Rabbit Anti-Human CFTR (internal) Polyclonal antibody

Context: Although diabetes affects 40% to 50% of adults with cystic fibrosis, remarkably little is known regarding the underlying mechanisms leading to impaired pancreatic beta-cell insulin secretion. Efforts toward improving the functional beta-cell deficit in cystic fibrosis-related diabetes (CFRD) have been hampered by an incomplete understanding of whether beta-cell function is intrinsically regulated by cystic fibrosis transmembrane conductance regulator (CFTR). Definitively excluding meaningful CFTR expression in human beta-cells in situ would contribute significantly to the understanding of CFRD pathogenesis. Objective: To determine CFTR messenger ribonucleic acid (mRNA) and protein expression within beta-cells in situ in the unmanipulated human pancreas of donors without any known pancreatic pathology. Design: In situ hybridization for CFTR mRNA expression in parallel with insulin immunohistochemical staining and immunofluorescence co-localization of CFTR with insulin and the ductal marker, Keratin-7 (KRT7), were undertaken in pancreatic tissue blocks from 10 normal adult, nonobese deceased organ donors over a wide age range (23-71 years) with quantitative image analysis. Results: CFTR mRNA was detectable in a mean 0.45% (range 0.17%-0.83%) of insulin-positive cells. CFTR protein expression was co-localized with KRT7. One hundred percent of insulinpositive cells were immunonegative for CFTR. Conclusions: For the first time, in situ CFTR mRNA expression in the unmanipulated pancreas has been shown to be present in only a very small minority (<1%) of normal adult beta-cells. These data signal a need to move away from studying endocrine-intrinsic mechanisms and focus on elucidation of exocrine-endocrine interactions in human cystic fibrosis.

Purpose of review The pancreas is highly affected in cystic fibrosis, with complications occurring early in childhood. This review highlights recent research in exocrine pancreatic function in the era of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies and discusses how these are affecting pancreatitis and exocrine pancreatic insufficiency (EPI) in children. Additionally, new research into exocrine--endocrine interactions sheds light on how CFTR dysfunction in ductal cells may affect beta cells. Recent findings Ivacaftor has disproved the hypothesis that EPI in children with cystic fibrosis is irreversible. Improvements in pancreatic function have increased pancreatitis episodes in some children and reduced them in others. Imaging advances are providing complementary methods for exocrine pancreatic function testing. New research into the interplay between the exocrine and endocrine components of the pancreas are elucidating the intertwined and complex relationship between the exocrine and endocrine pancreas. Pancreatic complications contribute to the morbidity and mortality of children with cystic fibrosis. Increasing use of highly effective CFTR modulators will not only abrogate these but will also advance our understanding of pancreatic pathophysiology in cystic fibrosis. New frontiers into pancreatic gene therapy and exocrine--endocrine research will help provide new therapeutic opportunities for pancreatitis, EPI, and diabetes in cystic fibrosis.