Pigs and humans with cystic fibrosis have reduced insulin-like growth factor 1 (IGF1) levels at birth.
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.
Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Mark P
MP
Rogan
Leah R
LR
Reznikov
Alejandro A
AA
Pezzulo
Nicholas D
ND
Gansemer
Melissa
M
Samuel
Randall S
RS
Prather
Joseph
J
Zabner
Douglas C
DC
Fredericks
Paul B
PB
McCray
Michael J
MJ
Welsh
David A
DA
Stoltz
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn / Q000097:blood*; D015415:Biomarkers / Q000032:analysis / Q000097:blood*; D001837:Body Weights and Measures; D015519:Bone Density; D003550:Cystic Fibrosis / Q000097:blood*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D055786:Gene Knockout Techniques; D013006:Growth Hormone / Q000378:metabolism; D006801:Humans; D006811:Humerus / Q000033:anatomy & histology / Q000737:chemistry; D007231:Infant, Newborn; D007334:Insulin-Like Growth Factor I / Q000032:analysis*; D010902:Pituitary Gland / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D034421:Sus scrofa
D015415:Biomarkers; D017931:DNA Primers; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone