High sugar, insulin may make airway leakier in cystic fibrosis
CF-related diabetes may weaken barrier protecting airway: Study
Airway epithelial cells carrying mutations that cause cystic fibrosis (CF) become more loosely connected when grown in the lab in the presence of insulin and high amounts of sugar, a study found, suggesting that CF-related diabetes may weaken the barrier that normally protects the airway tract.
Researchers working at Emory University in Atlanta also observed that treatment with the CFTR modulator Trikafta (elexacaftor, tezacaftor, and ivacaftor), which targets the cause of the disease, helped to restore the proteins that hold that barrier together, even under high amounts of sugar.
The work also identified “promising targets for future investigation,” according to the researchers.
“Gaining a better understanding of the pathways that play a role in [CF-related diabetes] will inform future therapeutic agents to treat this devastating [coexisting condition] and improve the quality and length of life of patients with [CF-related diabetes],” the team wrote.
Their study, “Effects of hyperglycemia on airway epithelial barrier function in WT and CF 16HBE cells,” was published in the journal Scientific Reports.
Investigating the impact of high sugar levels, insulin in CF
Cystic fibrosis is caused by mutations in the CFTR gene that result in thick mucus in the lungs. This can block the airways and lead to frequent infections, which may result in respiratory symptoms such as shortness of breath and a persistent cough.
Many people with the genetic disease develop CF-related diabetes, characterized by low production of insulin — a hormone that helps move sugar, or glucose, from the blood into cells — and insulin resistance, a decreased response of cells to the hormone. As in other forms of diabetes, this results in hyperglycemia or high sugar levels in the blood.
While some treatments are available to ease symptoms of CF, not all patients benefit from them. Because CF-related diabetes is linked to faster-progressing respiratory symptoms, the Emory researchers tested whether hyperglycemia may weaken the barrier that lines the airway, causing it to leak sugar.
Their study used human airway epithelial cells called 16HBE that were either normal (wild-type) or carried F508del/V470 mutations in the CFTR gene. Epithelial cells are tightly packed cells that form a protective barrier by lining the body’s organs, and F508del is the most common mutation known to cause CF.
To test the tightness of that barrier, the researchers measured how much of a dye moved across a layer of lab-grown 16HBE cells by passing through the spaces between them. In the presence of high amounts of glucose, insulin increased the movement of the dye across CF cells, indicating a weaker barrier. In contrast, wild-type cells maintained a tight barrier.
“These results highlight that airway epithelial cell barrier integrity is compromised in CF cells in response to hyperglycemia and insulin treatment,” the researchers wrote, noting that “[wild-type] cells appear to be better able to adapt to hyperglycemia.”
These results highlight that airway epithelial cell barrier integrity is compromised in CF cells in response to hyperglycemia and insulin treatment.
Next, the researchers looked at the role of proteins involved in maintaining tight junctions — structures that seal the spaces between cells. One of those proteins, called claudin-4 (CLDN4), was not located where it should in CF cells, whereas in WT cells, it remained properly localized, even under hyperglycemia.
CLDN4 prevents glucose from leaking into the airway tract by keeping the spaces between cells tightly sealed. In CF, the spaces may not be sealed as well, causing glucose to leak into the lungs, according to the researchers.
“These observations make CLDN4 an interesting target for further investigation in CF,” the team wrote.
Treatment with Trikafta got CLDN4 back to its proper location, even in the presence of insulin, suggesting that treatments “that correct CFTR folding and function may have downstream consequences on proteins impacted by mutant CFTR and might impact tight junction barrier integrity,” the researchers wrote.
When the team compared the activity of genes between WT and CF cells, they found that one particular gene, which provides instructions for protein tyrosine phosphatase receptor type G, or PTPRG, was significantly more active in CF cells. PTPRG is linked to insulin resistance.
Thus, PTPRG may be “a potential therapeutic target to improve insulin sensitivity [increased response to insulin] and reduce airway glucose burden in [CF-related diabetes],” the researchers wrote, adding that this and other potential therapeutic targets warrant “further investigation.”
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