free fraction available to the IGF-1 receptor (IGF-1R; some insulin-receptor cross-activity at high levels) ↓ PI3K-Akt and MAPK signaling ↓ increased cell proliferation, protein synthesis and glucose uptake; reduced protein breakdown. Its stronger effect comes mainly from avoiding binding proteins rather than from stronger receptor binding.

What Does the Research Show?

Human research

NONE. No human clinical studies of des(1-3)IGF-1 were found.

Animal research

LIMITED: acute hypoglycemia studies in pigs and marmosets, and earlier rodent work.

In-vitro research

MODERATE: isolation, sequencing, binding-protein and cell-potency studies.

Notable Studies

Isolation and characterization of variant IGF-1 as well as IGF-2 from adult human brain

in-vitro

Carlsson-Skwirut C, Jörnvall H, Holmgren A, et al. · 1986

Journal: FEBS Letters. Purified two peptides from adult human brain and identified them as IGF-2 and the N-terminally truncated IGF-1 variant previously isolated from human fetal brain, suggesting roles as neuropeptides.

Limitations: Biochemical isolation study; no functional or clinical outcomes.

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Insulin-like growth factors 1 and 2 in bovine colostrum. Sequences and biological activities compared with those of a potent truncated form

in-vitro

Francis GL, Upton FM, Ballard FJ, et al. · 1988

Journal: Biochemical Journal. Purified and sequenced IGF-1, IGF-2 and a truncated IGF-1 lacking Gly-Pro-Glu from bovine colostrum. In rat L6 myoblasts, the truncated form was more potent than IGF-1 (about 10-fold) for stimulating protein synthesis, inhibiting protein breakdown and stimulating DNA synthesis.

Limitations: Cell-culture potency only.

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Insulin-like growth factor (IGF)-binding proteins inhibit the biological activities of IGF-1 and IGF-2 but not des-(1-3)-IGF-1

in-vitro

Ross M, Francis GL, Szabo L, et al. · 1989

Journal: Biochemical Journal. An IGF-binding protein strongly inhibited IGF-2 and partly inhibited IGF-1 but did not affect des(1-3)IGF-1 in chick embryo fibroblasts; biological potency correlated inversely with binding-protein affinity.

Limitations: Cell-culture system; specific binding proteins tested.

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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

animal

Tomas FM, Walton PE, Dunshea FR, et al. · 1997

Journal: Journal of Endocrinology. Single IV doses of IGF-1 variants (including des(1-3)IGF-1 and LR3IGF-1) were 2-3 times more potent than IGF-1 at lowering plasma glucose in pigs and marmosets, with 4-8-fold greater cumulative hypoglycemia over four hours. Des(1-3)IGF-1 was the most potent.

Limitations: Acute single-dose studies; hypoglycemia is a safety signal rather than a benefit.

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What We Still Don't Know

• Any human safety or pharmacokinetic data (none published) • Whether local muscle effects claimed in the research market occur in vivo • Hypoglycemia risk and duration in people • Long-term cancer-related risk from unopposed IGF-1 receptor stimulation • Purity and identity of research-market material

Related Compounds

IGF-1 LR3MGF (Mechano Growth Factor)PEG-MGFHGH (Somatropin)

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Sources & References

  1. Carlsson-Skwirut C et al. Isolation and characterization of variant IGF-1 as well as IGF-2 from adult human brain. FEBS Letters. 1986.
  2. Francis GL et al. Insulin-like growth factors 1 and 2 in bovine colostrum. Sequences and biological activities compared with those of a potent truncated form. Biochemical Journal. 1988.
  3. Ross M et al. Insulin-like growth factor (IGF)-binding proteins inhibit the biological activities of IGF-1 and IGF-2 but not des-(1-3)-IGF-1. Biochemical Journal. 1989.
  4. Tomas FM et al. 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. 1997.
  5. Ballard FJ, et al. Des(1-3)IGF-I: a truncated form of insulin-like growth factor-I. Int J Biochem Cell Biol. 1996.
  6. Ballard FJ, et al. Natural and synthetic forms of insulin-like growth factor-1 (IGF-1) and the potent derivative, destripeptide IGF-1: biological activities and receptor binding. Biochem Biophys Res Commun. 1987.

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