CFTR mutations may drive CF diabetes, independent of mucus
Study finds mutations directly impair pancreatic function
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CFTR mutations, the underlying cause of cystic fibrosis (CF), may contribute to CF-related diabetes (CFRD) by directly impairing pancreatic function, independent of mucus buildup, a study suggested.
CF patients with residual CFTR protein function responded better to sugar intake than those with minimal CFTR function, as indicated by lower blood sugar levels and higher beta-cell glucose sensitivity (a key indicator of insulin secretion efficiency), according to data.
“These findings aim to provide deeper insights into the complex relationship between the degree of CFTR channel dysfunction, pancreatic function, and glucose regulation in CF,” the researchers wrote.
The study, “Mutations with residual CFTR function are associated with better glucose tolerance and insulin secretion in people with Cystic fibrosis,” was published in the Journal of Cystic Fibrosis.
In CF, mutations in the CFTR gene disrupt the production and/or function of the CFTR channel protein. As a result, the body produces abnormally thick and sticky mucus that affects multiple organs, including the lungs, pancreas, liver, and intestines.
Mucus and pancreas damage
CFRD, a common complication of CF, is characterized by elevated blood glucose (sugar) levels. It’s thought that the thick mucus can damage the pancreas, leading to insufficient secretion of insulin, a protein hormone that regulates blood glucose levels.
CFTR protein is also found in beta cells, the pancreatic cells that produce insulin, suggesting that CFTR plays a direct role in pancreatic function. If so, CFTR mutations may directly affect beta-cell function and insulin production, thereby contributing to CFRD, in addition to mucus-driven damage.
“Further research is needed to better understand the mechanisms underlying the development of CFRD and the impact of CFTR channel dysfunction on pancreatic function,” wrote the researchers, in Italy.
The clinical study involved 341 CF patients (57% female) from three CF centers across Italy. Most (79%) had pancreatic insufficiency, a condition in which the pancreas fails to produce sufficient digestive enzymes. Study participants represented a broad CF population as reflected in clinical practice, with a range of ages, disease severities, and genetic variants.
The oral glucose tolerance test (OGTT), which measures the body’s immediate response to sugar, was used to assess beta-cell function. Participants consumed a sugary drink, and glucose, insulin, and C-peptide (an indicator of insulin secretion) levels were measured every 30 minutes for a period of two hours.
The team then compared OGTT test results of two genetically distinct groups: CF patients who carried a minimal-function mutation in both CFTR gene copies (very little CFTR protein function) and those with at least one residual-function mutation (some CFTR protein activity).
CF patients who carry at least one residual-function CFTR mutation responded better to sugar intake, as indicated by consistently lower glucose levels during the OGTT. Even so, insulin and C-peptide responses were similar between the two groups.
The residual-function group also showed better beta-cell glucose sensitivity (the ability of beta cells to adjust insulin secretion in proportion to blood glucose levels) as well as slower insulin clearance. The results remained the same after adjustment for the use of CFTR modulator therapy.
In cell-based studies, CFTR mutational status in a subset of participants was associated with chloride conductance, a direct assessment of CFTR protein function, as measured in Fisher rat thyroid cells or CF bronchial epithelial cells.
In both cell models, a higher mean chloride conductance, indicating increased CFTR protein activity, was significantly associated with greater beta-cell glucose sensitivity. This relationship remained strong after adjusting for age, sex, and other clinical factors.
“This relationship is consistent regardless of the cell line used to measure chloride conductance, indicating that higher CFTR function …, as reflected by increased chloride conductance, is closely linked to improved [beta]-cell function,” the team wrote.
Although pancreatic insufficiency was generally associated with poorer beta-cell function, CFTR chloride conductance remained independently associated with beta-cell function in CF.
“Our findings demonstrate that CFTR function [is] associated [with] improved glucose tolerance and insulin secretion in [people with CF],” the researchers wrote. “Future studies … will be crucial to further elucidate … the complex interplay between CFTR channel activity, pancreatic function, and glucose metabolism in CF.”
