The Potential Causes of Cystic Fibrosis-Related Diabetes

Abstract

Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity, affecting more than 50% of adult CF patients. Despite this high prevalence, the etiology of CFRD remains incompletely understood. Studies in young CF children show pancreatic islet disorganization, abnormal glucose tolerance, and delayed first-phase insulin secretion suggesting that islet dysfunction is an early feature of CF. Since insulin-producing pancreatic β-cells express very low levels of CFTR, CFRD likely results from β-cell extrinsic factors. In the vicinity of β-cells, CFTR is expressed in both the exocrine pancreas and the immune system. In the exocrine pancreas, CFTR mutations lead to the obstruction of the pancreatic ductal canal, inflammation, and immune cell infiltration, ultimately causing the destruction of the exocrine pancreas and remodeling of islets. Both inflammation and ductal cells have a direct effect on insulin secretion and could participate in CFRD development. CFTR mutations are also associated with inflammatory responses and excessive cytokine production by various immune cells, which infiltrate the pancreas and exert a negative impact on insulin secretion, causing dysregulation of glucose homeostasis in CF adults. In addition, the function of macrophages in shaping pancreatic islet development may be impaired by CFTR mutations, further contributing to the pancreatic islet structural defects as well as impaired first-phase insulin secretion observed in very young children. This review discusses the different factors that may contribute to CFRD.

Association between cystic fibrosis transmembrane regulator genotype and clinical outcomes, glucose homeostasis indices and CF-related diabetes risk in adults with CF

“…Severe phenotype ( De Braekeleer et al, 1997 b), including exocrine pancreatic insufficiency, associated with the 621+1G>T variant ( Hamosh and Corey, 1993 ; Witt et al, 1996 ; Mckone et al, 2003 ) are two well-established risk factors for CFRD risk ( Coderre et al, 2021 ; Potter et al, 2021 ). In our study as well as in another small case report also in French-Canadian patients (De Braekeleer et al, 1997c), this did not translate into a high risk of developing CFRD.…”

The Role of Continuous Glucose Monitoring in Detecting Early Dysglycemia and Clinical Outcomes in Patients with Cystic Fibrosis

“…Systemic inflammation, due to respiratory infection, is another contributing factor in the development of CFRD, through its mediators like interleukin (IL)-1 beta, IL-6, CXCL10, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma. Inflammation leads to pancreatic damage and the immune infiltration of other islet components and also leads to insulin resistance, resulting in altered glucose tolerance and CFRD [ 36 , 37 ]. Hepatic insulin resistance and unsuppressed gluconeogenesis lead to increased hepatic glucose production and dysglycemia.…”

What the future holds: cystic fibrosis and aging

“…Unlike type 1 or type 2 diabetes, the pathophysiology of CFRD is not completely understood. It is likely multifactorial related to both β-cell dysfunction and a reduction in islet cell mass and ongoing chronic inflammation ( 33 , 34 ). Regardless of etiology, it has been repeatedly proven that CFRD increases morbidity and mortality in CF patients ( 35 ).…”