The IGF family of peptides belong to a large family of over ten structurally similar proteins including IGF-1, IGF-2, insulin, relaxin, and pro-insulin . They are all highly homologous in both structure and function and the metabolic effects of IGF-1 have even been characterized as “insulin-like” due to the similarities, and pathways, they share with one another. IGF-1 has over a 50% amino acid sequence homology with insulin and the IGF-1 receptor has a 60% amino acid sequence homology with the insulin receptor [121,130-131]. The similarities in structure are due to the fact that these peptides evolved from a single precursor molecule found in vertebrates over 60 million years ago . Both IGF-1 and insulin secretion is stimulated by food intake, while being inhibited by fasting .
Due to these structural similarities, IGF family members can often bind with one another’s native receptor types . To briefly summarize these cross-binding relationships, the IGF-1 molecule binds with the IGF-1 receptor with the highest affinity, however the IGF-1 receptor also binds with IGF-2 and insulin, but with significantly lower affinities. The IGF-2 receptor binds the IGF-2 molecule with the highest affinity but it also binds IGF-1 with a lower affinity, and it will not ever bind with insulin.
The family of IGF receptors have densities which vary significantly based upon the cell types in which they are present . This is one of the reasons why insulin and IGF-1 can possess differing metabolic actions despite being so structurally similar. Cells such as hepatocytes and adipocytes have many more insulin receptors than IGF-1 receptors. Conversely, vascular smooth muscle cells located in blood vessels have significantly more IGF-1 receptors than insulin receptors.
Since we already did a deep-dive earlier on the chemical underpinnings which occur during GHR activation, I won’t do it again here. But please understand that the IGF family of receptors are also tyrosine kinase activated which, as we now know, leads to phosphorylation of substrates, activation of cellular pathways, and ultimately gene expression and protein synthesis . IGF-1 receptor activation seems to be independent of the isoform from which IGF-1 was produced. Also, please note that both IGF receptor types have been found in human skeletal muscle cells .
Serum levels of IGF-1 are stable in healthy adults and there is little variation from day-to-day, or even week-to-week. In fact, looking at an individual’s serum IGF-1 levels can be a pretty decent indicator that one has GH sensitivity issues when compared against well-defined ranges, as corrected for their age and sex . Of course, things like the individual’s overall nutritional state, as well as liver health, must also be considered when trying to decide if actual sensitivity issues exist.
In circulation, IGF-1 exists primarily in a bound state with IGF binding proteins (IGFBPs). The IGFBP superfamily includes six high-affinity proteins dubbed IGFBP-1 through IGFBP-6, as well as a number of lower affinity proteins referred to as IGFBP-related proteins . Nearly 95% of all circulating IGF-1 exists in a bound state, with roughly 75% bound specifically with IGFBP-3 . A small fraction of IGF-1 (normally under 5%) may also exist in the free state, and these unbound molecules importantly act as a negative regulator of GH secretion . The IGFBPs can bind with either IGF-1 and IGF-2, but not insulin 
Going a bit further, bound IGF-1 most commonly exists in a 150-kDa ternary complex while in circulation. This ternary complex consists of one molecule each of IGF-1, IGFBP-3, and the acid labile subunit (ALS) – although it can exist in a binary complex with other IGFBPs [139-140]. These complexes serve valuable purposes by increasing the bioavailability of circulating IGFs, extending their serum half-life, transporting the IGFs to target cells, and modulating the interaction of the IGFs with their respective surface cellular membrane receptors [141-144]. For example, in plasma, the ternary complex stabilizes IGF-1, significantly increasing its half-life from less than 5 minutes to over 16 hours in some cases .
The IGFBPs normally appear to inhibit the action of IGFs, and this is because they compete with the IGF receptors for IGF binding affinity . This is not always the case though, as IGFBPs are also capable of enhancing IGF actions, potentially by facilitating IGF delivery into the receptors . Although there is a somewhat complex interplay, just remember that the primary role of IGFBPs are to transport IGFs from circulation and into peripheral tissues. Once this has been accomplished, the IGFBPs are released from the binary and ternary complexes either by proteolysis or via binding to the extracellular matrix of the IGF-1 receptor . Once released, the IGF-1 molecules become unbound, active, and believed at this point to become available for action [137,143].
Once in the tissues the IGFBPs modulate IGF’s actions as they have a higher affinity for IGFs than the receptors , however they may also exert IGF-independent effects . Some of the direct effects of IGFBPs that have already been elucidated include growth inhibition, direct induction of apoptosis, and modulating the effects of non-IGF growth factors .
Alternative splicing of the IGF-1 gene is also known to produce three distinct isoforms in humans which have both direct and indirect actions contributing to the growth promoting effects of IGF-1 [150-151]. Although they are not required for IGF-1 secretion, these isoforms may enhance the actual bioavailability of serum IGF-1 to its receptor . The three isoforms are referred to as IGF-1Ea, IGF-1Eb, and IGF-1Ec. It is worth mentioning here that rodents and fish only possess two isoforms but the article will only be referring to human isoforms, unless otherwise clearly stated, to hopefully keep a confusing topic a little less confusing.
IGF-1Ea is similar to the main IGF isoform expressed by the hepatocytes of the liver and has exon 4 of the mature IGF-1 gene spliced directly to exon 6 . IGF-1Eb is thought to be predominantly expressed in the liver but its role in muscle is still not completely understood . It extends further downstream on exon 5 but only the first 17 aminos of this isoform are identical to those in the final isoform variant which I’ll cover momentarily . This isoform is also thought to be unique to primates as it has not been found in rodents or fish .
IGF-1Ec is also referred to as mechano growth factor (MGF) and is named as such due to the fact it is expressed in a manner which responds to mechanical tension and stress [156-157]. Earlier we learned these are two of the primary mechanisms behind the hypertrophy process within skeletal muscle, and we’ll be talking a lot more about MGF as this article goes on. This isoform contains part of exon 5 spliced to exon 6 which results in a frame-shift and this mRNA is translated into an isoform with an alternative 25 aminos at the C-terminus . Rodent IGF-1Eb shares a high homology with human MGF and both are often used interchangeably in the literature . I only mention this because it can become a bit confusing when reviewing the literature on this isoform, especially when hopping back and forth between animal and human models.