Cystic Fibrosis-related Diabetes Research Articles

Polymorphisms of the Vitamin D Binding Protein (VDBP) and Free Vitamin D in Patients with Cystic Fibrosis

Objectives/Background: Vitamin D-binding protein (VDBP) and free vitamin D are new markers that are being studied as a possible markers of vitamin D status. The main aim of our study was to analyze the VDBP genotype and quantify the levels of free vitamin D in a sample of cystic fibrosis (CF) patients. Methods: We conducted a multicenter, cross-sectional, and prospective study including patients with CF and exocrine pancreatic insufficiency who were clinically stable. We investigated vitamin D levels (total and free) and the different VDBP haplotypes. Free vitamin D levels were measured using an electro-chemiluminescence assay. Results: A sample of 48 patients was obtained (52% male; median age 13.8 years). The most common allele of VDBP was Gc1s (72%) > Gc2 (52%) > Gc1f (27%). The median calcidiol was 21.2 ng/mL (IR 15.3–26.9), and 81% had levels in the insufficiency range: 23 patients (48%) below 20 ng/mL, and 16 (33%) between 20 and 30 ng/mL. The median free vitamin D level was 4.2 pg/mL (IR 3.9–5.6). A positive correlation was observed between calcidiol and free vitamin D levels (r = 0.871; p < 0.0001). After adjustment for season, vitamin D supplementation, sex, and CF-related diabetes, patients with Gc1f polymorphism had a lower risk of vitamin D deficiency, OR 0.22 (95% CI 0.05–0.99), and p = 0.027. A negative linear trend was observed between the polymorphisms grouped into three categories (Gc1/Gc1, Gc1/Gc2, and Gc2/Gc2, in that order) and vitamin D and free vitamin D levels (p = 0.025 and p = 0.033, respectively). Conclusion: In CF, as in the general population, the most common VDBP haplotype in the Caucasian race is Gc1s. VDBP polymorphisms influence serum vitamin D and free vitamin D levels in CF patients. There is a good correlation between free vitamin D and calcidiol levels, suggesting that measuring the latter in CF does not seem to provide any additional benefit.

Endocrine pathology in young rabbits with cystic fibrosis

BackgroundCystic fibrosis (CF) is an autosomal recessive genetic disorder caused by loss-of-function mutations in the CF transmembrane conductance regulator gene. CF-related pancreatic lesions are known to cause exocrine dysfunctions such...

A cross-sectional study in adiponectin, glucose metabolism, and body composition in cystic fibrosis.

We hypothesized that the insulin-sensitizing adipokine adiponectin (ADP) is upregulated in cystic fibrosis (CF) related diabetes (CFRD) and underweight adults with CF. We aimed to assess correlations between glucose metabolism, body composition and ADP in CF. We performed a cross-sectional study among adults with CF at the Copenhagen CF Center. The study included a fasting level of ADP, an oral glucose tolerance test (OGTT), and a dual energy-x-ray absorptiometry scan. In total, 115 patients were included of whom 104 had an OGTT performed. Glucose intolerance was not correlated with ADP in multivariable analysis, while increased hepatic insulin resistance (i.e., HOMA-IR) was correlated with reduced ADP levels. ADP declined by 4% (eβ 0.96, 95% CI: 0.94, 0.98), 5% (eβ 0.95, 95% CI: 0.93, 0.98), 9% (eβ 0.91, 95% CI: 0.87, 0.95), and 83% (eβ 0.17, 95% CI: 0.08, 0.37) for each one unit (kg/m2) increase in body mass index, fat mass index, muscle mass index, and bone mineral content index, respectively. In CF, ADP was negatively correlated with hepatic insulin resistance as well as low fat, muscle, and bone mass, but not with glucose intolerance. This suggests that malnutrition leads to higher ADP levels in CF.

Cystic fibrosis-related diabetes is associated with reduced islet protein expression of GLP-1 receptor and perturbation of cell-specific transcriptional programs

Insulin secretion is impaired in individuals with cystic fibrosis (CF), contributing to high rates of CF-related diabetes (CFRD) and substantially increasing disease burden. To develop improved therapies for CFRD, better knowledge of pancreatic pathology in CF is needed. Glucagon like peptide-1 (GLP-1) from islet α cells potentiates insulin secretion by binding GLP-1 receptors (GLP-1Rs) on β cells. We determined whether expression of GLP-1 and/or its signaling components are reduced in CFRD, thereby contributing to impaired insulin secretion. Immunohistochemistry of pancreas from humans with CFRD versus no-CF/no-diabetes revealed no difference in GLP-1 immunoreactivity per islet area, whereas GLP-1R immunoreactivity per islet area or per insulin-positive islet area was reduced in CFRD. Using spatial transcriptomics, we observed several differentially expressed α- and/or β-cell genes between CFRD and control pancreas. In CFRD, we found upregulation of α-cell PCSK1 which encodes the enzyme (PC1/3) that generates GLP-1, and downregulation of α-cell PCSK1N which inhibits PC1/3. Gene set enrichment analysis also revealed α and β cell-specific pathway dysregulation in CFRD. Together, our data suggest intra-islet GLP-1 is not limiting in CFRD, but its action may be restricted due to reduced GLP-1R protein levels. Thus, restoring β-cell GLP-1R protein expression may improve β-cell function in CFRD.

Cardiac structure and function in people with cystic fibrosis

Abstract Background Cystic fibrosis (CF) is an autosomal recessive disease affecting multiple organs, however the extent of cardiac involvement in CF is yet to be determined. The remarkable therapeutic advancements with new highly effective CF transmembrane conductance regulator (CFTR) modulator treatment and subsequent increase in life expectancy substantiates further research. Purpose We aimed to explore the prevalence of abnormalities and potential subclinical alterations in cardiac structure and function in adults with CF compared to matched controls and investigate potential cardiovascular risk factors in people with CF (pwCF). Methods In this cross-sectional study, 104 adult pwCF in Denmark underwent clinical and echocardiographic examination. All participants were matched 1:1 with controls from the general population on age and sex. Uni- and multivariable linear regression models with adjustment for heart rate, FEV1, smoking status, hypertension and CF-related diabetes (CFRD) were used to test for differences in echocardiographic parameters between cases and controls. Abnormal cardiac function was defined as left ventricular ejection fraction (LVEF) <50%, left ventricular (LV) global longitudinal strain (GLS) < 16% or presence of diastolic dysfunction. Uni- and multivariable logistic regression models adjusted for age, sex, homozygous genotype, FEV1/FVC, BMI, smoking status, CFRD, pancreatic insufficiency, hypertension, and ischemic heart disease were performed to assess associations between potential risk factors and cardiac dysfunction in CF. Forest plots were constructed to visually represent the findings. Results Of 104 pwCF, 44% were female, mean age was 34 years, 93% received CFTR modulator treatment, and 91% had mutations with only minimal CFTR function (mutation class I-III). The prevalence of abnormal cardiac function in pwCF was 44% versus 22% in controls. Compared to controls, pwCF were found to have smaller LV dimensions, worse LV diastolic function, and more impaired right ventricle (RV) as well as LV systolic function (Table). After multivariable adjustment, LV diastolic function as well as LV and RV systolic function remained impaired in pwCF as compared to controls. Male sex and decreasing FEV1/FVC ratio remained independently associated with abnormal cardiac function in pwCF (male sex: OR 3.94 (1.56; 9.95), p=0.004 and FEV1/FVC ratio: OR 2.05 per 0.1 unit decrease (1.21; 3.52), p=0.008, respectively) (Figure). Conclusion Both left- and right-sided cardiac alterations were found in pwCF. After adjustments for potential risk factors, both RV and LV systolic measures remained altered in pwCF, compared to controls. Male sex and decreasing pulmonary function evaluated by FEV1/FVC-ratio were identified as factors associated with abnormal cardiac function in pwCF.Figure

Effects of hyperglycemia on airway epithelial barrier function in WT and CF 16HBE cells

Cystic fibrosis related diabetes (CFRD), the main co-morbidity in cystic fibrosis (CF), is associated with higher rates of lung function decline. We hypothesize that airway epithelial barrier function is impaired in CF and is further exacerbated under hyperglycemia, worsening pulmonary outcomes. Using 16HBE cells, we studied the effects of hyperglycemia in airway epithelial barrier function. Results show increased paracellular dye flux in CF cells in response to insulin under hyperglycemia. Gene expression experiments identified claudin-4 (CLDN4) as a key tight junction protein dysregulated in CF cells. CLDN4 protein localization by confocal microscopy showed that CLDN4 was tightly localized at tight junctions in WT cells, which did not change under hyperglycemia. ln contrast, CLDN4 was less well-localized in CF cells at normal glucose and localization was worsened under hyperglycemia. Treatment with highly effective modulator compounds (ETI) reversed this trend, and CFTR rescue was not affected by insulin or hyperglycemia. Bulk RNA sequencing showed differences in transcriptional responses in CF compared to WT cells under normal or high glucose, highlighting promising targets for future investigation. One of these targets is protein tyrosine phosphatase receptor type G (PTPRG), which has been previously found to play a role in defective Akt signaling and insulin resistance.

One-Year Effect of Elexacaftor/Tezacaftor/Ivacaftor Therapy on HbA1c Levels and Insulin Requirement in Patients with Insulin-Dependent Cystic Fibrosis-Related Diabetes: A Retrospective Observational Study.

The impact of ETI therapy on pulmonary function and nutritional status has been widely studied; the literature on the possible outcomes on glycemic control and insulin requirement in patients affected by CFRD is controversial. The main objective of our study was to evaluate HbA1c levels in patients with cystic fibrosis-related diabetes (CFRD) after one year of therapy with elexacaftor/tezacaftor/ivacaftor (ETI). The secondary objective was to study the changes in the total daily insulin dose (TDD), pulmonary function and metabolism in this population. A retrospective single-center observational study was conducted at the Regional Cystic Fibrosis Centre and Diabetology Centre of IRCCS Istituto Giannina Gaslini. The observation period was divided into four different time points: initiation (T0), 3 months (T3mo), 6 months (T6mo) and 12 months (T12mo) of ETI therapy. Demographic and clinical data were collected. The results were then stratified by genotype (homozygous or heterozygous F508del). Twenty-eight patients with CFRD undergoing insulin therapy were included. TDD (IU) significantly decreased at T3mo and T6mo, but not at T12mo, whereas HbA1c decreased significantly at all three times. The number of hospitalizations and pulmonary exacerbations decreased significantly. We demonstrated both improvement in glycemic control (by means of HbA1c) and insulin requirement in insulin-dependent CFRD patients after one year of ETI treatment.

7522 Effects of Trikafta On Bone Mineral Density And Body Composition In Patients With Cystic Fibrosis

Abstract Disclosure: N. Mon: None. S.S. Krishnasamy: None. G. Bakeerathan: None. L. Healy: None. E. Favier: None. S. Foushee: None. Background: Cystic fibrosis related bone disease (CFBD) is a common complication of adult Cystic fibrosis (CF) patients due to calcium, vitamin D and K malabsorption from exocrine pancreatic insufficiency, increased inflammatory cytokines, glucocorticoid therapy, delayed puberty, physical inactivity, and hypogonadism. Newer CF transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (Trikafta) has proven benefit in pulmonary and nutritional outcomes. There is limited data on effects of Trikafta on bone health and body composition. The aim is to examine the effects of Trikafta on bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), and body composition in terms of fat free mass index (FFMI) and fat mass index (FMI) in our CF patients. Method: We conducted a cross sectional and retrospective review of 38 adults with CF (Ages 20-59, 28 males and 10 females) in our CF clinic. Body Mass Index (BMI), Body composition measured by bioelectric impedance analysis, BMD of LS and FN by Dual-energy X-ray absorptiometry, Vitamin D level, and forced expiratory volume in one second (FEV1 % predicted) in patients taking Trikafta were analyzed and compared with control CF group who were not on Trikafta. Results: 38 subjects on Trikafta, aged 33.29 ± 10.36 years with FEV1 % predicted 65.11± 28.14% were studied. Serum 25-hydroxyvitamin D level was 35.92 ± 18.52 ng/dL. Of the 38 study patients, 23 (60.53%) had a diagnosis of CF related diabetes (CFRD). Among the Trikafta cohort, 18 (50%) had low BMD with Z-scores ≤ -2.0 and 7 (19.44%) of them had Z score ≤ -1.0 and > -2.0. Compared with the control group, LS BMD 0.93 ± 0.16 g/cm2 and FN BMD 0.73± 0.13g/cm2 (p >0.05) were not improved significantly. BMI of study population 23.09 ± 4.21 kg/m2 (p <0.05) and FMI 6.11 ± 4.25 kg/m2 (p <0.05) increased significantly; however, there was a decrease in FFMI 9.60 ± 1.44 kg/m2 (p <0.05). Conclusion: Treatment with Trikafta in CF patients was associated with increases in BMI and fat mass index but decrease in fat free mass index. There was no statistically significant difference in BMD at LS and FN in our study cohort. This study has limitations in terms of gender differences within the study cohort, duration of Trikafta use in relation to bone mass, and also extent of glucocorticoid use among the study subjects. Larger prospective clinical trials are needed to study efficacy of Trikafta on CFBD. Presentation: 6/3/2024

12503 An Observational Study Of The Glycemic Variability In Type 1 Diabetes Mellitus Women Preconception And During Pregnancy And Its Associations With Adverse Maternal And Neonatal Outcomes

Abstract Disclosure: S. Avula: None. A.R. Ankireddypalli: None. K. Tessier: None. E.R. Seaquist: None. Background: Pregnancy in T1 diabetes mellitus (T1DM) women is associated with increased risk of maternal/fetal complications. Despite glycemic optimization during pregnancy in T1DM, offspring are at increased risk for neonatal complications. Aim: To examine glycemic variability by continuous glucose monitor (CGM) preconception and during pregnancy by trimester and assess the association with adverse maternal/fetal outcomes. Methods: This was a retrospective cohort study of pregnant patients with T1DM who used real-time CGM and delivered at a U.S. tertiary center (2012-2023). Multiple gestations, Cystic fibrosis-related diabetes (CFRD), twin or multiple births, and no valid CGM data for at least one trimester were excluded. 63 met the inclusion criteria. The primary outcome was composite neonatal morbidity (CNM), including large or small for gestational age (LGA/SGA), NICU admission, neonatal hypoglycemia, shoulder dystocia, respiratory distress syndrome, APGAR 1 or 5 minutes < 7, prematurity (<37 weeks), intrauterine growth restriction (IUGR), CPAP, and ventilator. We also collected data about maternal outcomes. Results:54 patients (86%) met at least one outcome included in the CNM. 20 patients (32%) were LGA, 3 (5%) were SGA, 32 (51%) premature, 29 (46%) required NICU admission, 44 (70%) had neonatal hypoglycemia, 3 (5%) had shoulder dystocia, 23 (37%) had respiratory distress, 22 (35%) needed CPAP, 3 (5%) were on ventilator, 11 (18%) had APGAR 1 minute <7. Among maternal outcomes, 18 (29%) developed pre-eclampsia, and 46 (73%) had a cesarean delivery. Overall, individuals with neonatal morbidity had a lower target in range (TIR) and higher target above range(TAR), average glucose, standard deviation(SD), and coefficient of variation (CV) compared with those without the primary composite, but statistical significance was seen for average glucose and TAR. For every 5 mg/dl increase in average glucose (mean of the 3-trimester values), there was a 25% increase in odds of neonatal morbidity (OR 1.25; 95% CI 1.04-1.56; p=0.028). There was a significant association between 1st trimester SD and neonatal morbidity (OR 1.11; 95% CI 1.02-1.24; p=0.027). There was a trend toward significance between the 3rd-trimester average blood glucose and neonatal morbidity (OR 1.26; 95% CI 1.02-1.63; p=0.051). Conclusion: In our single-center cohort, we found maternal average glucose and TAR, as well as first trimester SD, were significantly associated with CNM. This confirms that maternal hyperglycemia and demonstrates that first trimester SD are associated with poorer neonatal outcomes. Presentation: 6/1/2024

GLP-1 Receptor Agonist Therapy in Cystic Fibrosis-Related Diabetes: A Case Report.

GLP-1 Receptor Agonist Therapy in Cystic Fibrosis-Related Diabetes: A Case Report.

Dynamics of inflammatory markers in patients with normal and impaired glucose metabolism during lung exacerbation treatment

Cystic fibrosis (CF) is one of the most common autosomal-recessive inherited diseases. The primary genetic defect in CF is aligned CFTR gene mutation which encodes a membrane protein functioning as cAMP-depended chloride channel. Classic phenotypical manifestations of CF include chronic obstructive pulmonary disease with bronchiectasis, persisting infection (St. aureus, Ps. aeruginosa, B. cepacia) and aberrant inflammatory response, as well as exocrine pancreatic insufficiency with malabsorption, hypotrophy and growth retardation. CFTR deficiency is also accompanied by β-cell pancreatic dysfunction, causing glucose metabolism disturbances and CF-related diabetes. The aim of the study was the comparison of inflammatory markers dynamics in patients with normal and disturbed glucose metabolism during pulmonary exacerbation treatment. The study included 10 patients with impaired glucose tolerance (Group 1) and 24 patients with normal carbohydrate metabolism (Group 2). Patients of the two groups did not significantly differ in demographic characteristics, pulmonary function test and body mass index parameters, as well as in the number of F508del mutation carriers and in the number of those who were infected with Ps. aeruginosa and B. cepacia complex. Blood sampling was performed twice: before and after a routine course of antibiotic therapy. Plasma levels of biomarkers including the antibodies to single- and double-stranded DNA (ss-DNA-IgG, ds-DNA-IgG, respectively), the hormones (dehydroepiandrosterone (DHEA) and DHEA sulfate), C-reactive protein (CRP), Mn-dependent superoxide dismutase (Mn-SOD), and the cytokines (tumor necrosis factor-α (TNFα), interferon-γ (IFNγ), IFNα, tissue growth factor-β1 (TGF-β1), interleukin-4 (IL-4), IL-6, IL-10, IL-17A) were assessed using commercial immunoassay kits. Our study shows that antibiotic treatment did not have a sufficient influence on levels of inflammatory markers in patients with disturbances of glucose metabolism while patients with normal glucose tolerance demonstrated a significant reduction in inflammatory marker values after the therapy. The data may suggest both impaired effectivity of antibiotic treatment and aberrant inflammatory response in patients with glucose intolerance.

Development of a programmable automated cell culture system to study the lung pathophysiology of Cystic Fibrosis-related diabetes

The study of many diseases is limited by the in vitro systems available. Cystic Fibrosis-Related Diabetes (CFRD), the main co-morbidity of Cystic Fibrosis (CF), is a perfect example. Cells in vivo experience glucose fluctuations after meals. In contrast, cells cultured in vitro are initially exposed to high glucose media. Glucose gets progressively depleted until the next media change days later, which is not physiologically relevant and could negatively impact the results of research studies. To better study the mechanisms driving CFRD pathophysiology, we developed a programmable and automated cell culture system (PACCS) capable of mimicking acute hyperglycemic episodes experienced by CFRD patients after meals. We adapted a commercially available perfusion system and performed 3D modeling to develop this system. Results show that PACCS can be successfully used to culture airway epithelial cells, both immortalized and primary cells. Further, CF cells responded differently to meal-like conditioning when compared to controls, suggesting impaired adaptative responses in CF cells. Overall, PACCS will allow us to better study CFRD pathophysiology, and it could be used for a wide range of other applications.

Impact of triple transmembrane regulator therapy on glucose metabolism in cystic fibrosis related diabetes during clinical practice

AimsTo evaluate the impact of elexacaftor/tezacaftor/ivacaftor (ETI) therapy on Cystic Fibrosis Related Diabetes (CFRD) glycemic control and insulin treatment in patients with CFRD during clinical practice. MethodsWe carried out a retrospective observational study of 23 adult patients with CFRD who started treatment with ETI. They had, at least, one F508del mutation. Data were collected before ETI initiation and 3, 6, and 12 months after. ResultsGlycemic control measured by HbA1c significantly improved by 0.3 % (0.1–0.5) after 3 months of ETI therapy (p = 0.004) and kept this improvement during follow-up (p < 0.001). The proportion of patients needing multiple daily injections of insulin was reduced by 16 % (p = 0.023). Total daily insulin dose dropped by 0.12 (0.05–0.18) UI/kg/day (p < 0.001). Data derived from Flash Continuous Glucose Monitoring (CGM) for patients treated with insulin stayed unchanged after insulin reduction, except for a significant 8 % (0.3–15.6) increase in the Time In Tight Range (TITR) between 70 and 140 mg/dL (p = 0.043). ConclusionETI therapy impacted CFRD in clinical practice reducing insulin needs and improving glycemic control measured by HbA1c and CGM. The improvements can be observed from the first 3 months of treatment.

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

Background & AimsCystic fibrosis (CF)-related diabetes (CFRD), a common comorbidity in CF, is often preceded and characterized with elevated postprandial glycaemia (PPG). 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. MethodsThis 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 mins or sedentary activity. Blood glucose and insulin were measured every 15 to 30 minutes during the interventions. ResultsPlasma glucose (PG) was higher 30 mins 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 3h post-breakfast glucose area under the curve (AUC) was similar between interventions. Post-breakfast 3h insulin AUC was significantly lower during the SK+PA intervention compared to the sedentary behavior interventions. ConclusionRepeated 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.

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. 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. 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. 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.

Association of race and ethnicity with the development of cystic fibrosis-related diabetes

BackgroundCF-related diabetes (CFRD) is a common, life-expectancy limiting complication of CF. While Black race and Hispanic ethnicity in youth-onset type 1 and type 2 diabetes are well-recognized risk factors for worse diabetes complications, the potential for racial/ethnic disparities in CFRD has received limited attention. MethodsWe conducted a retrospective cohort study utilizing the CF Foundation Patient Registry from 2010 to 2019 to determine the prevalence and incidence of CFRD by race/ethnicity. Three age cohorts were identified at baseline in 2010 (11–20y, 21–30y, and 31–40y). Logistic regression and Cox regression stratified by age group were used to determine the prevalence and incidence, respectively, among Hispanic, non-Hispanic Blacks (NHB), and non-Hispanic whites (NHW) after adjustment for relevant confounders, including demographics, socioeconomic status, clinical factors, and chronic medication use. ResultsAmong 14,660 registry participants, 510 were NHB and 890 Hispanic. NHB associated with higher odds of CFRD baseline prevalence in all age cohorts (11–20y: OR 2.53 (95 % CI: 1.88–3.41, P < 0.05), 21–30y: OR 1.80 (1.25–2.59, P < 0.05), and 31–40y: OR 1.93 (1.00–3.73, P < 0.05)) relative to NHW. In the 11–20y cohort, the hazard of new-onset CFRD was 40 % higher in NHB (HR 1.40 (1.09–1.8, P < 0.05)) and 19 % higher in Hispanics (HR 1.19 (1.01–1.41, P < 0.05)). ConclusionNHB had a higher prevalence of CFRD across all age groups, with NHB and Hispanics showing higher incidence of CFRD in the youngest group. Multicenter studies performed in diverse CF populations are warranted to identify modifiable factors influencing earlier CFRD development in minoritized groups and their potential contribution to diabetes complication disparities.

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

Aims/hypothesisThe 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.MethodsIn 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.ResultsAmong 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/interpretationIn 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.Graphical

Metabolomics Panel Associated with Cystic Fibrosis-Related Diabetes toward Biomarker Discovery.

The most prevalent comorbidity among cystic fibrosis (CF) patients is cystic fibrosis-related diabetes (CFRD). CFRD has been linked to one of the worse clinical outcomes and a higher mortality. Improved clinical results have been related to earlier diagnosis and treatment of CFRD. Therefore, the present study aimed to investigate the metabolome of human serum of patients with CFRD. This might aid in identifying novel biomarkers linked with the pathophysiology of CFRD and its diagnosis. The liquid chromatography-high-resolution mass spectrometry (LC-HRMS) metabolomics approach was utilized for serum samples from patients with CF (n = 36) and healthy controls (n = 36). Nine patients in the CF group had CFRD, and 27 were non-CFRD patients (nCFRD). A total of 2328 metabolites were significantly altered in CF compared with the healthy control. Among those, 799 significantly dysregulated metabolites were identified between CFRD and nCFRD. Arachidonic acid (AA), ascorbate, and aldarate metabolism were the most common metabolic pathways dysregulated in CF. l-Homocysteic acid (l-HCA) levels were significantly reduced in CF and CFRD compared to the control and nCFRD, respectively. In addition, gamma-glutamylglycine and l-5-hydroxytryptophan (5-HTP) had the highest discrimination between CFRD and nCFRD with AUC (0.716 and 0.683, respectively). These biomarkers might serve as diagnostic biomarkers and aid in understanding potential metabolic changes linked to CF and CFRD.

Chronic hyperglycemia aggravates lung function in a Scnn1b-Tg murine model.

Cystic fibrosis-related diabetes (CFRD), the most common comorbidity in cystic fibrosis (CF), leads to increased mortality by accelerating the decline in lung function. Scnn1b-Tg transgenic mice overexpressing the epithelial sodium channel β subunit exhibit spontaneous CF-like lung disease, including airway mucus obstruction and chronic inflammation. Here, we established a chronic CFRD-like model using Scnn1b-Tg mice made diabetic by injection of streptozotocin (STZ). In Ussing chamber recordings of the trachea, Scnn1b-Tg mice exhibited larger amiloride-sensitive currents and forskolin-activated currents, without a difference in adenosine triphosphate (ATP)-activated currents compared with wild-type (WT) littermates. Both diabetic WT (WT-D) and diabetic Scnn1b-Tg (Scnn1b-Tg-D) mice on the same genetic background exhibited substantially elevated blood glucose at 8 wk; glucose levels also were elevated in bronchoalveolar lavage fluid (BALF). Bulk lung RNA-seq data showed significant differences between WT-D and Scnn1b-Tg-D mice. Neutrophil counts in BALF were substantially increased in Scnn1b-Tg-D lungs compared with controls (Scnn1b-Tg-con) and compared with WT-D lungs. Lung histology data showed enhanced parenchymal destruction, alveolar wall thickening, and neutrophilic infiltration in Scnn1b-Tg-D mice compared with WT-D mice, consistent with the development of a spontaneous lung infection. We intranasally administered Pseudomonas aeruginosa to induce lung infection in these mice for 24 h, which led to severe lung leukocytic infiltration and an increase in pro-inflammatory cytokine levels in the BALF. In summary, we established a chronic CFRD-like lung mouse model using the Scnn1b-Tg mice. The model can be used for future studies toward understanding the mechanisms underlying the lung pathophysiology associated with CFRD and developing novel therapeutics.NEW & NOTEWORTHY We established a chronic CFRD-like mouse model using the Scnn1b-Tg transgenic mice overexpressing the epithelial sodium channel β subunit made diabetic by injection of streptozotocin. The results underscore the urgent need to develop novel therapeutics for CF lung disease.

Advances in diabetes technology to improve the lives of people with cystic fibrosis.

People with cystic fibrosis (CF) are at risk for dysglycaemia caused by progressive beta cell dysfunction and destruction due to pancreatic exocrine disease and fibrosis. CF-related diabetes (CFRD) is a unique form of diabetes that has distinctive features from both type 1 and type 2 diabetes. Recent advances in diabetes technology may be of particular benefit in this population given the complex, multi-system organ involvement and challenging health issues that people with CFRD often face. This review summarises how diabetes technologies, such as continuous glucose monitors (CGMs) and insulin delivery devices: (1) have improved our understanding of CFRD, including how hyperglycaemia affects clinical outcomes in people with CF; (2) may be helpful in the screening and diagnosis of CFRD; and (3) offer promise for improving the management of CFRD and easing the burden that this diagnosis can add to an already medically complicated patient population.