Insulin sensitivity, disposition index and insulin clearance in cystic fibrosis: a cross-sectional study.

AIMS/HYPOTHESIS: The aim of this study was to investigate insulin secretion, insulin sensitivity, disposition index and insulin clearance by glucose tolerance status in individuals with cystic fibrosis (CF) and exocrine pancreatic insufficiency. METHODS: In a cross-sectional study, we conducted an extended (ten samples) OGTT in individuals with pancreatic-insufficient CF (PI-CF). Participants were divided into normal glucose tolerance (NGT), early glucose intolerance (EGI), impaired glucose tolerance (IGT) and CF-related diabetes (CFRD) groups. We used three different oral minimal models to assess insulin secretion, insulin sensitivity and insulin clearance during the OGTT. We evaluated insulin secretion using total secretion (Φ total), first-phase secretion (Φ dynamic) and second-phase secretion (Φ static) from the model, and we estimated the disposition index by multiplying Φ total and insulin sensitivity. RESULTS: Among 61 participants (NGT 21%, EGI 33%, IGT 16%, CFRD 30%), insulin secretion indices (Φ total, dynamic and static) were significantly lower in the CFRD group compared with the other groups. Insulin sensitivity declined with worsening in glucose tolerance (p value for trend <0.001) and the disposition index declined between NGT and EGI and between IGT and CFRD. Those with CFRD had elevated insulin clearance compared with NGT (p=0.019) and low insulin secretion (Φ total) was also associated with high insulin clearance (p<0.001). CONCLUSIONS/INTERPRETATION: In individuals with PI-CF, disposition index declined with incremental impairment in glucose tolerance due to a reduction in both insulin secretion and insulin sensitivity. Moreover in CF, reduced insulin secretion was associated with higher insulin clearance.

The effect of a pre-meal snack and/or postprandial exercise on breakfast glycemic excursion in adults with cystic fibrosis: A pilot study.

BACKGROUND & AIMS: Cystic fibrosis (CF)-related diabetes (CFRD), a common comorbidity in CF, is often preceded and characterized with elevated postprandial glycemic (PPG) excursions. In the general population, the consumption of a pre-meal protein snack and/or physical activity (PA) hinder the elevation of PPG levels. Our objective is to evaluate the effect of a pre-meal snack and/or post-meal PA on PPG excursions in CF. METHODS: This is a double-blinded randomized controlled crossover interventional study in 14 adults with CF, with 4 interventions: placebo pre-meal snack + no PA (control: CTL), pre-meal soy snack + no PA (SK), placebo pre-meal snack + PA (PA), and pre-meal soy snack + PA (SK + PA). The pre-meal soy snack or placebo beverage (vanilla flavoured water) is served at 8 AM, followed by a standardized breakfast at 9 AM and, postprandially, 5 repeated bouts of 3-min walk every 30 min or sedentary activity. Blood glucose and insulin were measured every 15-30 min during the interventions. RESULTS: Plasma glucose (PG) was higher 30 min after snack consumption compared to placebo beverage. One-hour post-breakfast, PG levels were lower during both PA interventions than with sedentary behavior. However, the overall 3 h post-breakfast glucose area under the curve (AUC) was similar between interventions. Post-breakfast 3 h insulin AUC was significantly lower during the SK + PA intervention compared to the sedentary behavior interventions. CONCLUSION: Repeated short bouts of post-meal physical activity may positively impact PPG control in adults with CF, with or without the addition of a pre-meal soy snack. A pre-meal snack alone does not improve PPG.

Cystic fibrosis-related diabetes develops from a combination of insulin secretion defects and insulin resistance.

AIM: The relative contributions of insulin secretory defects and possible additional contribution of insulin resistance for the development of cystic fibrosis (CF)-related diabetes (CFRD) are poorly understood. We aimed to (a) determine which indices of insulin resistance predict progression to CFRD, and (b) to model the relative contributions of insulin secretory function and insulin resistance to predict the risk of CFRD. MATERIALS AND METHODS: Three hundred and three individuals living with CF underwent a 2-h oral glucose tolerance test with blood sampling every 30 min at 12-24-month intervals until they developed CFRD or until the end of follow-up (up to 15 years). Indices of insulin resistance (e.g. Stumvoll) and insulin secretion were calculated from oral glucose tolerance test glucose and insulin measurements. CFRD-free survival was assessed by survival analysis. RESULTS: Estimated insulin resistance showed associations with glucose homeostasis and risk of progression to CFRD. The CFRD-free survival was significantly different between quartiles of insulin resistance (p < 0.0001). When patients were subdivided according to both insulin resistance and insulin secretion (insulinogenic index), CFRD-free survival was significantly lower in those with combined lowest insulin secretion and highest insulin resistance (Stumvoll) indices (hazard ratio: 11.2; p < 0.0001). There was no significant difference when the same analysis was performed for the nine other indices. CONCLUSIONS: Insulin resistance is correlated with glucose homeostasis and the risk of progression to CFRD. Patients combining low insulin secretion and high insulin resistance had the greatest odds of developing CFRD over a 15-year period.

A rapid LC-MS/MS method for the simultaneous quantification of ivacaftor, lumacaftor, elexacaftor, tezacaftor, hexyl-methyl ivacaftor and ivacaftor carboxylate in human plasma.

Cystic fibrosis is one of the most common genetic diseases among caucasian population. This disease is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding for the CFTR protein. Lumacaftor, elexacaftor, tezacaftor, and ivacaftor were currently used as the treatment to Cystic fibrosis. In this study, we describe a new method for the simultaneous quantification of four molecules: lumacaftor, elexacaftor, tezacaftor, and ivacaftor, alongside two metabolites of ivacaftor, specifically hexyl-methyl ivacaftor and ivacaftor carboxylate by liquid chromatography-tandem mass spectrometry. This method holds significant utility for therapeutic drug monitoring and the optimization of treatments related to CFTR modulators. Molecules were extracted from 100 µL of plasma by a simple method of protein precipitation using acetonitrile. Following extraction, chromatographic separation was carried out by reverse chromatography on a C18 analytical column, using a gradient elution of water (0.05 % formic acid, V/V) and acetonitrile (0.05 % formic acid, V/V). The run time was 7 minutes at a flow rate of 0.5 mL/min. After separation, molecules were detected by electrospray ionization on a Xevo TQD triple-quadrupole-mass-spectrometer (Waters®, Milford, USA). The calibration range were: 0.053-20.000 mg/L for elexacaftor, tezacaftor and lumacaftor, 0.075-14.000 mg/L for ivacaftor, and 0.024-6.500 mg/L for hexyl-methyl ivacaftor and ivacaftor carboxylate. The proposed method underwent throughout validation demonstrating satisfactory precision (inter- and intra-day coefficients of variation less than 14.3 %) and a good accuracy (inter- and intra-day bias ranging between -13.7 % and 14.7 %) for all the analytes. The presented method for the simultaneous quantification of CFTR modulators and their metabolites in human plasma has undergone rigorous validation process yielding good results including strong precision and accuracy for all analytes. This method has been effectively used in routine analytical analysis and clinical investigations within our laboratory.

Neutrophil-to-lymphocyte ratio as a biomarker of acute pulmonary exacerbations in children with cystic fibrosis: a retrospective cohort study.

BACKGROUND: Neutrophils are key contributors to chronic airway inflammation in cystic fibrosis (CF) lung disease, although airway and blood-based neutrophil markers are seldom used. The neutrophil-to-lymphocyte ratio (NLR) is an accessible biomarker, the clinical utility of which has not been adequately studied. OBJECTIVE: This study aimed to investigate the characteristics of the NLR in children with CF and its correlations with acute pulmonary exacerbations and spirometry. DESIGN: A previous study had collected clinical data from children with CF for a 3-year period between 2016 and 2021. Retrospectively, NLR values were categorised according to patients' clinical status during blood sample collection as 'stable', 'acute pulmonary exacerbation' or 'elective admission for chronic clinical concern'. MAIN OUTCOME MEASURES: Demographic characteristics associated with the NLR; changes in NLR values in relation to clinical status; relationship between NLR and lung function. RESULTS: 141 children with CF were included. NLR values during clinical stability were higher in females and increased with age. For children admitted for intravenous antibiotics, NLR values significantly increased from clinical stability (median (IQR)=1.13 (0.75-1.51)) to acute pulmonary exacerbations (median (IQR)=1.50 (0.96-2.65), p=0.001), but similar changes were not observed in elective admissions. The NLR was not associated with lung function. CONCLUSIONS: The NLR demonstrated associations with clinical status in children with CF with significant elevations during acute pulmonary exacerbations. While its utility as a single-marker measure is limited, monitoring the NLR over time may help identify periods of increased inflammation.

Feasibility and accuracy of at-home glucose tolerance tests for cystic fibrosis related diabetes screening.

BACKGROUND: Adult people living with Cystic Fibrosis (CF) undergo annual screening for CF-related diabetes. These tests represent a burden and can lead to undesirable effects resulting in low adherence. The objectives of this study were to 1) compare gold-standard in-hospital oral glucose tolerance testing (OGTT) with at-home options, and 2) evaluate acceptability of at-home options. METHODS: A total of 34 adults living with CF undertook 3 types of OGTTs in standardized conditions within two weeks: 1) in a hospital using a 75 g glucose beverage, 2) at home with the same glucose beverage, and 3) at home using a standardized quantity of candy. Glucose levels were measured prior to the OGTT, after 1 and 2 hours. Concordance of glucose measurement, side effects and general appreciation were assessed across the three options. RESULTS: Mean blood glucose was comparable among the three tests. Glucose tolerance categorization (normal, impaired glucose tolerance, or diabetes) was concordant with the hospital reference test in 59 % of participants for the glucose beverage and 75 % for the candies. Side effects were mild with all types of OGTTs, and 94 % of participants preferred the home options. Among the at-home OGTTs, the glucose beverage was preferred to the candy option. CONCLUSIONS: Home-based OGTT could be an alternative to gold standard hospital-based OGTT testing, improving adherence to annual testing and reducing costs. However, the discrepancy between various OGTT testing methods could lead to diagnosis dilemma. This approach should be tested on a larger sample size.

Vitamin K Status Based on K1, MK-4, MK-7, and Undercarboxylated Prothrombin Levels in Adolescent and Adult Patients with Cystic Fibrosis: A Cross-Sectional Study.

The available evidence on vitamin K status in cystic fibrosis (CF) is scarce, lacking data on vitamin K2 (menaquinones-MK). Therefore, we assessed vitamin K1, MK-4 and MK-7 concentrations (LC-MS/MS) in 63 pancreatic insufficient and modulator naïve CF patients, and compared to 61 healthy subjects (HS). Vitamin K1 levels did not differ between studied groups. MK-4 concentrations were higher (median <1st-3rd quartile>: 0.778 <0.589-1.086> vs. 0.349 <0.256-0.469>, p < 0.0001) and MK-7 levels lower (0.150 <0.094-0.259> vs. 0.231 <0.191-0.315>, p = 0.0007) in CF patients than in HS. MK-7 concentrations were higher in CF patients receiving K1 and MK-7 supplementation than in those receiving vitamin K1 alone or no supplementation. Moreover, vitamin K1 concentrations depended on the supplementation regime. Based on multivariate logistic regression analysis, we have found that MK-7 supplementation dose has been the only predictive factor for MK-7 levels. In conclusion, vitamin K1 levels in CF are low if not currently supplemented. MK-4 concentrations in CF patients supplemented with large doses of vitamin K1 are higher than in HS. MK-7 levels in CF subjects not receiving MK-7 supplementation, with no regard to vitamin K1 supplementation, are low. There do not seem to be any good clinical predictive factors for vitamin K status.

A comparison of aminoglycoside antibiotic serum concentrations collected by peripheral veins and peripherally inserted central catheters in adults with cystic fibrosis.

BACKGROUND: People with cystic fibrosis (PwCF) are frequently hospitalized for treatment of pulmonary exacerbation. The Cystic Fibrosis Foundation Pulmonary Guidelines support the use of intravenous aminoglycosides with therapeutic drug monitoring for the treatment of pulmonary exacerbation due to Pseudomonas aeruginosa. Serum intravenous tobramycin concentrations are commonly collected by peripheral venipuncture (PV). Discomfort associated with collection of samples by PV prompts collection via PICC, but the accuracy of intravenous tobramycin serum levels collected by PICC has not been documented in adult PwCF. The primary study objective was to evaluate the difference between intravenous tobramycin serum levels collected by PV and PICC in adult PwCF. METHODS: The authors conducted a prospective case-control study of adult PwCF admitted to University of Utah Health for a pulmonary exacerbation receiving tobramycin by a single lumen PICC. The authors compared tobramycin peak and random serum levels collected by PV and PICC using a detailed flush and waste protocol. RESULTS: The authors analyzed a total of 19 patients with peripheral and PICC samples. The mean tobramycin peak collected by PV (27.2 mcg/mL) was similar to the mean peak collected by PICC (26.9 mcg/mL) (paired samples Wilcoxon signed-rank test, p = .94). The correlation coefficient was 0.88 (95% CI = 0.85-0.91, p < .001). CONCLUSION: Tobramycin serum samples collected by PICC appear to be similar in value to PV collections. Collecting aminoglycoside levels by PICC rather than PV may reduce patient discomfort and improve quality of life. Additional multicenter studies are needed to confirm these results.

Galectin-3 levels in children with cystic fibrosis.

Cystic fibrosis (CF) is a multisystemic disease in which airway obstruction, infection, and inflammation play a critical role in the pathogenesis and progression of CF lung disease. The carbohydrate-binding protein Galectin-3 is increased in several inflammatory and fibrotic diseases and has recently been forwarded as a biomarker in these diseases. We aimed to define the role of serum Galectin-3 in children with CF by comparison with healthy subjects. This is a cross-sectional, case-control study. 143 CF and 30 healthy subjects were enrolled in the study. Peripheral blood and sputum concentrations of Galectins-3, interleukin (IL)-17A, IL-8, and neutrophil elastase (NE) were determined with commercial ELISA kits. There was no significant difference between the groups in age and gender (p = 0.592, p = 0.613, respectively). Serum Galectin-3 and NE concentrations were higher in the patient group than in healthy controls (p = 0.002, p < 0.001, respectively). There were no significant differences between groups according to IL-17A and IL-8 concentrations. Serum Galectin-3 was correlated with age (r = 0.289, p < 0.001) and body mass index (BMI) (r = 0.493, p < 0.001) in children with CF. Sputum Galectin-3 levels are negatively correlated with percent predictive forced expiratory volume in 1 s (FEV1) (r = - 0.297, p = 0.029), FEV1 z-score, (r = - 0.316, p = 0.020), percent predictive forced vital capacity (FVC) (r = - 0.347, p = 0.010), and FVC z-score (r = - 0.373, p = 0.006).   Conclusion: The study shows that serum Galectin-3 levels increased in clinically stable CF patients, and serum Galectin-3 response may depend on age, gender, and BMI. The sputum Galectin-3 was found to be negatively correlated with patients' lung functions. What is known: • Galectin-3 is a key regulator of chronic inflammation in the lung, liver, kidney, and tumor microenvironment. What is new: • Children with cystic fibrosis (CF) have higher serum Galectin-3 concentrations than healthy children. • Serum Galectin-3 expression influenced by age, BMI, and gender in children with CF.