Mature IGF-II prevents the formation of "big" IGF-II/IGFBP-2 complex in the human circulation

IGF-II plays an important role in physiological and pathological processes involved in growth and metabolism. Despite the fact that "big" IGF-IIs, IGF-II(1-87) and IGF-II(1-104), have been identified in the circulation for decades in addition to "mature" IGF-II, the biological properties of these "big" IGF-IIs and the mechanisms regulating their bioavailability have not been fully elucidated. In this study we demonstrated that IGF-II (1-87), as an abundant "big" IGF-II form, exists at a molar ratio of 0.24 (CI 0.13-0.62) with respect to mature IGF-II in the normal human circulation. Mature and "big" IGF-II can equally form complexes with IGFBP-2 and IGFBP-3 in vitro, resulting in the inhibition of IGF-II's biological function. However, under physiological conditions which entails the presence of both "big" and mature IGF-II, "big" IGF-IIs preferably formed complexes with IGFBP-3 but not IGFBP-2, unlike mature IGF-II which was equally associated with both IGFBP-3 and IGFBP-2. "Big" IGF-II binding to IGFBP-2 was only evident when the "big"/mature IGF-II ratio approached 1 or higher. We concluded that mature IGF-II prevents the formation of "big" IGF-II/IGFBP-2 complex in the circulation of healthy human controls. This finding suggests the presence of previously unknown mechanisms in the regulation of IGF-II bioavailability. Elevation of the ratio of "big" to mature IGF-II in the circulation may result in altered bioavailability of "big" IGF-IIs. This mechanism is relevant in pathological conditions such as Non-Islet Cell Tumor-induced Hypoglycemia (NICTH) and Hepatitis C-associated Osteosclerosis (HCAO), in which "big" IGF-II(1-87) and IGF-II(1-104) are significantly elevated.