Is cystic fibrosis-related diabetes an apoptotic consequence of ER stress in pancreatic cells? Bassam R. Ali * Department of Pathology, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, P.O. Box 17666, United Arab Emirates article info Article history: Received 9 July 2008 Accepted 21 July 2008 summary Cystic fibrosis-related diabetes (CFRD) has emerged in the last thirty years as a critical complication of cystic fibrosis (CF) and is present in about 15% of CF patients with increasing prevalence with age approaching 50 for over 30 year olds. The mechanism of diabetes development in this group of patients is not very well defined but it seems to involve pancreatic insufficiency and loss of b-cells in the pancreas. I propose that loss of b-cell mass and thus the development of diabetes in CF patients is likely due to an apoptotic mechanism in pancreatic b-cells resulting from chronic endoplasmic reticulum stress due to the presence of malfolded CFTR in islet cells. The proposed mechanism is supported by several pieces of evidence including: (1) the absolute essentiality of an intact unfolded protein response (UPR) machin- ery for survival of pancreatic b-cells, (2) the high susceptibility of b-cells to prolonged ER stress leading to induction of pro-apoptotic factors and apoptosis pathways in b-cells, (3) CF patients with mutations in CFTR gene that are engaging the ER quality control system (ERAD) and hence UPR signalling are twenty time more likely to develop diabetes than those with other types of CF-causing mutations, and (4) the high levels of CFTR gene expression in pancreatic islet cells. Establishing the exact mechanism underlying the development of diabetes in CF patients is likely to have positive implications for the treatment and the development of prevention strategies of this condition. Furthermore, this paper offers a testable hypothesis to enhance our understanding of the mechanism of CFRD. Ó 2008 Elsevier Ltd. All rights reserved. Introduction Cystic fibrosis (CF) is a life threatening, multisystem condition and is the most common autosomal recessive disorder in Cauca- sian populations [28]. It affects 1 in 2000 people and is caused by over 900 mutations in the cystic fibrosis transmembrane conduc- tance regulator (CFTR) gene with a phenylalanine deletion (DF508) present in 60–70% of CF patients [12]. Cystic fibrosis-re- lated diabetes (CFRD) and glucose intolerance are common compli- cations in patients with CF and are generally associated with deterioration in the patient’s health due to the primary disease. The prevalence of CFRD is on the increase, largely due higher sur- vival rates as a result of improved healthcare provided to CF pa- tients. Most CF subjects now live well into their fourth decade whereas it was lower than one year 50 years ago [3]. The current average onset of CFRD is around the age of 20 and the overall prev- alence in CF patients is over 15% with higher proportions in older patients, approaching 50% in over 30 year olds [16,2]. CF patients with CFRD experience an accelerated decline in health including reduced pulmonary function and suffer from higher mortality rates [13]. Insulin replacement therapy is the only currently recom- mended treatment for CFRD [20]. Understanding and management of CFRD is becoming crucial for improving the quality of life and life expectancy in CF patients. Possible mechanisms of CFRD The aetiology of CFRD is complex and not fully understood. However, several possible mechanisms have been suggested and others have been excluded. Patients with CFRD rarely present with ketoacidosis, a common feature in type 1 diabetic patients, which indicates that CFRD patients have some basal insulin secretion [19]. In addition, involvement of an immune system attack has been excluded and therefore CFRD is distinct from type 1. Further- more, several studies found no evidence for the involvement of insulin resistance as a mechanism (summarised by [2]. The most widely accepted hypothesis is that the abnormal expression of CFTR in intralobular duct cells and pancreatic centroacinar cells may cause reduction in chloride and bicarbonate ion secretion with reduced fluid secretion into pancreaticobiliary ducts [6,14]. This results in the concentration of pancreatic proteins including 0306-9877/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2008.07.058 Abbreviations: CFRD, cystic fibrosis-related diabetes; UPR, unfolded protein response; ERAD, ER-associated degradation; CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance channel; QC, quality control. * Tel.: +971 3 7137470; fax: +971 3 7671966. E-mail address: bassam.ali@uaeu.ac.ae Medical Hypotheses 72 (2009) 55–57 Contents lists available at ScienceDirect Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy