# Mechanisms of mucociliary dysfunction in cystic fibrosis related diabetes

> **NIH NIH R01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2024 · $660,756

## Abstract

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).

## Key facts

- **NIH application ID:** 10812497
- **Project number:** 5R01HL157942-04
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** MICHAEL D KIM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $660,756
- **Award type:** 5
- **Project period:** 2021-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812497

## Citation

> US National Institutes of Health, RePORTER application 10812497, Mechanisms of mucociliary dysfunction in cystic fibrosis related diabetes (5R01HL157942-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10812497. Licensed CC0.

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