Elevated serum levels of IGF-1 are sufficient to establish normal body size and skeletal properties even in the absence of tissue IGF-1

Abstract

Use of recombinant insulin-like growth factor 1 (IGF-1) as a treatment for primary IGF-1 deficiency in children has become increasingly common. When untreated, primary IGF-1 deficiency may lead to a range of metabolic disorders, including lipid abnormalities, insulin resistance, and decreased bone density. To date, results of this therapy are considered encouraging; however, our understanding of the role played by IGF-1 during development remains limited. Studies on long-term treatment with recombinant IGF-1 in both children and animals are few. Here, we used two novel transgenic mouse strains to test the long-term effects of elevated circulating IGF-1 on body size and skeletal development. Overexpression of the rat igf1 transgene in livers of mice with otherwise normal IGF-1 expression (HIT mice) resulted in approximately threefold increases in serum IGF-1 levels throughout growth, as well as greater body mass and enhanced skeletal size, architecture, and mechanical properties. When the igf1 transgene was overexpressed in livers of igf1 null mice (KO-HIT), the comparably elevated serum IGF-1 failed to overcome growth and skeletal deficiencies during neonatal and early postnatal growth. However, between 4 and 16 weeks of age, increased serum IGF-1 fully compensated for the absence of locally produced IGF-1 because body weights and lengths of KO-HIT mice became comparable with controls. Furthermore, micro-computed tomography (µCT) analysis revealed that early deficits in skeletal structure of KO-HIT mice were restored to control levels by adulthood. Our data indicate that in the absence of tissue igf1 gene expression, maintaining long-term elevations in serum IGF-1 is sufficient to establish normal body size, body composition, and both skeletal architecture and mechanical function. © 2010 American Society for Bone and Mineral Research.

Elevated Circulating IGF-I Promotes Mammary Gland Development and Proliferation

“…In agreement with previous reports, HIT mice with elevated serum IGF-I had increased body weight compared with control mice at 8 and 16 wk of age ( Fig. 1A) (17,19). Mammary gland weight of HIT mice, however, was less than that of wild-type control (LL) mice at 4 wk of age, but did not differ from LL mice at 8 and 16 wk of age (Fig.…”

“…Liver-specific IGF-I transgene expression in HIT and KO-HIT mice led to threefold increase in serum IGF-I above control mice at 4, 8, and 16 wk of age, as previously reported (17,19). In agreement with previous reports, HIT mice with elevated serum IGF-I had increased body weight compared with control mice at 8 and 16 wk of age ( Fig.…”

IGF1 Gene Polymorphism in Selected Species of the Canidae Family

“…It has been shown that the more protein produced by the IGF1 gene is contained in the blood, the larger the individual. Mice with a damaged IGF1 gene have been shown to attain a very small size, while humans with a deletion in this gene are born with a body length considerably below the norm [7]. The IGF1 gene has a substantial effect on the size of individuals in some breeds of pig [8], cattle [9], as well as in canids [10,11].…”

The severe short stature in two siblings with a heterozygous IGF1 mutation is not caused by a dominant negative effect of the putative truncated protein

“…Recent studies revealed that autocrine and paracrine IGF-I appears crucial for early postnatal and pubertal development of cortical bone, while circulating IGF-I, responsible for the endocrine effect, is mainly important for growth after puberty. In autocrine and paracrine IGF-I deficient mice high levels of serum IGF-I can permit postpubertal "catch-up" growth [18][19][20].…”