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.
Qiu
Qing
Q
Chronic Disease Program, Ottawa Health Research Institute, Ottawa, Ontario, Canada.
Yan
Xiaojuan
X
Bell
Michael
M
Di
Jianmin
J
Tsang
Benjamin K
BK
Gruslin
Andrée
A
D000328:Adult; D001775:Blood Circulation; D016022:Case-Control Studies; D005260:Female; D006031:Glycosylation; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood* / Q000737:chemistry / Q000378:metabolism*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D008970:Molecular Weight; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000097:blood* / Q000737:chemistry / Q000378:metabolism; D009994:Osmolar Concentration; D011247:Pregnancy; D020033:Protein Isoforms / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology
D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D046912:Multiprotein Complexes; D020033:Protein Isoforms; D007335:Insulin-Like Growth Factor II