IGF-1 DES (1-3)

What Is IGF-1 DES (1-3)?

IGF-1 DES (1-3) is a naturally occurring, shortened form of insulin-like growth factor 1 (IGF-1) that is missing its first three amino acids, Gly-Pro-Glu. It has been isolated from bovine colostrum, human brain and porcine uterus and probably arises from post-translational cleavage of IGF-1.^[1]

The truncation matters because it removes the glutamate at position 3, which sharply reduces binding to IGF binding proteins (IGFBPs). As a result, des(1-3)IGF-I is generally about 10-fold more potent than IGF-1 at stimulating growth and proliferation of cultured cells.^[1] Its affinity for the type 1 IGF receptor, by contrast, matches that of IGF-1.^[2]

Research on the variant spans cell culture, rodent growth studies, transgenic mice and anti-doping analytics. It has never been approved for human use.^[3]

Chemical Structure and Molecular Identity

IGF-1 DES (1-3) is a protein: the human IGF-1 sequence with the N-terminal tripeptide Gly-Pro-Glu deleted. PubChem has no compound record for it, so this page lists no formula or molecular weight.^[1]

Recombinant production was described in 1991, when human IGF-1 and des(1-3)IGF-I were secreted from transfected Chinese hamster ovary cells. The purified peptides were confirmed by high-performance liquid chromatography and N-terminal sequence analysis and matched the biological potency of the authentic proteins.^[4]

Binding profile

In HT29-D4 human colon-carcinoma cells, none of the secreted IGFBP forms could bind des(1-3)IGF-I, while cell-surface type 1 IGF receptors bound IGF-1 and the truncated analog identically, with a dissociation constant of about 0.5 nanomolar.^[2] This split, receptor binding kept and binding-protein capture lost, defines the molecule.

Analytical identification

A 2021 anti-doping method used immunopurification followed by nano-liquid chromatography and high-resolution mass spectrometry to detect des(1-3)IGF-I and related analogs. The authors found abundant lower-quality, oxidized peptide forms in black-market products and recommended monitoring both native and mono-oxidized forms.^[3]

Research History and Development

Des(1-3)IGF-I was first characterized as a natural IGF-1 variant, then adopted as an experimental tool for separating receptor effects from binding-protein effects. Studies from the early 1990s tested whether its high potency in cell culture carried over to living animals.^[5]

A 1990 study in growth hormone-deficient lit/lit mice concluded that the higher potency seen in cultured cells also applies in vivo in that strain.^[5] In 1991, two rat studies tested it after partial kidney removal and after extensive gut resection.^[6][7] A 1996 review summarized the evidence and noted that its potency is retained in part in vivo, with selective anabolic effects particularly evident in gut tissues.^[1]

Researchers also used the variant to study development in the brain and the mammary gland, where it had been found naturally or where IGF signaling was being mapped.^[8][9] Clinical applications were proposed in a 1996 review but had not been evaluated.^[1]

Mechanisms Studied in Research

The core mechanism is escape from IGF binding proteins: des(1-3)IGF-I reaches the type 1 IGF receptor without being sequestered, so a given amount produces a larger signal. Studies used this property to show how strongly binding proteins limit IGF-1 activity.^[1][2]

Binding-protein modulation

In mammary epithelial cells from prepubertal heifers grown in collagen gels, des(1-3)IGF-I was the most potent of the IGF-family mitogens tested. IGFBP-2 and IGFBP-3 inhibited the mitogenic effect of IGF-1, showing that binding proteins regulate IGF activity at the cellular level.^[10] In colon-carcinoma cells, the analog was used to mimic an IGF-II autocrine loop that the cells’ own binding proteins otherwise blocked.^[2]

Proliferation and apoptosis

In human benign prostatic hyperplasia (BPH) stromal cells, des(1-3)IGF-I acted as a potent mitogen through a dual mechanism: stimulating growth and inhibiting apoptosis.^[11] In transgenic mice, overexpression reduced both apoptosis and proliferation in normal mammary glands by 75%.^[12]

Mediating growth hormone action

Because des(1-3)IGF-I mimicked growth hormone’s effect on mammary terminal end buds in hormone-depleted rats, and growth hormone raises IGF-1 mRNA in the mammary gland, reviewers proposed that IGF-1 partly mediates growth hormone’s role in mammary development. Transgenic models overexpressing IGF-1 or des(1-3)IGF-I were used to test this idea.^[9]

Key Findings From Published Studies

Animal studies show that des(1-3)IGF-I promotes growth and nitrogen retention at least as effectively as IGF-1, while cell and transgenic studies show strong mitogenic and tumor-promoting potential. Results are grouped by model below.

Animal growth models

• GH-deficient lit/lit mice: over 3 weeks, des(1-3)IGF-I increased total and nose-rump length more than controls, and at the lower level tested, unlike IGF-1, increased relative kidney and heart weights.^[5]
• Rats with reduced kidney mass: body weight gain, food utilization and nitrogen balance improved, and lower urinary 3-methylhistidine pointed to reduced muscle protein breakdown.^[6]
• Rats after removal of 80% of the small intestine: over the last 3 days, weight gain was 20.8 g with des(1-3)IGF-I versus 14.0 g with vehicle, with a more positive nitrogen balance; kidney and thymus weights also rose.^[7]

Cell and organ culture

• Newborn rat olfactory bulb: 3- to 5-fold more potent than IGF-1 for amino acid uptake, with better tissue morphology and marked neuronal expression.^[8]
• Human colon-carcinoma cells: nanomolar concentrations induced a differentiated phenotype, with carcinoembryonic antigen release and cysts lined by organized microvilli, plus a slight early inhibition of proliferation.^[2]
• Bovine mammary epithelial cells: des(1-3)IGF-I, IGF-1, IGF-II and insulin all stimulated proliferation, with des(1-3)IGF-I the most potent and insulin the least; EGF-family factors were weaker than IGF-family factors.^[10]
• Human BPH stromal cells: growth driven by des(1-3)IGF-I was inhibited by a non-hypercalcemic vitamin D3 analog.^[11]

Transgenic and detection studies

Mice overexpressing des(1-3)IGF-I in the mammary gland developed hyperplastic lesions, and 53% developed mammary adenocarcinomas by 23 months; a mutant p53 background shortened tumor latency by 8 months. Aneuploidy appeared in tumors carrying mutant p53 but not in those expressing only the des(1-3)IGF-I transgene.^[12] In hypophysectomized, gonadectomized rats, des(1-3)IGF-I mimicked growth hormone’s action on mammary terminal end bud formation.^[9] In rats, unchanged des(1-3)IGF-I remained detectable in blood for up to 24 hours.^[3]

Because truncated and oxidized IGF-1 forms are hard to tell apart, identity is typically confirmed with HPLC and mass spectrometry on a certificate of analysis.

Regulatory and Research Status

IGF-1 DES (1-3) has never been approved for human use by the FDA or any other regulator, and it is a prohibited substance in sport. A 2021 anti-doping study listed it with LongR3-IGF-I and R3-IGF-I as IGF-1 analogs banned in sport and noted that they are sold on the black market for bodybuilding.^[3]

The same study identified degradation products of the analogs after incubation in human whole blood that matched those seen in rats. The authors concluded that their validated mass spectrometry method may be applicable to routine anti-doping testing.^[3]

No controlled human trials of des(1-3)IGF-I appear in the studies reviewed here. Its scientific role remains that of a laboratory reagent for studying IGF receptor signaling, binding-protein biology and tissue growth.^[1]

The only recombinant IGF-1 drug approved in the United States is mecasermin, which corresponds to full-length native human IGF-1 rather than the truncated variant.