Cystic fibrosis–related diabetes (CFRD) is among the most common extrapulmonary co-morbidity associated with cystic fibrosis (CF), affecting an estimated 50% of adults with the condition. Cystic fibrosis is prevalent in 1 in every 2500 Caucasian live births and is caused by a mutation in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene. Mutated CFTR leads to dehydrated epithelial surfaces and a build-up of mucus in a variety of tissues including the lungs and pancreas. The leading cause of mortality in CF is repeated respiratory bacterial infections, which prompts a decline in lung function. Co-morbid diabetes promotes bacterial colonisation of the airways and exacerbates the deterioration in respiratory health. Cystic fibrosis–related diabetes is associated with a 6-fold higher mortality rate compared with those with CF alone. The management of CFRD adds a further burden for the patient and creates new therapeutic challenges for the clinical team. Several proposed hypotheses on how CFRD develops have emerged, including exocrine-driven fibrosis and destruction of the entire pancreas and contrasting theories on the direct or indirect impact of CFTR mutation on islet function. The current review outlines recent data on the impact of CFTR on endocrine pancreatic function and discusses the use of conventional diabetic therapies and new CFTR-correcting drugs on the treatment of CFRD.

A new technique is described for the study of mammalian pituitary cells in vivo and in vitro. The method involves encapsulation of freshly trypsinized rat, sheep or human pituitary cells in XM-50 Amicon hollow fibers followed by their intracranial implantation into hypophysectomized rats. These pituitary fiber units promoted recipient growth for ∼3 weeks before weight gains plateaued. Body composition analyses showed that significant quantities of protein, fat and ash accounted for the weight gain. Morphological study of the capsule contents 7–39 days postimplantation revealed the presence of intact somatotrophs and corticotrophs. The hollow fibers may provide an immunologically privileged site by virtue of the fact that the 50,000 dalton pores making up the lumen surface permit pituitary hormones to diffuse from the capsule, but theoretically do not permit immunoglobulin molecules to penetrate the capsule. Growth of hypox rats receiving capsules containing allogeneic rat pituitary cells, sheep cells or pieces of human postmortem pituitary support this concept. Furthermore, rats implanted with human PRL adenoma cells had detectable quantities of circulating hPRL 100 days post-implantation. It is suggested that the pituitary hollow fiber units function when they come in contact with a ventricular surface of a hypox animal. With these units, it will be possible to study function of the same group of pituitary cells in vitro and in vivo.

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.

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