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.

Cystic Fibrosis and the Nervous System

“…65 Our studies in newborn pigs revealed CFTR mRNA in the pituitary and hypothalamus and demonstrated that release of growth hormone is reduced in pituitary slice cultures isolated from CF pigs compared with non-CF littermates. 56 These studies are all consistent with a function of CFTR in modulating the neuroendocrine axis.…”

“…37 In pigs, CFTR is expressed in both the peripheral and central nervous systems. 55,56 In humans, CFTR has been identified in parvocellular ganglion, 57 hypothalamic neurons, 58 spinal cord neurons, 59 ganglion cells of the heart, 60 and sympathetic ganglion. 61 Both neuronal and glial cell CFTR expression has been reported in multiple species, 55,[62][63][64] with the exception of humans, in whom only neuronal CFTR has been reported.…”

Cystic fibrosis transmembrane conductance regulator with a shortened R domain rescues the intestinal phenotype of CFTR −/− mice

“…2A), similar to observations in CFTR −/− mice (24,28), CFTR −/− pigs (29), and humans with CF (30,31). These results suggest that the growth defect may not be due solely to reduced or absent CFTR in intestinal epithelium, a result consistent with findings in CF pigs and humans with CF (29).…”

Effects of dietary nucleotide supplementation on growth performance and hormonal and immune responses of piglets

“…Porcine GH (pGH; AFP10864B) and anti-pGH antiserum (AFP5672099) were provided by Dr A. F. Parlow (National Hormone and Pituitary Program, Harbor-University of California-Los Angeles Medical Center, La Jolla, CA, USA). Plasma IGF-1 content was evaluated using a multispecies IGF-1 ELISA (Alpco Diagnostic, Salem, NH, USA), according to manufacturer's instructions, previously applied by Rogan et al (2010). The intra-and interassay coefficients of variation were 7.8% and 5.3%, respectively.…”