Structural and functional impact of cystic fibrosis on endocrine pancreatic innervation

In health, the autonomic nervous system modifies secretion of the islet hormones insulin, glucagon, and pancreatic polypeptide (PP). Uniquely, PP secretion is nearly fully dependent upon parasympathetic innervation. In people with cystic fibrosis (CF), physiological secretion of all three hormones is impaired, but the role of the autonomic nervous system in this dysfunction is unknown. We thus examined PP secretion and pancreatic neuronal immunostaining in humans and ferrets with CF. Both young humans and ferrets with CF had greatly impaired PP secretion, despite an abundance of islet PP cells and intact PP secretion from perifused CF ferret islets. Pan-neuronal staining in pancreas was nearly absent from CF humans and of aberrant morphology and distribution in CF ferrets. Parasympathetic neuronal staining was nearly absent in both ferret and human CF pancreata. When exocrine pancreatic disease was delayed until after the first month of life by administering a CFTR modulator in CFTRG551D homozygous ferrets, there was preservation of pancreatic neuronal markers and restoration of PP secretory responsiveness to oral glucose. We conclude that the CF pancreas is impacted by a loss and remodeling of its innervation, secondary to early-life pancreatic disease, likely contributing to impaired islet hormone secretion.