Tuesday, April 23, 2024
4/23/2024
Project Summary/Abstract Cystic fibrosis (CF)-related diabetes mellitus (CFRD) is a major predictor of worse lung function and affects ~20% of adolescents and >40% of adults with CF. Highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies can improve glycemic control in patients and reduce prevalence of CFRD. However, the follow up of the Irish ivacaftor cohort shows that FEV1 in the >18-year old group still declines after an initial increase (not distinguishing between patients with and without CFRD). This is opposed to findings in younger ages where FEV1 continues to rise. Since prevalence of CFRD increases with age, we wondered whether lung function decline in the older Irish CF population on ivacaftor could be related to CFRD. In support of this hypothesis, our CF center-specific data show that lung function decline in patients on ivacaftor with CFRD remains worse than in patients without CFRD. Thus, it is imperative to initiate epidemiological, mechanistic, and therapeutic studies on lung function preservation in CF patients with altered glucose control that go beyond achieving normoglycemia and take the new era of highly effective modulators into account. We have shown that, in CF bronchial epithelial (CFBE) cells, hyperglycemia signals through the receptor for advanced glycation end products (RAGE or AGER), which is highly expressed in the lung and linked to the pathogenesis of chronic inflammatory airway diseases, including CF. Activation of RAGE by hyperglycemia or the RAGE agonist high- mobility group box-1 (HMGB1) decreases the activity of apically expressed large-conductance, Ca2+-activated, voltage-dependent K+ (BK) channels and reduces airway surface liquid (ASL) volume. Clinically low but relevant concentrations of metformin, approved for treating diabetes mellitus and known to block RAGE signaling, reversed hyperglycemia-induced BK dysfunction and ASL volume depletion in CFBE cells despite the continued presence of high glucose. Furthermore, metformin improved elexacaftor/tezacaftor/ivacaftor triple combination- mediated rescue of CFTR function and ASL volumes in CFBE cells under high glucose. Finally, continuous monitoring of glucose levels in CF and CFRD patients over a one-week period revealed that hyperglycemic episodes inversely correlated with mRNA expression of LRRC26, the g subunit of BK critical for its function in non-excitable cells. We therefore hypothesize that worsening lung function in CF patients with abnormal glucose control is associated with BK and even modulator-rescued CFTR dysfunction due to RAGE signaling and that low dose metformin ameliorates RAGE-induced ion channel dysfunction, including CFTR in the presence of highly effective modulators, independent of glucose control. We will test this hypothesis in mechanistic and translational studies in vitro (Aims 1 and 2) and in vivo (Aim 3).
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