Abstract
Cystic fibrosis-related diabetes (CFRD) worsens CF lung disease leading to early mortality. Loss of beta cell area, even without overt diabetes or pancreatitis is consistently observed. We investigated whether short-term CFTR inhibition was sufficient to impact islet morphology and function in otherwise healthy mice. CFTR was inhibited in C57BL/6 mice via 8-day intraperitoneal injection of CFTRinh172. Animals had a 7-day washout period before measures of hormone concentration or islet function were performed. Short-term CFTR inhibition increased blood glucose concentrations over the course of the study. However, glucose tolerance remained normal without insulin resistance. CFTR inhibition caused marked reductions in islet size and in beta cell and non-beta cell area within the islet, which resulted from loss of islet cell size rather than islet cell number. Significant reductions in plasma insulin concentrations and pancreatic insulin content were also observed in CFTR-inhibited animals. Temporary CFTR inhibition had little long-term impact on glucose-stimulated, or GLP-1 potentiated insulin secretion. CFTR inhibition has a rapid impact on islet area and insulin concentrations. However, islet cell number is maintained and insulin secretion is unaffected suggesting that early administration of therapies aimed at sustaining beta cell mass may be useful in slowing the onset of CFRD.
Highlights
Cystic fibrosis-related diabetes (CFRD) worsens CF lung disease leading to early mortality
Others report that CFTR expression is very low or absent in human pancreatic endocrine cells[10,11,12] and suggest that impairments in insulin secretion likely result from decreased islet mass, intra-islet inflammation or exocrine-derived inflammatory mediators[10,11]
Beta cell area was reduced by as much as 50% in children less than 4 years old when compared with age-matched controls and this was shown to be independent of the degree of exocrine pancreatic fibrosis or the presence/absence of diabetes[20]
Summary
Cystic fibrosis-related diabetes (CFRD) worsens CF lung disease leading to early mortality. We investigated whether short-term CFTR inhibition was sufficient to impact islet morphology and function in otherwise healthy mice. Notwithstanding, the debate surrounding the location of CFTR within the pancreas, compelling evidence from human tissue and CF animal models consistently reports reductions in beta cell area and insulin content. Subsequent studies have repeatedly shown reductions in islet mass or beta cell area in animal models of CF16–19 and in post mortem pancreas from patients with CF10,20 including children under the age of 4 years[20]. Beta cell area was reduced by as much as 50% in children less than 4 years old when compared with age-matched controls and this was shown to be independent of the degree of exocrine pancreatic fibrosis or the presence/absence of diabetes[20]. The inhibition of CFTR in otherwise healthy animals allows for the assessment of whether CFTR has an essential role to play in the maintenance of islet area, whether loss of islet area could be attributed to developmental deficiencies, or whether loss of islet area is solely driven by a hyperinflammatory state in the pancreas
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