*3.3. Putative Role of Inositols in IGF-1 Signaling*

Insulin and insulin-like growth factor 1 (IGF-1) are both hormones with a high structural similarity and share some cross-reactivity due to the low-affinity binding of insulin to the IGF-1 receptor (IGF-1R) and from IGF-1 to IR. The existence of active IGF-1/IR heterodimers has also been demonstrated, although their physiological role has not been fully described. In contrast to insulin, IGF-1 is released in the liver and is stimulated by the growth hormone and its function is strongly anabolic. IGF-1 circulates as a ternary complex consisting of IGF-1, IGF binding protein 3 (IGFBP-3) or 5 (IGFBP-5), and the acid labile subunit (ALS), avoiding IGF-1 non-specific insulin-like hypoglycemic activity. The metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) is involved in the proteolysis of the IGF-1 ternary complex, releasing free and active IGF-1 on target tissues [113].

Like insulin, IGF-1 is also able to stimulate GPI cleavage and IPG formation, as seen in vitro in 3T3 fibroblasts, BC3H-1 myocytes, and Chinese hamster ovary (CHO) cell lines [114–116]. Moreover, antibody binding to IPGs formed after the addition of IGF-1 blocks the growth-promoting effect on the ears of chicken embryos [117]. However, the addition IPGs without the presence of IGF-1 has a negligible effect on growth, which suggests that IPG formation is necessary, but not necessarily able to promote an IGF-1-mediated growth effect [117]. This effect is likely mediated by IPG-A, since IPG activity has been measured by its capacity of inhibiting PKA [117]. Another study showed that the addition of antibodies against IPG-P blocked the stimulatory effects of both IGF-1 on progesterone synthesis by swine ovary granulosa cells [118]. However, in adult rat hepatocytes, insulin mediates GPI cleavage and IPG formation, and it has been observed that fetal hepatocyte formation of IPGs is dependent on IGF-1 but not insulin activity. Furthermore, the addition of isolated IPG-P, but not insulin, has reduced the activity of glycogen phosphorylase (the rate limiting enzyme for glycogen hydrolysis) [119].

The results mentioned earlier suggest a role for IPGs as putative mediators of IGF-1 signaling. The involvement of IPGs on IGF-1 activity seems to be complementary to the canonical IGF-1 activation of the PI3K/Akt/mTOR and Ras/MEK/ERK pathways during development, acquiring a more prominent role for insulin signaling in adulthood. Despite these results, the study of inositols for IGF-1-like properties has long been neglected and no more recent data are available, including a lack of complementary in vivo results. It is yet to be unveiled whether inositol deficiencies may cause growth and development problems due to poor IGF-1 signaling. The addition of free inositols as compared to inositol glycans during postnatal growth may provide deeper insight inositol mechanisms of action for insulin/IGF-1 signaling.
