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Most of the anabolic effects attributed to growth hormone are not produced by GH directly but by IGF-1, synthesized mainly in the liver under GH stimulation. Understanding IGF-1 is understanding half of the somatotropic axis.
The IGF system
- IGF-1: a 70-amino-acid peptide with structural homology to proinsulin. It acts on the IGF-1R receptor (tyrosine kinase) and, with lower affinity, on the insulin receptor.
- IGFBP (binding proteins, 1 to 6): in plasma, almost all IGF-1 circulates bound to them, mainly in a ternary complex with IGFBP-3 and the acid-labile subunit. Only the free fraction is active.
- Feedback: IGF-1 inhibits GH secretion in the pituitary and stimulates somatostatin secretion in the hypothalamus.
IGF-1 LR3
It is a variant with a 13-amino-acid extension at the N-terminus and a Glu to Arg substitution at position 3. The result is a greatly reduced affinity for IGFBPs: a larger free fraction and a half-life much longer than native IGF-1's. That same property means its activity is not «buffered» by the binding protein system.
MGF (mechano growth factor)
It is an alternative splicing product of the IGF-1 gene (the IGF-1Ec variant in humans) expressed in muscle after mechanical stimulus. The peptide studied corresponds to its C-terminus (E peptide). The literature is mostly preclinical with heterogeneous results; its natural half-life is very short, which motivated the PEGylated version.
Safety considerations specific to the axis
- Hypoglycemia: because of their action on the insulin receptor, IGF-1 and its analogs can lower blood glucose. It is the most relevant acute effect.
- Cell proliferation: IGF-1R is a mitogenic and anti-apoptotic pathway. That is why active neoplasia is a recurring contraindication across the entire GH/IGF-1 axis, including approved drugs.
In clinical practice, serum IGF-1 is the integrated marker of GH activity, because GH is pulsatile and a single measurement says little. Secretagogue studies use it as the primary endpoint for the same reason.
Catalogue compounds mentioned in this lesson
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