Pigs and humans with cystic fibrosis have reduced insulin-like growth factor 1 (IGF1) levels at birth

Abstract

People with cystic fibrosis (CF) exhibit growth defects. That observation has been attributed, in part, to decreased insulin-like growth factor 1 (IGF1) levels, and the reduction has been blamed on malnutrition and pulmonary inflammation. However, patients with CF already have a reduced weight at birth, a manifestation not likely secondary to poor nutrition or inflammation. We found that, like humans, CF pigs were smaller than non-CF littermates and had lower IGF1 levels. To better understand the basis of IGF1 reduction, we studied newborn pigs and found low IGF1 levels within 12 h of birth. Moreover, humerus length and bone mineral content were decreased, consistent with less IGF1 activity in utero. These findings led us to test newborn humans with CF, and we found that they also had reduced IGF1 levels. Discovering lower IGF1 levels in newborn pigs and humans indicates that the decrease is not solely a consequence of malnutrition or pulmonary inflammation and that loss of cystic fibrosis transmembrane conductance regulator function has a more direct effect. Consistent with this hypothesis, we discovered reduced growth hormone release in organotypic pituitary slice cultures of newborn CF pigs. These findings may explain the long-standing observation that CF newborns are smaller than non-CF babies and why some patients with good clinical status fail to reach their growth potential. The results also suggest that measuring IGF1 levels might be of value as a biomarker to predict disease severity or the response to therapeutics. Finally, they raise the possibility that IGF1 supplementation beginning in infancy might be beneficial in CF.

Fig. 1.

IGF1 deficits and growth parameters in CF pigs. (A) CF pigs (n = 5) gained less weight than did non-CF pigs (n = 7). Data are mean ± SE. (B) CF pigs (n = 5) had reduced plasma IGF1 levels compared with non-CF pigs (n = 7). Differences became more exaggerated over time. CF pigs, two females and three males; non-CF pigs, three females and four males. Data are for individual animals; line represents mean ± SE. *P = 0.003 compared with non-CF pigs at 8–12 wks and P = 0.016 at 15–25 wks versus non-CF pigs. (C) Plasma IGF1 levels in newborn piglets 6–12 h old indicated that CF piglets (five females and four males) had significantly reduced plasma IGF levels relative to non-CF piglets (seven females and four males); P = 0.005. Data are for individual animals; line represents mean ± SE. (D) Average birth weight was lower, but not statistically different, in CF compared with non-CF piglets (P = 0.12). (E) Humerus length of newborn CF piglets was shorter than that of non-CF animals (P = 0.04). For D and E, CF, 7 females and 11 males; non-CF, 7 females and 10 males. Data are mean ± SE.

Fig. 2.

Decreased GH release in CF pituitary cultures. (A) Representative example of RT-PCR products of CFTR in hypothalamus and pituitary. (B–E) There were no differences in mRNA levels of key somatotropic hormones and IGF1 in newborn piglet samples. (B) Hypothalamic somatostatin (SST) mRNA (non-CF, four females and four males; CF, four females and six males; P = 0.39). (C) Hypothalamic GH-releasing hormone (GHRH) mRNA (non-CF, four females and five males; CF, three females and five males; P = 0.21). (D) Pituitary GH mRNA (non-CF, five females and four males; CF, five females and four males; P = 0.70). (E) Liver IGF1 mRNA (non-CF, three females and three males; CF, four females and four males; P = 0.62). Data are expressed relative to non-CF and represent mean ± SEM. (F and G) Forskolin increased GH content in media of pituitary slice cultures (non-CF, four females and three males; CF, three females and four males). Two male CFTR^+/− heterozygotes were included as non-CF controls. Data are from individual animals; filled symbols are mean ± SE. *Relative to basal levels; P = 0.006. ^#Forskolin-induced increase in CF was different from that in non-CF; P < 0.02.

Fig. 3.

IGF1 levels in CF infants. IGF1 levels in human newborns with CF (n = 23) were lower than in non-CF newborns (n = 41); *P = 0.016. Symbols indicate individual newborns; lines represent mean ± SE. We detected no relationship between the CFTR genotype and IGF1 levels (not shown), although our sample size may have been too small to detect one if it exists.