Serum complexes of insulin‐like growth factor‐1 modulate skeletal integrity and carbohydrate metabolism

Serum insulin‐like growth factor (IGF) ‐1 is secreted mainly by the liver and circulates bound to IGF‐binding proteins (IGFBPs), either as binary complexes or ternary complexes with IGFBP‐3 or IGFBP‐5 and an acid‐labile subunit (ALS). The purpose of this study was to genetically dissect the role of IGF‐1 circulatory complexes in somatic growth, skeletal integrity, and metabolism. Phenotypic comparisons of controls and four mouse lines with genetic IGF‐1 deficits— liver‐specific IGF‐1 deficiency (LID), ALS knockout (ALSKO), IGFBP‐3 (BP3) knockout, and a triply deficient LID/ALSKO/BP3 line—produced several novel findings. 1 ) All deficient strains had decreased serum IGF‐1 levels, but this neither predicted growth potential or skeletal integrity nor defined growth hormone secretion or metabolic abnormalities. 2 ) IGF‐1 deficiency affected development of both cortical and trabecular bone differently, effects apparently dependent on the presence of different circulating IGF‐1 complexes. 3 ) IGFBP‐3 deficiency resulted in increased linear growth. In summary, each IGF‐1 complex constituent appears to play a distinct role in determining skeletal phenotype, with different effects on cortical and trabecular bone compartments.— Yakar, S., Rosen, C. J., Bouxsein, M. L., Sun, H., Mejia, W., Kawashima, Y., Wu, Y., Emerton, K., Williams, V., Jepsen, K., Schaffler, M. B., Majeska, R. J., Gavrilova, O., Gutierrez, M., Hwang, D., Pennisi, P., Frystyk, J., Boisclair, Y., Pintar, J., Jasper, H., Domene, H., Cohen, P., Clemmons, D., LeRoith, D. Serum complexes of insulin‐like growth factor‐1 modulate skeletal integrity and carbohydrate metabolism. FASEB J. 23, 709–719 (2009)