Cystic fibrosis-related diabetes: from CFTR dysfunction to oxidative stress

Abstract

Cystic fibrosis (CF) represents the most common lethal autosomal recessive disorder in the Caucasian population. It is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in abnormal Na(+) and Cl(-) transport in several tissues. Its main clinical manifestations include bronchopulmonary infections along with gastrointestinal and nutritional disorders. Intense and recurrent inflammation ultimately leads to an overabundance of activated neutrophils and macrophages that contribute to free radical generation. Furthermore, CFTR defects directly affect glutathione transport and homeostasis, while intestinal fat malabsorption limits uptake of endogenous antioxidant vitamins. Collectively, these abnormal events disturb the balance between pro- and anti-oxidants and promote oxidative stress, which may play a significant role in CF-related diabetes (CFRD), a severe complication associated with a drastic increase of morbidity and mortality. This review will focus on the involvement of oxidative stress in CF pathology, especially its role in the occurrence of CFRD. The multiple abnormalities in the oxidant/antioxidant balance could be a potential target for a new therapeutic approach.

Figures

Figure 1

CFTR structure and mutation categories. The six classes of mutations frequently found on the CFTR gene that are involved in the absence or altered expression of the CFTR protein responsible for the cystic fibrosis pathology.

Figure 2

CFTR dysfunction and inflammation in activated stress-sensitive pathways. A decrease in both GSH and GSH/GSSG ratio, even in the absence of infection, leads to the activation of the transcription factor NF-κB with a cascade of pro-inflammatory cytokines such as IL-1β and TNF-α. Altered CFTR function and increased oxidative stress events occurring in the CF pathology can further affect the glutathione homeostasis and induce cell death by sustained activation of stress-sensitive pathways.

Figure 3

Hypothesis of oxidative and ER stresses-induced β-cells death. Calcium homeostasis is important for β-cell function as it is involved in the folding of insulin protein as well as the exocytosis mechanism of insulin granules in the presence of glucose molecules. Oxidative stress and inflammatory events can alter calcium homeostasis by inhibiting the protein SERCA which ensures the entry of calcium into the endoplasmic reticulum (ER) for insulin folding and release. The accumulation of misfolded protein in the ER will lead to ER stress involved in apoptosis and death of β-cells.

Figure 4

Possible links between CFTR dysfunction, oxidative stress and the occurrence of CFRD in CF. The multi-organ dysfunction of the CFTR protein is directly associated with an increase in oxidative stress which can alter glucose tolerance by reducing insulin secretion or inhibiting its signalling pathways then leading to CFRD.