Heterogeneous expression of CFTR in insulin-secreting β-cells of the normal human islet

Cystic fibrosis (CF) is due to mutations in the CF-transmembrane conductance regulator (CFTR) and CF-related diabetes (CFRD) is its most common co-morbidity, affecting similar to 50% of all CF patients, significantly influencing pulmonary function and longevity. Yet, the complex pathogenesis of CFRD remains unclear. Two non-mutually exclusive underlying mechanisms have been proposed in CFRD: i) damage of the endocrine cells secondary to the severe exocrine pancreatic pathology and ii) intrinsic beta-cell impairment of the secretory response in combination with other factors. The later has proven difficult to determine due to low expression of CFTR in beta-cells, which results in the general perception that this Cl(-)channel does not participate in the modulation of insulin secretion or the development of CFRD. The objective of the present work is to demonstrate CFTR expression at the molecular and functional levels in insulin-secreting beta-cells in normal human islets, where it seems to play a role. Towards this end, we have used immunofluorescence confocal and immunofluorescence microscopy, immunohistochemistry, RT-qPCR, Western blotting, pharmacology, electrophysiology and insulin secretory studies in normal human, rat and mouse islets. Our results demonstrate heterogeneous CFTR expression in human, mouse and rat beta-cells and provide evidence that pharmacological inhibition of CFTR influences basal and stimulated insulin secretion in normal mouse islets but not in islets lacking this channel, despite being detected by electrophysiological means in similar to 30% of beta-cells. Therefore, our results demonstrate a potential role for CFTR in the pancreatic beta-cell secretory response suggesting that intrinsic beta-cell dysfunction may also participate in the pathogenesis of CFRD.