IGF1 LR3.

Introduction.

IGF1 LR3 (insulin-like growth factor-1 Long R3) is a non-glycosylated, recombinant polypeptide chain made up of 83 amino acids. IGF1 LR3 is the recombinant form of human IGF-1, and as such it contains the entire native amino acid sequence but with two major modifications: substitution of arginine (abbreviated R or arg) at position 3 with glutamic acid (abbreviated E or Glu) hence the label R3; and the extension of the N-terminus of the native sequence by a 13 amino-acid peptide hence the label long. The native form of a polypeptide refers to the naturally occurring amino acid sequence and the resultant conformational structure. The molecular weight of IGF1 LR3 as measured by Mass Spectrometry is 9.116 kD (kiloDaltons). A patented protein expression system is utilized in the production of IGF1 LR3 in Escherichia Coli. Thereafter, chromatographic techniques are used to correctly fold and purify the nascent IGF1 LR3 to the highly-active and functional IGF1 LR3 that can bind to human IGF-1R (insulin-like growth factor-1 receptor).

Insulin-like growth factor-1 (IGF-1).

IGF-1 is an endocrine peptide hormone encoded by the IGF-1 gene, and produced in the liver. Growth hormone (GH) stimulates its production. IGF-1 is made up of a 70 amino acid sequence which contains 3 intra-molecular disulfide bridges. It shares its molecular structure with insulin, and as such it exerts anabolic effects on the body. It uses autocrine and paracrine signaling mechanisms to interact with its target tissues. Its molecular weight is 7.649 kD.

IGF-1 has also been termed as the sulfation factor and its corresponding effects christened NSILA (non-suppressible insulin-like activity). Currently, the alternative name for IGF-1 is somatomedin C.

IGF-1 promotes efficient energy metabolism by sensitizing cells to insulin while concurrently increasing the rate of fat catabolism (a form of destructive metabolism whereby fat is broken down to simpler compounds and in the process, energy is released) in order to provide energy for cellular processes. It also promotes fat metabolism in muscle tissue while simultaneously conserving glucose and up-regulating protein synthesis in individual myocytes. Thus, the net result is muscle hypertrophy (enlargement due to increase in cell size). Definitive studies have also shown that IGF-1 reduces the overall fat content of the body.

The actions of IGF-1 are mediated by the IGF-1R which is found in various cell types. Molecular studies have shown that IGF-1R belongs to the tyrosine-kinase family of receptors, and as such ligand binding activates the intracellular AKT signaling pathway whose terminal downstream effects include inhibition of apoptosis, and stimulation of cellular growth and proliferation. Therefore, IGF-1 stimulates cell growth, differentiation and proliferation; and this ultimately results in systemic body growth.

Current studies have shown that IGF-1 mediates the effects of GH. It can therefore be inferred that the actions of IGF-1 affects most cells of the body. IGF-1 is normally produced at peak levels during puberty, and it is responsible for the growth spurt and muscle growth that occurs during this period. Therefore, a deficiency in either GH or IGF-1 leads to stunted bodily growth which in turn brings about a diminished stature. Various therapeutic models have proposed that recombinant forms of either GH or IGF-1 can be used to stimulate growth in GH or IGF-1 deficient individuals.

Research has also shown that IGF-1 regulates neuronal growth and development; as well as neuronal nucleotide synthesis. Therapeutics studies have also shown that recombinant IGF-1 can be used to manage peripheral neuropathies such as motor axons degeneration.

Studies have shown that IGF1 LR3 has the same functional biologic profile as the endogenous IGF-1. It has also been documented that IGF1 LR3 increases glucose and amino acid transportation into cells. IGF1 LR3 also increases both RNA and protein synthesis; while simultaneously inhibiting the degradation of proteins, thus resulting in a net increase in the protein content of cells. Likewise, studies have shown that IGF1 LR3 stimulates hypertrophy and hyperplasia of muscle cells.

The following studies have been selected for review since their findings do have an impact on the therapeutic use of IGF1 LR3.

Selected studies.

1.      IGF1 LR3 and protein metabolism.

In 1999, Hill et al did a study entitled “Action of long (R3)-insulin-like growth factor-1 on protein metabolism in beef heifers.” The main aim of this study was to investigate the effects that IGF1 LR3 have on protein metabolism. The subjects used in this study were beef heifers which were intentionally underfed in order for them to lose weight. The subjects were divided into two groups: the test group and the control group. IGF1 LR3 was administered only to the test group using the intravenous route. The results obtained showed that heifers in the test group were able to conserve both their skeletal muscle protein and the whole-body protein. Moreover, these heifers (belonging to the test group) showed a decrease in both amino acids and glucose plasma concentrations. Additionally, the test group showed a significant decline in the plasma concentrations of endogenous IGF-1 and IGF-2. For the control groups, the plasma concentrations of these endogenous hormones remained relatively stable.  Also, the plasma concentrations of IGF-binding protein increased significantly in the test group, and the protein was even detected using radio-ligand blot.

2.      IGF1 LR3 and atherosclerotic plaques.

In 2011, von der Thüsen et al conducted a study entitled “IGF-1 has plaque-stabilizing effects in atherosclerosis by altering vascular smooth muscle cell phenotype.” The aim of this study was to investigate the effects that both IGF1 and IGF1 LR3 have on atherosclerotic plaques. This study used a mouse model to evaluate the effects that the inflammatory milieu of atherosclerotic plaques have on the functional stability of IGF-1 signaling pathways; and also the effects of IGF-1 supplementation (using recombinant analogues) on the plaque phenotype. The results revealed that a macrophage-conditioned M1-polarized medium did inhibit IGF-1 signaling pathways. The inhibition occurred through the following processes: ablation of IGF1, up-regulation of IGF-binding protein-3 expression, increased vascular smooth muscle cell apoptosis coupled with its decreased degradation. Moreover, the medium inhibited the expression of both col3a1and α-actin genes. However, the matrix-degrading enzymes were overexpressed in the medium.

The results also revealed that IGF1 LR3 could correct all the aforementioned observations as evidenced by the fact that there was an attenuation of all the measurable plaques parameters in nascent atherosclerotic plaques. IGF1 LR3 also increased the vascular smooth muscle content of advanced atherosclerotic plaques, therefore reducing the probability of intra-plaque hemorrhage by more than 50%.