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Frost FJ, Peckham DG, Felton IC, Snowball JE, Gray RD, Jones AM, Simmonds NJ, Lord RW, Lip GYH, Chandler H, Murphy K, Downey DG, Sheppard DN, Davies JC, Bull J, Sommer P, Cupid B, Allen L, Duckers J. Managing an ageing cystic fibrosis population: challenges and priorities. Eur Respir Rev 2025; 34:240261. [PMID: 40368426 PMCID: PMC12076158 DOI: 10.1183/16000617.0261-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 02/23/2025] [Indexed: 05/16/2025] Open
Abstract
The increasing life expectancy of people with cystic fibrosis (pwCF), largely driven by advancements in early diagnosis, multidisciplinary care and the recent introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies, is likely to herald a shift in the focus of care toward managing the complexities of ageing. This review highlights key challenges and research priorities for addressing the health needs of an ageing CF population. A growing body of evidence underscores the heightened risks of cancers, cardiovascular diseases and changing nutritional and metabolic profiles as pwCF age. CFTR modulators have improved clinical outcomes, but their effects on inflammation, immunity and long-term disease trajectories remain incompletely understood. Nutritional management, particularly the implications of obesity and body composition, poses new challenges, as does the potential accelerated ageing of immune and pulmonary systems in CF. Emerging issues such as menopause in females with CF, lifetime antimicrobial resistance and the interplay between chronic inflammation and ageing further complicate the care landscape. The review emphasises the urgent need for multidisciplinary research programmes that integrate clinical, patient and community perspectives. Leveraging established CF registries, clinical trial networks and collaborations with ageing research frameworks is critical to addressing these challenges. Ultimately, the goal is to ensure that pwCF not only live longer but also experience improved quality of life and holistic wellbeing as they realise the full benefits of therapeutic advances.
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Affiliation(s)
- Freddy J Frost
- Adult Cystic Fibrosis Centre Liverpool Heart and Chest Hospital NHS Foundation Trust, Liverpool, UK
- Liverpool Centre for Cardiovascular Sciences at University of Liverpool, Liverpool John Moores University and Liverpool Heart and Chest Hospital NHS Foundation Trust, Liverpool, UK
| | - Daniel G Peckham
- Leeds Institute of Medical Research, University of Leeds, Leeds, UK
| | - Imogen C Felton
- Adult Cystic Fibrosis Centre, Royal Brompton and Harefield Hospitals, part of Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Joanna E Snowball
- Oxford Adult CF Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Robert D Gray
- School of Infection and Immunity, University of Glasgow, Glasgow, UK
| | - Andrew M Jones
- Manchester Adult Cystic Fibrosis Centre, Manchester University NHS Foundation Trust, Manchester, UK
- Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK
| | - Nicholas J Simmonds
- Adult Cystic Fibrosis Centre, Royal Brompton and Harefield Hospitals, part of Guy's and St Thomas' NHS Foundation Trust, London, UK
- National Heart and Lung Institute, Imperial College, London, UK
| | - Robert W Lord
- Manchester Adult Cystic Fibrosis Centre, Manchester University NHS Foundation Trust, Manchester, UK
- Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK
| | - Gregory Y H Lip
- Liverpool Centre for Cardiovascular Sciences at University of Liverpool, Liverpool John Moores University and Liverpool Heart and Chest Hospital NHS Foundation Trust, Liverpool, UK
- Danish Center for Clinical Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Hannah Chandler
- Cardiff University Brain Research Imaging Centre, Cardiff University, Cardiff, UK
| | - Kevin Murphy
- Cardiff University Brain Research Imaging Centre, Cardiff University, Cardiff, UK
| | - Damian G Downey
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK
| | - David N Sheppard
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
| | - Jane C Davies
- National Heart and Lung Institute, Imperial College, London, UK
| | | | | | | | | | - Jamie Duckers
- All Wales Adult Cystic Fibrosis Centre, University Hospital Llandough, Penarth, UK
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Aguilera García I, Barquiel Alcalá B, Vázquez Pérez P, Prados Sánchez MC, González Pérez de Villar N. Time to change guidelines? Suboptimal glycemic control measures by CGM associated with cystic fibrosis exacerbations despite adequate HbA1c. Acta Diabetol 2025; 62:429-431. [PMID: 39888447 DOI: 10.1007/s00592-025-02457-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 01/20/2025] [Indexed: 02/01/2025]
Affiliation(s)
- I Aguilera García
- Endocrinology Department, University Hospital La Paz, Madrid, Spain.
- Escuela de Doctorado, Universidad Autónoma de Madrid (UAM), Madrid, Spain.
- Currently working at Diabetology Department, University Hospital Cochin, The University of Paris, Paris, France.
| | | | - P Vázquez Pérez
- Endocrinology Department, University Hospital La Paz, Madrid, Spain
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Schiavon M, Cobelli C, Nair KS, Klaus K, Toffolo G, Zhang L, Moran A. Exogenous insulin does not reduce protein catabolism in pre-diabetic cystic fibrosis patients: A randomized clinical trial. J Cyst Fibros 2025; 24:57-65. [PMID: 39516143 PMCID: PMC11788023 DOI: 10.1016/j.jcf.2024.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 08/26/2024] [Accepted: 10/20/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Cystic Fibrosis (CF) patients historically suffered from undernutrition, infection and inflammation. Insulin insufficiency-related protein catabolism further compromised health. We aimed to determine whether insulin improves protein catabolism in CF youth with abnormal glucose tolerance (AGT). METHODS This double-masked, placebo-controlled trial in CF youth age 10-25 with AGT who were in their usual state of health used triple-tracer stable-isotope methodology to measure protein turnover during a baseline test meal and after four weeks of insulin/placebo treatment. Healthy controls were assessed once. CF patients were randomized 1:1:1 to once-daily long-acting insulin (0.25 U/kg/d), three-times daily rapid-acting insulin (0.5 U/15gr carbohydrate), or injectable placebo. RESULTS Thirty CF patients completed the study. There were no differences in any measure of protein turnover between insulin- and placebo-treated subjects, including endogenous protein breakdown (primary study endpoint). In contrast to earlier studies, protein turnover in the 37 CF patients who completed the baseline meal was normal compared to 20 healthy controls. Meal isotope appeared in plasma earlier in CF than controls, suggesting more rapid gut emptying. The study was interrupted by the pandemic; futility analysis led to study discontinuation before the planned remaining 15 CF patients were studied. CONCLUSIONS Recent advances in CF have led to remarkable clinical improvements. In this study, CF youth with AGT had normal protein catabolism at baseline. Pre-meal or daily basal insulin therapy, while safe and well tolerated, did not significantly enhance protein turnover and does not appear to be necessary in clinically stable patients prior to development of CFRD.
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Affiliation(s)
- Michele Schiavon
- Department of Information Engineering, University of Padova, Via Gradenigo 6b, 35131, Padova, Italy.
| | - Claudio Cobelli
- Department of Woman and Child's Health, University of Padova, Via Giustiniani n 3, 35128, Padova, Italy.
| | - K Sreekumaran Nair
- Mayo Clinic College of Medicine, Division of Endocrinology and Research, 200 1st St SW, 5-194 Joseph, Rochester MN 55905.
| | - Katherine Klaus
- Mayo Clinic College of Medicine, Division of Endocrinology and Research, 200 1st St SW, 5-194 Joseph, Rochester MN 55905.
| | - Gianna Toffolo
- Department of Information Engineering, University of Padova, Via Gradenigo 6b, 35131, Padova, Italy.
| | - Lin Zhang
- Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, University Office Plaza, Suite 200, 2221 University Avenue SE, Minneapolis, MN 55414.
| | - Antoinette Moran
- Department of Pediatrics, University of Minnesota, Academic Office Building, AOB-120, 2450 Riverside Ave, Minneapolis, Minnesota 55454.
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Ratti GA, Smith H, Mirfakhraee S, Reisch J, Cohen L, Jain R, Finklea JD. Development of metabolic syndrome in people with Cystic Fibrosis one year after exposure to elexacaftor-tezacaftor-ivacaftor. J Cyst Fibros 2025; 24:47-52. [PMID: 39419654 DOI: 10.1016/j.jcf.2024.09.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 08/27/2024] [Accepted: 09/24/2024] [Indexed: 10/19/2024]
Abstract
BACKGROUND The constellation of hypertension, truncal obesity, impaired fasting glucose, low high-density lipoprotein, and hypertriglyceridemia is known as metabolic syndrome (MetSyn) and is associated with cardiovascular and other diseases. Elexacaftor-tezacaftor-ivacaftor (ETI) in people with cystic fibrosis (pwCF) is associated with weight gain but effects on cardiovascular risk are unknown. This study sought to investigate ETI exposure and risk for development of MetSyn in pwCF. METHODS A prospective cohort study including pwCF ≥ 18 years old exposed to ETI was performed. All data for calculating MetSyn was collected from the electronic medical record at initiation and 1 year ± 3 months after starting ETI. A total of 152 pwCF exposed to ETI and 34 pwCF never exposed to CF transmembrane conductance regulator modulators were included in the analysis. Changes to hypertension classification was also examined over this period. RESULTS After 1 year of ETI there was an increase in MetSyn from 13 to 30 pwCF, p < 0.0001. No new cases of MetSyn were seen in the group not exposed to ETI. After 1 year of ETI, more people met criteria for class 1 (BP 130-139/90-99 mm Hg) or class 2 hypertension (BP ≥140/≥90 mm Hg) regardless of prior modulator exposure, p < 0.0001. CONCLUSIONS Exposure to ETI for 1 year resulted in an increased number of cases of MetSyn. There was an increased incidence of hypertension associated with ETI exposure. Additional studies are needed to further examine this trend and to determine if these changes will translate to cardiovascular complications over time.
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Affiliation(s)
- Gregory A Ratti
- Division of Pulmonary and Critical Care, University of Texas Southwestern, Dallas, TX, USA.
| | - Hannah Smith
- Division of Internal Medicine, University of Texas Southwestern, Dallas, TX, USA
| | - Sasan Mirfakhraee
- Division of Endocrinology, University of Texas Southwestern, Dallas, TX, USA
| | - Joan Reisch
- Department of Clinical Sciences, University of Texas Southwestern, Dallas, TX, USA
| | - Leah Cohen
- Division of Pulmonary and Critical Care, University of Texas Southwestern, Dallas, TX, USA
| | - Raksha Jain
- Division of Pulmonary and Critical Care, University of Texas Southwestern, Dallas, TX, USA
| | - James D Finklea
- Division of Pulmonary and Critical Care, University of Texas Southwestern, Dallas, TX, USA
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Aguilera García I, García Moreno RM, López Plaza B, Barquiel Alcalá B, Vázquez Pérez P, Barreda Bonis AC, Zamarrón de Lucas E, Palma Milla S, Prados Sánchez MC, González Pérez de Villar N. Impact of triple transmembrane regulator therapy on glucose metabolism in cystic fibrosis related diabetes during clinical practice. Diabetes Res Clin Pract 2024; 216:111839. [PMID: 39187175 DOI: 10.1016/j.diabres.2024.111839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 08/01/2024] [Accepted: 08/23/2024] [Indexed: 08/28/2024]
Abstract
AIMS To 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. METHODS We 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. RESULTS Glycemic 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). CONCLUSION ETI 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.
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Affiliation(s)
- I Aguilera García
- Endocrinology Department, University Hospital La Paz, Madrid, Spain; Escuela de Doctorado, Universidad Autónoma de Madrid, Spain.
| | | | - B López Plaza
- Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain
| | | | - P Vázquez Pérez
- Endocrinology Department, University Hospital La Paz, Madrid, Spain
| | - A C Barreda Bonis
- Pediatric Endocrinology Department, University Hospital La Paz, Madrid, Spain
| | | | - S Palma Milla
- Endocrinology Department, University Hospital La Paz, Madrid, Spain; Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain
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Mujammami M, Nimer RM, Al Mogren M, Almalki R, Alabdaljabar MS, Benabdelkamel H, Abdel Rahman AM. Metabolomics Panel Associated with Cystic Fibrosis-Related Diabetes toward Biomarker Discovery. ACS OMEGA 2024; 9:32873-32880. [PMID: 39100315 PMCID: PMC11292812 DOI: 10.1021/acsomega.4c03626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 07/08/2024] [Accepted: 07/10/2024] [Indexed: 08/06/2024]
Abstract
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.
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Affiliation(s)
- Muhammad Mujammami
- Endocrinology
and Diabetes Unit, Department of Medicine, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia
- Diabetes
University Center, King Saud University Medical City, King Saud University, Riyadh 12372, Saudi Arabia
| | - Refat M. Nimer
- Department
of Medical Laboratory Sciences, Jordan University
of Science and Technology, Irbid 22110, Jordan
| | - Maha Al Mogren
- Metabolomics
Section, Department of Clinical Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre
(KFSHRC), Riyadh 11211, Saudi Arabia
| | - Reem Almalki
- Metabolomics
Section, Department of Clinical Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre
(KFSHRC), Riyadh 11211, Saudi Arabia
| | | | - Hicham Benabdelkamel
- Proteomics
Resource Unit, Obesity Research Center, College of Medicine, King Saud University, Riyadh 11362, Saudi Arabia
| | - Anas M. Abdel Rahman
- Metabolomics
Section, Department of Clinical Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre
(KFSHRC), Riyadh 11211, Saudi Arabia
- Department
of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
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Kéri AF, Bajzát D, Andrásdi Z, Juhász MF, Nagy R, Kói T, Kovács G, Hegyi P, Párniczky A. Early onset of abnormal glucose tolerance in patients with cystic fibrosis: A systematic review and meta-analysis. J Cyst Fibros 2024; 23:616-624. [PMID: 38458829 DOI: 10.1016/j.jcf.2024.02.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 02/14/2024] [Accepted: 02/19/2024] [Indexed: 03/10/2024]
Abstract
BACKGROUND Despite translational evidences suggesting that cystic fibrosis-related abnormal glucose tolerance (CF-related AGT) may begin early in life and is known to be associated with increased morbidity and mortality, current guidelines recommend screening for AGT only from 10 years of age, thus missing the opportunity for early detection and intervention. METHODS A systematic review and meta-analysis (PROSPERO number: CRD42021282516) was conducted on studies that reported data on the prevalence of AGT or its subtypes in CF populations. Pooled proportions, risk, and odds ratios with 95 % confidence intervals (CI) were calculated. One-stage dose-response random-effect meta-analysis was used to assess the effect of age on CF-related diabetes (CFRD). RESULTS The quantitative analysis included 457 studies and data from 520,544 patients. Every third child with CF (chwCF) (0.31 [95 % CI 0.25-0.37]) and every second adult with CF (awCF) (0.51 [95 % CI 0.45-0.57]) were affected by AGT. Even in the 5-10 years of age subgroup, the proportion of AGT was 0.42 [95 % CI 0.34-0.51]. The prevalence of prediabetes remained unchanged (impaired glucose tolerance in chwCF:0.14 [95 % CI 0.10-0.18]) vs. awCF:0.19 [95 % CI 0.14-0.25]), whereas the proportion of CFRD increased with age (0-5: 0.005 [95 % CI 0.0001-0.15]; 5-10: 0.05 [95 % CI 0.01-0.27]; 10-18: 0.11 [95 % CI 0.08-0.14]; >18 years of age: 0.27 [95 % CI 0.24-0.30]). CONCLUSION CF-related AGT is common under 10 years of age. Our study suggests considering earlier AGT screening, starting from 5 years of age. This highlights the imperative for additional research for guideline adjustments and provides the opportunity for early intervention.
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Affiliation(s)
- Adrienn F Kéri
- Heim Pál National Pediatric Institute, Budapest, Hungary; Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Dorina Bajzát
- Heim Pál National Pediatric Institute, Budapest, Hungary; Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Zita Andrásdi
- Heim Pál National Pediatric Institute, Budapest, Hungary
| | - Márk Félix Juhász
- Heim Pál National Pediatric Institute, Budapest, Hungary; Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Rita Nagy
- Heim Pál National Pediatric Institute, Budapest, Hungary; Centre for Translational Medicine, Semmelweis University, Budapest, Hungary; Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Tamás Kói
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary; Department of Stochastics, Institute of Mathematics, Budapest University of Technology and Economics, Budapest, Hungary
| | - Gábor Kovács
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary; 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Péter Hegyi
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary; Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary; Institute of Pancreatic Diseases, Semmelweis University, Budapest, Hungary; Translational Pancreatology Research Group, Interdisciplinary Centre of Excellence for Research Development and Innovation, University of Szeged, Szeged, Hungary
| | - Andrea Párniczky
- Heim Pál National Pediatric Institute, Budapest, Hungary; Centre for Translational Medicine, Semmelweis University, Budapest, Hungary; Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary.
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Lacombe J, Ferron M. Vitamin K-dependent carboxylation in β-cells and diabetes. Trends Endocrinol Metab 2024; 35:661-673. [PMID: 38429160 DOI: 10.1016/j.tem.2024.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 02/05/2024] [Accepted: 02/07/2024] [Indexed: 03/03/2024]
Abstract
Vitamin K is an essential micronutrient and a cofactor for the enzyme γ-glutamyl carboxylase, which adds a carboxyl group to specific glutamic acid residues in proteins transiting through the secretory pathway. Higher vitamin K intake has been linked to a reduced incidence of type 2 diabetes (T2D) in humans. Preclinical work suggests that this effect depends on the γ-carboxylation of specific proteins in β-cells, including endoplasmic reticulum Gla protein (ERGP), implicated in the control of intracellular Ca2+ levels. In this review we discuss these recent advances linking vitamin K and glucose metabolism, and argue that identification of γ-carboxylated proteins in β-cells is pivotal to better understand how vitamin K protects from T2D and to design targeted therapies for this disease.
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Affiliation(s)
- Julie Lacombe
- Molecular Physiology Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, QC, H2W 1R7, Canada.
| | - Mathieu Ferron
- Molecular Physiology Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, QC, H2W 1R7, Canada; Programme de Biologie Moléculaire, Université de Montréal, Montréal, QC, H3T 1J4, Canada; Département de Médecine, Université de Montréal, Montréal, QC, H3T 1J4, Canada.
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Alkhateeb AA, Mancl LA, Ramos KJ, Rothen ML, Kotsakis GA, Trence DL, Chi DL. The association between cystic fibrosis-related diabetes and periodontitis in adults: A pilot cross-sectional study. PLoS One 2024; 19:e0305975. [PMID: 38917148 PMCID: PMC11198763 DOI: 10.1371/journal.pone.0305975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 06/07/2024] [Indexed: 06/27/2024] Open
Abstract
OBJECTIVES Periodontitis is a highly prevalent complication of diabetes. However, the association between cystic fibrosis-related diabetes (CFRD) and periodontitis has not yet been evaluated. The objective of this study was to assess if: 1) CFRD is associated with periodontitis among adults with CF, and 2) periodontitis prevalence differs by CF and diabetes status. METHODS This was a pilot cross-sectional study of the association between CFRD and periodontitis in adults with cystic fibrosis (CF) (N = 32). Historical non-CF controls (N = 57) from the U.S. National Health and Nutrition Examination Survey (NHANES) dataset were frequency matched to participants with CF on age, sex, diabetes status, and insulin use. We defined periodontitis using the U.S. Centers for Disease Control and Prevention and the American Academy of Periodontology (CDC/AAP) case definition, as the presence of two or more interproximal sites with CAL ≥3 mm and two or more interproximal sites with PD ≥4 mm (not on the same tooth) or one site with PD ≥5 mm. Because NHANES periodontal data were only available for adults ages ≥30 years, our analysis that included non-CF controls focused on this age group (CF N = 19, non-CF N = 57). Based on CF and diabetes status, we formed four groups: CFRD, CF and no diabetes, non-CF with diabetes, and non-CF and no diabetes (healthy). We used the Fisher's exact test for hypotheses testing. RESULTS There was no association between CFRD and periodontitis for participants with CF ages 22-63 years (CFRD 67% vs. CF no diabetes 53%, P = 0.49), this was also true for those ages ≥30 years (CFRD 78% vs. CF no diabetes 60%, P = 0.63). For the two CF groups, the prevalence of periodontitis was significantly higher than for healthy controls (CFRD 78% vs. healthy 7%, P<0.001; CF no diabetes 60% vs. healthy 7%, P = 0.001) and not significantly different than the prevalence for non-CF controls with diabetes (CFRD 78% vs. non-CF with diabetes 56%, P = 0.43; CF no diabetes 60% vs. non-CF with diabetes 56%, P = 0.99). CONCLUSION Among participants with CF, CFRD was not associated with periodontitis. However, regardless of diabetes status, participants with CF had increased prevalence of periodontitis compared to healthy controls.
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Affiliation(s)
- Alaa A. Alkhateeb
- Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, United States of America
- Department of Dental Health Sciences, School of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Lloyd A. Mancl
- Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, United States of America
| | - Kathleen J. Ramos
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, United States of America
| | - Marilynn L. Rothen
- Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, United States of America
| | - Georgios A. Kotsakis
- Department of Periodontics, Dental School, University of Texas Health at San Antonio, San Antonio, TX, United States of America
- Department of Global Health, University of Washington, Seattle, WA, United States of America
| | - Dace L. Trence
- Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, WA, United States of America
| | - Donald L. Chi
- Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, United States of America
- Department of Health Systems and Population Health, School of Public Health, University of Washington, Seattle, WA, United States of America
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10
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Sivapiromrat AK, Suppakitjanusant P, Wang Y, Hu C, Binongo J, Hunt WR, Weinstein S, Jathal I, Alvarez JA, Chassaing B, Ziegler TR, Gewirtz AT, Tangpricha V. Vitamin D and prebiotics for intestinal health in cystic fibrosis: Rationale and design for a randomized, placebo-controlled, double-blind, 2 x 2 trial of administration of prebiotics and cholecalciferol (vitamin D 3) (Pre-D trial) in adults with cystic fibrosis. Contemp Clin Trials Commun 2024; 38:101278. [PMID: 38435430 PMCID: PMC10904905 DOI: 10.1016/j.conctc.2024.101278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 01/18/2024] [Accepted: 02/17/2024] [Indexed: 03/05/2024] Open
Abstract
Individuals with cystic fibrosis (CF) have dysfunctional intestinal microbiota and increased gastrointestinal (GI) inflammation also known as GI dysbiosis. It is hypothesized that administration of high-dose cholecalciferol (vitamin D3) together with a prebiotic (inulin) will be effective, and possibly additive or synergistic, in reducing CF-related GI and airway dysbiosis. Thus, a 2 x 2 factorial design, placebo-controlled, double-blinded, pilot and feasibility, clinical trial was proposed to test this hypothesis. Forty adult participants with CF were block-randomized into one of four groups: 1) high-dose oral vitamin D3 (50,000 IU weekly) plus oral prebiotic placebo daily; 2) oral prebiotic (12 g inulin daily) plus oral placebo vitamin D3 weekly; 3) combined oral vitamin D3 weekly and oral prebiotic inulin daily; and 4) oral vitamin D3 placebo weekly and oral prebiotic placebo. The primary endpoints included 12-week changes in the microbial bacterial communities, gut and airway microbiota richness and diversity before and after the intervention. This pilot study examined whether vitamin D3 with or without prebiotics supplementation was feasible, changed airway and gut microbiota, and reduced dysbiosis, which in turn, may improve health outcomes and quality of life of patients with CF.
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Affiliation(s)
- Alisa K. Sivapiromrat
- Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Emory College, Emory University, Atlanta, GA, USA
| | - Pichatorn Suppakitjanusant
- Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Yanling Wang
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
| | - Chengcheng Hu
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Jose Binongo
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - William R. Hunt
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | | | | | - Jessica A. Alvarez
- Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Benoit Chassaing
- INSERM U1016, Team “Mucosal Microbiota in Chronic Inflammatory Diseases”, CNRS, UMR, 8104, Université Paris Cité, Paris, France
| | - Thomas R. Ziegler
- Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Atlanta VA Medical Center, Decatur, GA, USA
| | - Andrew T. Gewirtz
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
| | - Vin Tangpricha
- Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Atlanta VA Medical Center, Decatur, GA, USA
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11
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Lurquin F, Gohy S, Hermans MP, Preumont V. Novel time-saving OGTT sparing HbA1c-HOMA2 based algorithm for the diagnosis of cystic fibrosis-related diabetes. Diabetes Res Clin Pract 2024; 208:111124. [PMID: 38309533 DOI: 10.1016/j.diabres.2024.111124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 01/25/2024] [Accepted: 01/29/2024] [Indexed: 02/05/2024]
Abstract
AIMS The diagnosis of cystic fibrosis-related diabetes (CFRD) faces several challenges. We propose a novel screening algorithm to alleviate the burden of cystic fibrosis (CF). METHODS Through a retrospective cross-sectional single-centre study, HbA1c and HOMA2 indices were assessed in multiple models as alternative diagnostic tools from OGTT data. We sought to establish specific thresholds for CFRD screening with oral glucose tolerance test (OGTT) as gold standard. We evaluated various straightforward or sequential approaches, in terms of diagnostic accuracy while also quantify the potential reduction in OGTTs through these different methods. RESULTS HOMA indices were recovered in 72 patients. We devised a composite index that combines HbA1c and HOMA-B: Diabetes Predicting Index in cystic fibrosis (DIPIc) = (HbA1c(%) × 3.455) - (HOMA-B(%) × 0.020) - 19.294. This index yields the highest screening accuracy according to receiver-operating characteristics curves. Using a stepwise algorithm that incorporates DIPIc decreases the requirement for annual OGTTs. A CFRD exclusion cutoff less than -1.7445 (sensitivity 98 %), in conjunction with a CFRD diagnostic threshold greater than 0.4543 (specificity 98 %) allows for 71 % OGTT sparing. CONCLUSION The composite index DIPIc is a suitable, less invasive screening method for CFRD, which enables to avoid many OGTTs.
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Affiliation(s)
- Fabian Lurquin
- Department of Endocrinology and Nutrition, Cliniques universitaires Saint-Luc, Institut de recherche expérimentale et clinique, UCLouvain, Brussels, Belgium.
| | - Sophie Gohy
- Department of Pneumology, CF Reference Centre, Cliniques universitaires Saint-Luc, Institut de recherche expérimentale et clinique, UCLouvain, Brussels, Belgium
| | - Michel P Hermans
- Department of Endocrinology and Nutrition, Cliniques universitaires Saint-Luc, Institut de recherche expérimentale et clinique, UCLouvain, Brussels, Belgium
| | - Vanessa Preumont
- Department of Endocrinology and Nutrition, Cliniques universitaires Saint-Luc, Institut de recherche expérimentale et clinique, UCLouvain, Brussels, Belgium
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12
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Sivapiromrat AK, Suppakitjanusant P, Wang Y, Binongo J, Hunt WR, Gewirtz A, Alvarez JA, Hu C, Weinstein S, Jathal I, Ziegler TR, Tangpricha V. Vitamin D and Prebiotics for Intestinal Health in Cystic Fibrosis: Rationale and design for a randomized, placebo-controlled, double-blind, 2 × 2 trial of administration of prebiotics and cholecalciferol (vitamin D 3) (Pre-D Trial) in adults with cystic fibrosis. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.01.04.24300860. [PMID: 38343811 PMCID: PMC10854319 DOI: 10.1101/2024.01.04.24300860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
Individuals with cystic fibrosis (CF) have dysfunctional intestinal microbiota and increased gastrointestinal (GI) inflammation also known as GI dysbiosis. It is hypothesized that administration of high-dose cholecalciferol (vitamin D3) together with a prebiotic (inulin) will be effective, and possibly additive or synergistic, in reducing CF-related GI dysbiosis and improving intestinal functions. Thus, a 2 × 2 factorial design, placebo-controlled, double-blind, clinical trial was proposed to test this hypothesis. Forty adult participants with CF will be block-randomized into one of four groups: 1) high-dose oral vitamin D3 (50,000 IU weekly) plus oral prebiotic placebo daily; 2) oral prebiotic (12 g inulin daily) plus oral placebo vitamin D3 weekly; 3) combined oral vitamin D3 weekly and oral prebiotic inulin daily; and 4) oral vitamin D3 placebo weekly and oral prebiotic placebo. The primary endpoints will include 12-week changes in the reduced relative abundance of gammaproteobacteria, and gut microbiota richness and diversity before and after the intervention. This clinical study will examine whether vitamin D3 with or without prebiotics will improve intestinal health and reduce GI dysbiosis, which in turn, should improve health outcomes and quality of life of patients with CF.
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Affiliation(s)
| | - Pichatorn Suppakitjanusant
- Emory University, Atlanta, GA, USA
- Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Yanling Wang
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
| | - Jose Binongo
- Emory University, Atlanta, GA, USA
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - William R Hunt
- Emory University, Atlanta, GA, USA
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Andrew Gewirtz
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
| | - Jessica A Alvarez
- Emory University, Atlanta, GA, USA
- Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Chengcheng Hu
- Emory University, Atlanta, GA, USA
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | | | | | - Thomas R Ziegler
- Emory University, Atlanta, GA, USA
- Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Vin Tangpricha
- Emory University, Atlanta, GA, USA
- Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
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13
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Flatt AJ, Sheikh S, Peleckis AJ, Alvarado P, Hadjiliadis D, Stefanovski D, Gallop RJ, Rubenstein RC, Kelly A, Rickels MR. Preservation of β-cell Function in Pancreatic Insufficient Cystic Fibrosis With Highly Effective CFTR Modulator Therapy. J Clin Endocrinol Metab 2023; 109:151-160. [PMID: 37503734 PMCID: PMC10735317 DOI: 10.1210/clinem/dgad443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 06/16/2023] [Accepted: 07/26/2023] [Indexed: 07/29/2023]
Abstract
CONTEXT Elexacaftor/tezacaftor/ivacaftor (ETI; Trikafta) enhances aberrant cystic fibrosis transmembrane conductance regulator function and may improve the insulin secretory defects associated with a deterioration in clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). OBJECTIVE This longitudinal case-control study assessed changes in β-cell function and secretory capacity measures over 2 visits in individuals with PI-CF who were initiated on ETI after the baseline visit (2012-2018) and (1) restudied between 2019 and 2021 (ETI group) vs (2) those restudied between 2015 and 2018 and not yet treated with cystic fibrosis transmembrane conductance regulator modulator therapy (controls). METHODS Nine ETI participants (mean ± SD age, 25 ± 5 years) and 8 matched controls were followed up after a median (interquartile range) 5 (4-7) and 3 (2-3) years, respectively (P < .01), with ETI initiation a median of 1 year before follow-up. Clinical outcomes, glucose-potentiated arginine, and mixed-meal tolerance test measures were assessed with comparisons of within- and between-group change by nonparametric testing. RESULTS Glucose-potentiated insulin and C-peptide responses to glucose-potentiated arginine deteriorated in controls but not in the ETI group, with C-peptide changes different between groups (P < .05). Deterioration in basal proinsulin secretory ratio was observed in controls but improved, as did the maximal arginine-induced proinsulin secretory ratio, in the ETI group (P < .05 for all comparisons). During mixed-meal tolerance testing, early insulin secretion improved as evidenced by more rapid insulin secretory rate kinetics. CONCLUSION ETI preserves β-cell function in CF through effects on glucose-dependent insulin secretion, proinsulin processing, and meal-related insulin secretion. Further work should determine whether early intervention with ETI can prevent deterioration of glucose tolerance in PI-CF.
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Affiliation(s)
- Anneliese J Flatt
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine and Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Saba Sheikh
- Division of Pulmonary and Sleep Medicine, Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Amy J Peleckis
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine and Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Paola Alvarado
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine and Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Denis Hadjiliadis
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Darko Stefanovski
- New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Kennett Square, PA 19348, USA
| | - Robert J Gallop
- Department of Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Ronald C Rubenstein
- Division of Allergy and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Andrea Kelly
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Michael R Rickels
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine and Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
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14
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Lurquin F, Buysschaert M, Preumont V. Advances in cystic fibrosis-related diabetes: Current status and future directions. Diabetes Metab Syndr 2023; 17:102899. [PMID: 37939435 DOI: 10.1016/j.dsx.2023.102899] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 10/25/2023] [Accepted: 10/26/2023] [Indexed: 11/10/2023]
Abstract
AIMS The aim of this review is to give an update of the recent advances in the pathophysiology, prognosis, diagnosis and treatments of cystic fibrosis-related diabetes (CFRD). METHODS The literature survey focuses on original and review articles dealing with CFRD between 2006 and 2023, and in particular with: pathophysiology, risk and predictive factors, screening, chronic complications of CFRD, management and the effects of CFTR channel modulator therapies on glucose homeostasis, using PubMed®. RESULTS The rising prevalence of CFRD is due to prolonged life survival among patients with cystic fibrosis (CF). Advances in the understanding of the pathophysiology highlight the singularity of CFRD. Adherence to diagnostic guidelines remains challenging. Besides the classical OGTT, alternative diagnostic tests are being considered: HbA1c measurement, continuous glucose monitoring (CGM), intermediate measurements of alternative glucose tolerance stages through OGTT and homeostatic model assessment (HOMA). Early treatment of (pre)diabetes in CF patients is mandatory. The advent of CFTR channel modulator therapies have created a paradigm shift in the management of CF: they seem to improve glucose homeostasis, but the mechanism remains unclear. CONCLUSION CFRD management is an ongoing concern. Optimal care has reduced the negative impact of CFRD on lung function, nutrition, and survival. Increasing prevalence of CFRD and prolonged lifespan lead to more microvascular complications. New screening tools (Hba1c, CGM, HOMA) show potential for better classification of patients. The effect of CFTR modulators on glucose metabolism warrants further research.
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Affiliation(s)
- F Lurquin
- Department of Endocrinology and Nutrition, Cliniques Universitaires Saint-Luc, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.
| | - M Buysschaert
- Department of Endocrinology and Nutrition, Cliniques Universitaires Saint-Luc, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
| | - V Preumont
- Department of Endocrinology and Nutrition, Cliniques Universitaires Saint-Luc, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
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15
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Syed A, Rawat A, Tariq UB, Haq I, Naz B, Hussain A, Maqsood M, Rasheed A. Insights Into Cystic Fibrosis Gene Mutation Frequency, Clinical Findings, and Complications Among Pakistani Patients. Cureus 2023; 15:e48564. [PMID: 38024076 PMCID: PMC10653747 DOI: 10.7759/cureus.48564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/09/2023] [Indexed: 12/01/2023] Open
Abstract
Background Cystic fibrosis (CF) is a genetic disorder with diverse symptoms. Understanding its genetic basis and prevalence is crucial for effective management and treatment. Objective The study aimed to provide comprehensive insights into the frequency of CF gene mutations, clinical presentations, and complications among the Pakistani population. Methodology A cohort comprising 892 patients, ranging in age from 18 to more than 40 years, was selected on the basis of clinical and genetic criteria for the diagnosis of CF. Polymerase chain reaction (PCR) was used to look for 34 variants in the CFTR gene in blood samples. Statistical analysis, which included figuring out the number of mutations, the average age of diagnosis, and the genetic diversity of the samples, was performed to analyze the percentage of patients with specific mutations, offering insights into the genetic diversity. Results In our comprehensive analysis of 892 patient samples, 77.47% (n=691) displayed consanguinity, indicating a family history. The prevailing symptoms included chronic cough (88.67%; n=791), recurrent respiratory infections (76.68%; n=684), and fatigue (73.76%; n=658). The major complications comprised pulmonary infections (22%; n=197), cystic fibrosis-related diabetes (21%; n=187), and malabsorption (20%: n=178). A paired t-test revealed a mean difference of 5.750 with a standard deviation of 9.147, a 95% confidence interval from -0.061 to 11.561, a t-value of 2.178 with 11 degrees of freedom, and a two-tailed p-value of 0.052, suggesting a potential trend towards significance. Nevertheless, the asymptotic significance values of 1.000 and 0.998 for both groups indicate no significant difference. Furthermore, the study identified 12 cystic fibrosis gene mutations, with F508del and N1303K being the most prevalent. Conclusion This research revealed significant consanguinity, confirmed typical CF symptoms, and identified common complications and prevalent CFTR gene mutations (with F508del and N1303K being the most common), providing insights for genetic guidance and treatment in the Pakistani community.
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Affiliation(s)
- Asaf Syed
- Medicine and Surgery, Ayub Medical College, Abbottabad, PAK
| | - Anurag Rawat
- Interventional Cardiology, Himalayan Institute of Medical Sciences, Dehradun, IND
| | - Umer Bin Tariq
- Department of Medicine, Nawaz Sharif Medical College, University of Gujrat, Gujrat, PAK
| | - Ihteshamul Haq
- Department of Biotechnology and Genetic Engineering, Hazara University, Mansehra, PAK
| | - Beenish Naz
- Pharmacology and Therapeutics, Khyber Medical University, Peshawar, PAK
| | - Abrar Hussain
- Biological Sciences, International Islamic University, Islamabad, PAK
| | - Mehdi Maqsood
- Internal Medicine, Khyber Medical College, Peshawar, PAK
| | - Arsalan Rasheed
- Molecular Biology and Genetics, Abdul Wali Khan University Mardan, Mardan, PAK
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16
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Collins S, Jones A, Woodward S, Sturt J. "It is like a pet in a way": The self-management experiences of people with cystic fibrosis diabetes. J Hum Nutr Diet 2023; 36:1621-1635. [PMID: 37158099 DOI: 10.1111/jhn.13181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 04/24/2023] [Indexed: 05/10/2023]
Abstract
BACKGROUND Cystic fibrosis diabetes (CFD) is a very common co-morbidity affecting the lives of people with cystic fibrosis. Surprisingly, minimal research has been undertaken to understand the experiences of people with CFD and how they self-mange this condition. METHODS Using interpretative phenomenological analysis, the present study examined the self-management experiences of people with CFD. In-depth semi-structure interviews were conducted with eight people who had CFD. RESULTS The following three superordinate themes were identified: forming a relationship with CFD, balancing the CFD self-management triad, and the unmet need for information and support. CONCLUSIONS The findings suggest that the management of CFD is challenging and, although people with CFD experience many adaptation and management processes similar to people with type 1 diabetes, they struggle with the additional complexity of balancing CF and CFD. The provision of appropriate education, support and person-centred care needs to be addressed.
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Affiliation(s)
| | - Andrew Jones
- Royal Brompton & Harefield Hospitals, London, UK
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17
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Prentice B, Nicholson M, Lam GY. Cystic fibrosis related diabetes (CFRD) in the era of modulators: A scoping review. Paediatr Respir Rev 2023; 46:23-29. [PMID: 36581478 DOI: 10.1016/j.prrv.2022.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022]
Abstract
Cystic fibrosis-related diabetes (CFRD) is a common complication of CF that increases in incidence as patients age. Poor glycemic control has been shown to negatively impact lung function and weight, resulting in higher risk of recurrent pulmonary exacerbations. With the advent of highly effective modulator therapies (HEMT), patients with CF are living longer and healthier lives. Consequently, CFRD and its microvascular complications are rising in prominence, becoming one of the most urgent clinical concerns. As HEMT were developed with the primary focus of improving pulmonary outcomes, it is not clear from the original phase III studies what the short- or long-term benefits of modulators might be on CFRD development and trajectory. In this review, we will examine the pathophysiology of CFRD, summarize and synthesize the available evidence of HEMT impact on CFRD and describe the emerging research needs in this field.
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Affiliation(s)
- Bernadette Prentice
- Department of Respiratory Medicine, Sydney Children's Hospital, Randwick Australia; Molecular and Integrative Cystic Fibrosis (miCF) Research Centre, Randwick, Australia; Discipline of Paediatrics and Child Health, School of Clinical Medicine, University of New South Wales, Randwick, Australia
| | - Michael Nicholson
- Division of Respirology, Department of Medicine, Western University, Ontario, Canada
| | - Grace Y Lam
- Division of Pulmonary Medicine, Department of Medicine, University of Alberta, Alberta, Canada.
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18
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Suppakitjanusant P, Kasemkosin N, Sivapiromrat AK, Weinsein S, Ongphiphadhanakul B, Hunt WR, Sueblinvong V, Tangpricha V. Predicting glycemic control status and high blood glucose levels through voice characteristic analysis in patients with cystic fibrosis-related diabetes (CFRD). Sci Rep 2023; 13:8617. [PMID: 37244957 DOI: 10.1038/s41598-023-35416-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 05/17/2023] [Indexed: 05/29/2023] Open
Abstract
Cystic fibrosis-related diabetes (CFRD) is associated with reduced life expectancy in adults with cystic fibrosis (CF). Voice analysis may be a convenient method for diagnosing and monitoring CFRD. This study aims to determine the relationship between voice characteristics and markers of glucose and glycemic control and to identify if voice analysis can predict high blood glucose levels and glycemic control in adults with CFRD. We conducted a prospective cross-sectional study in adults with CF from March to December 2021. We recorded 3-second voice samples of a sustained /a/ vowel and analyzed voice characteristic using the Computerized Speech Lab with the Multi-Dimensional Voice Program. In female participants with CFRD, the noise-to-harmonic ratio was significantly lower in those with HbA1c ≥ 7. Furthermore, fundamental frequency variation was significantly lower in both male and female participants with CFRD who had a glucose level of 200 mg/dL or higher at the time of collection. This finding was also associated with a high level of point-of-care glucose. The human voice has potential as a non-invasive tool for measuring glucose levels and glycemic control status in CFRD patients in the future.
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Affiliation(s)
- Pichatorn Suppakitjanusant
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Samut Prakan, Thailand.
- Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, USA.
| | - Nittaya Kasemkosin
- Department of Communication Science and Disorders, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | | | - Samuel Weinsein
- Emory College of Arts and Sciences, Emory University, Atlanta, USA
| | - Boonsong Ongphiphadhanakul
- Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - William R Hunt
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, USA
| | - Viranuj Sueblinvong
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, USA
| | - Vin Tangpricha
- Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, USA
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19
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Cho IR, Han KD, Lee SH, Choi YH, Chung KH, Choi JH, Park N, Lee MW, Paik WH, Ryu JK, Kim YT. Association between glycemic status and the risk of acute pancreatitis: a nationwide population-based study. Diabetol Metab Syndr 2023; 15:104. [PMID: 37208706 DOI: 10.1186/s13098-023-01086-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 05/11/2023] [Indexed: 05/21/2023] Open
Abstract
BACKGROUND Although diabetes is reportedly associated with the occurrence of acute pancreatitis (AP), the risk of AP according to the duration and severity of diabetes is not yet clear. We aimed to investigate the risk of AP based on glycemic status and the presence of comorbidities using a nationwide population-based study. METHODS We enrolled 3,912,496 adults who underwent health examinations under the National Health Insurance Service in 2009. All participants were categorized by glycemic status as normoglycemic, impaired fasting glucose (IFG), or diabetes. Baseline characteristics and the presence of comorbidities at the time of health check-up were investigated, and the occurrence of AP was followed up until 31 December 2018. We estimated the adjusted hazard ratios (aHRs) for AP occurrence according to the glycemic status, duration of diabetes (new-onset, duration < 5 years, or ≥ 5 years), type and number of anti-diabetic medications, and presence of comorbidities. RESULTS During the observation period of 32,116,716.93 person-years, 8,933 cases of AP occurred. Compared with normoglycemia, the aHRs (95% confidence interval) were 1.153 (1.097-1.212) in IFG, 1.389 (1.260-1.531) in new-onset diabetes, 1.634 (1.496-1.785) in known diabetes < 5 years, and 1.656 (1.513-1.813) in patients with known diabetes aged ≥ 5 years. The presence of comorbidities associated with diabetes severity had a synergistic effect on the relationship between diabetes and AP occurrence. CONCLUSION As glycemic status worsens, the risk of AP increases, and there is a synergistic effect when comorbidities coexist. To reduce the risk of AP, active control of factors that can cause AP should be considered in patients with long-standing diabetes and comorbidities.
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Affiliation(s)
- In Rae Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Kyung-Do Han
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea
| | - Sang Hyub Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
| | - Young Hoon Choi
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
| | - Kwang Hyun Chung
- Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea
| | - Jin Ho Choi
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Seoul, Republic of Korea
| | - Namyoung Park
- Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
| | - Min Woo Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Woo Hyun Paik
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ji Kon Ryu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yong-Tae Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
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20
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Weiss L, Reix P, Mosnier-Pudar H, Ronsin O, Beltrand J, Reynaud Q, Mely L, Burgel PR, Stremler N, Rakotoarisoa L, Galderisi A, Perge K, Bendelac N, Abely M, Kessler L. Screening strategies for glucose tolerance abnormalities and diabetes in people with cystic fibrosis. DIABETES & METABOLISM 2023; 49:101444. [PMID: 37030530 DOI: 10.1016/j.diabet.2023.101444] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 02/21/2023] [Accepted: 03/24/2023] [Indexed: 04/09/2023]
Abstract
The increase in life expectancy of patients with cystic fibrosis has come with new comorbidities, particularly diabetes. The gradual development of glucose tolerance abnormalities means that 30 to 40% of adults will be diabetic. Cystic fibrosis-related diabetes is a major challenge in the care of these patients because it is a morbidity and mortality factor at all stages of the disease. Early glucose tolerance abnormalities observed from childhood, before the stage of diabetes, are also associated with a poor pulmonary and nutritional outcome. The long asymptomatic period justifies systematic screening with an annual oral glucose tolerance test from the age of 10 years. However, this strategy does not take into account the new clinical profiles of patients with cystic fibrosis, recent pathophysiological knowledge of glucose tolerance abnormalities, and the emergence of new diagnostic tools in diabetology. In this paper, we summarise the challenges of screening in the current context of new patient profiles - patients who are pregnant, have transplants, or are being treated with fibrosis conductance transmembrane regulator modulators - and put forward an inventory of the various screening methods for cystic fibrosis-related diabetes, including their applications, limitations and practical implications.
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21
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Carvalho VHC, Wang Q, Xu X, Liu L, Jiang W, Wang X, Wang J, Li W, Chen J, Li T, Chen Y, Zhu W, Sun Z, Qiu S. Long-term exercise preserves pancreatic islet structure and β-cell mass through attenuation of islet inflammation and fibrosis. FASEB J 2023; 37:e22822. [PMID: 36809666 DOI: 10.1096/fj.202201879r] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 01/22/2023] [Accepted: 01/31/2023] [Indexed: 02/24/2023]
Abstract
Islet fibrosis is associated with the disruption of islet structure and contributes to β-cell dysfunction, playing an essential role in the pathogenesis of type 2 diabetes. Physical exercise has been shown to attenuate fibrosis in various organs; however, the effect of exercise on islet fibrosis has not been defined. Male Sprague-Dawley rats were divided into four groups: normal diet sedentary [N-Sed], normal diet + exercise [N-Ex], high-fat diet sedentary [H-Sed], and high-fat diet + exercise [H-Ex]. After 60 weeks of exercise, 4452 islets from Masson-stained slides were analyzed. Exercise led to a 68% and 45% reduction in islet fibrosis in the normal and high-fat diet groups and was correlated with a lower serum blood glucose. Fibrotic islets were characterized by irregular shapes and substantial loss of β-cell mass, which were significantly reduced in the exercise groups. Remarkably, the islets from exercised rats at week 60 were morphologically comparable to those of sedentary rats at 26 weeks. In addition, the protein and RNA levels of collagen and fibronectin, and the protein levels of hydroxyproline in the islets were also attenuated by exercise. This was accompanied by a significant reduction in inflammatory markers in the circulation Interleukin-1 beta (IL-1β)] and pancreas [IL-1β, Tumor Necrosis Factor-alpha, Transforming Growth Factor-β, and Phosphorylated Nuclear Factor Kappa-B p65 subunit], lower macrophage infiltration, and stellate cell activation in the islets of exercised rats. In conclusion, we have demonstrated that long-term exercise preserves pancreatic islet structure and β-cell mass through anti-inflammatory and anti-fibrotic actions, suggesting additional rationales for the success of exercise training in the prevention and treatment of type 2 diabetes that should be further explored.
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Affiliation(s)
- Vladmir H C Carvalho
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Qianqian Wang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Xiaohan Xu
- Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK
| | - Lijie Liu
- Department of Physiology, Medical College, Southeast University, Nanjing, China
| | - Weixin Jiang
- Department of Physical Education, Southeast University, Nanjing, China
| | - Xiaohang Wang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Jinbang Wang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Wei Li
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Juan Chen
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Tingting Li
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Yang Chen
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Wenwen Zhu
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Zilin Sun
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Shanhu Qiu
- Department of General Practice, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
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22
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van Wilpe R, Hulst AH, Siegelaar SE, DeVries JH, Preckel B, Hermanides J. Type 1 and other types of diabetes mellitus in the perioperative period. What the anaesthetist should know. J Clin Anesth 2023; 84:111012. [PMID: 36427486 DOI: 10.1016/j.jclinane.2022.111012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 10/31/2022] [Accepted: 11/15/2022] [Indexed: 11/23/2022]
Abstract
Diabetes mellitus is often treated as a uniform disease in the perioperative period. Type 2 diabetes is most commonly encountered, and only a minority of surgical patients have been diagnosed with another type of diabetes. Patients with a specific type of diabetes can be particularly prone to perioperative glycaemic dysregulation. In addition, certain type-related features and pitfalls should be taken into account in the operating theatre. In this narrative review, we discuss characteristics of types of diabetes other than type 2 diabetes relevant to the anaesthetist, based on available literature and data from our clinic.
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Affiliation(s)
- Robert van Wilpe
- Department of Anaesthesiology, Amsterdam UMC location AMC, University of Amsterdam, Meibergdreef 9, Postbus 22660, 1105 AZ Amsterdam, the Netherlands
| | - Abraham H Hulst
- Department of Anaesthesiology, Amsterdam UMC location AMC, University of Amsterdam, Meibergdreef 9, Postbus 22660, 1105 AZ Amsterdam, the Netherlands
| | - Sarah E Siegelaar
- Department of Endocrinology, Amsterdam UMC location AMC, University of Amsterdam, Meibergdreef 9, Postbus 22660, 1105 AZ Amsterdam, the Netherlands
| | - J Hans DeVries
- Department of Endocrinology, Amsterdam UMC location AMC, University of Amsterdam, Meibergdreef 9, Postbus 22660, 1105 AZ Amsterdam, the Netherlands
| | - Benedikt Preckel
- Department of Anaesthesiology, Amsterdam UMC location AMC, University of Amsterdam, Meibergdreef 9, Postbus 22660, 1105 AZ Amsterdam, the Netherlands.
| | - Jeroen Hermanides
- Department of Anaesthesiology, Amsterdam UMC location AMC, University of Amsterdam, Meibergdreef 9, Postbus 22660, 1105 AZ Amsterdam, the Netherlands
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23
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Potter KJ, Boudreau V, Bonhoure A, Tremblay F, Lavoie A, Carricart M, Senior PA, Rabasa-Lhoret R. Insulinogenic index and early phase insulin secretion predict increased risk of worsening glucose tolerance and of cystic fibrosis-related diabetes. J Cyst Fibros 2023; 22:50-58. [PMID: 36028423 DOI: 10.1016/j.jcf.2022.07.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 07/23/2022] [Accepted: 07/25/2022] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Measures of stimulated insulin secretion are emerging as important predictors of diabetes mellitus in at-risk populations. We analyzed the utility of clinical estimates of insulin secretion in a prospective cohort at risk for cystic fibrosis-related diabetes (CFRD). METHODS We divided the profiles of 189 people with CF (pwCF) followed longitudinally in the Montreal CF cohort (mean follow up 6.6 ± 1.2 years) according to quartiles of the insulinogenic index (IGI; (I30-I0)/(G30-G0)); area under the curve for insulin normalized for glucose (AUCins/glu), and HOMA-B at baseline to compare clinical characteristics and risk of CFRD according to quartiles for each measure. We also compared characteristics of 40 pwCF found to have de novo CFRD at baseline. RESULTS At baseline, IGI and AUCins/glu were lower in subjects with de novo CFRD and those who later developed CFRD than those who never developed CFRD (p < 0.0001 for each). Subjects with the lowest quartiles of IGI, AUCins/glu, and AUCins/glu 0-30 had increased risk of developing CFRD by Kaplan-Meier analysis (p = 0.0244, p = 0.0024, and p = 0.0338, respectively). There was no significant difference in risk between quartiles of HOMA-B. Subjects in the lowest quartile of IGI showed a significant increase in 2-hour OGTT glucose and AUCglu between the initial and final study visits (p = 0.0027 and p = 0.0044, respectively). CONCLUSION IGI is easily measured in a clinical setting and needs to be validated in prospective studies as a potential tool to improve risk stratification in CFRD with direct relevance to pathogenesis.
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Affiliation(s)
- Kathryn J Potter
- Montreal Clinical Research Institute (IRCM), Montréal, Québec, Canada
| | - Valérie Boudreau
- Montreal Clinical Research Institute (IRCM), Montréal, Québec, Canada; Department of Nutrition, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada
| | - Anne Bonhoure
- Montreal Clinical Research Institute (IRCM), Montréal, Québec, Canada
| | - François Tremblay
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada; Cystic Fibrosis Clinic, Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada
| | - Annick Lavoie
- Cystic Fibrosis Clinic, Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada
| | - Maité Carricart
- Cystic Fibrosis Clinic, Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada
| | - Peter A Senior
- Division of Endocrinology, University of Alberta, Edmonton, Alberta, Canada
| | - Rémi Rabasa-Lhoret
- Montreal Clinical Research Institute (IRCM), Montréal, Québec, Canada; Department of Nutrition, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada; Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, Québec, Canada; Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada; Cystic Fibrosis Clinic, Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada.
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24
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Kumar S, Soldatos G, Ranasinha S, Teede H, Pallin M. Continuous glucose monitoring versus self-monitoring of blood glucose in the management of cystic fibrosis related diabetes: A systematic review and meta-analysis. J Cyst Fibros 2023; 22:39-49. [PMID: 35906171 DOI: 10.1016/j.jcf.2022.07.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 06/20/2022] [Accepted: 07/20/2022] [Indexed: 10/16/2022]
Abstract
BACKGROUND Treatment of cystic fibrosis related diabetes (CFRD) can improve outcomes and use of continuous glucose monitoring (CGM) can positively impact glycemic control. We conducted a systematic review to assess current evidence on CGM compared to self-monitoring of blood glucose (SMBG) in the management of CFRD to determine its effect on glycemic, pulmonary, non-pulmonary and quality of life outcomes. METHODS Using pre-defined selection criteria, we searched MEDLINE, Embase, CENTRAL, Evidence-Based Medicine Reviews, grey literature and six relevant journals for studies using CGM and/or SMBG in CFRD with greater than 6 weeks of follow-up and reported change in HbA1c. The primary outcome was weighted mean difference (WMD) in plasma HbA1c between CGM and SMBG groups. Secondary outcomes included exploring interrelationships between CGM metrics and effects on disease-specific pulmonary, non-pulmonary and quality of life outcomes. RESULTS A total of 1671 references were retrieved, 862 studies screened and 124 full-texts assessed for eligibility. No studies directly compared CGM to SMBG. A meta-analysis of seventeen studies of 416 individuals (CGM = 138, SMBG = 278) found CGM group had 4.1 mmol/mol (95% CI -7.9 to -0.30, p = 0.034) lower HbA1c compared to SMBG group. Most studies demonstrated moderate-to-high risk of bias. Publication bias was also present. Heterogeneity was high and meta-regression identified duration of follow-up in SMBG group as main contributor. CONCLUSION Our findings suggest use of CGM may be associated with improved glycemic control compared to SMBG in CFRD, however evidence of benefit on pulmonary, non-pulmonary and psychosocial outcomes are lacking.
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Affiliation(s)
- Shanal Kumar
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Level 1, 43-51 Kanooka Grove, Clayton, VIC 3168, Australia; Diabetes and Vascular Medicine Unit, Monash Health, 246 Clayton Road, Clayton, VIC 3168, Australia
| | - Georgia Soldatos
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Level 1, 43-51 Kanooka Grove, Clayton, VIC 3168, Australia; Diabetes and Vascular Medicine Unit, Monash Health, 246 Clayton Road, Clayton, VIC 3168, Australia
| | - Sanjeeva Ranasinha
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Level 1, 43-51 Kanooka Grove, Clayton, VIC 3168, Australia
| | - Helena Teede
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Level 1, 43-51 Kanooka Grove, Clayton, VIC 3168, Australia; Diabetes and Vascular Medicine Unit, Monash Health, 246 Clayton Road, Clayton, VIC 3168, Australia
| | - Michael Pallin
- Monash Lung and Sleep, Monash Health, 246 Clayton Road, Clayton, VIC 3168, Australia.
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25
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Wilson A, Altman K, Schindler T, Schwarzenberg SJ. Updates in Nutrition Management of Cystic Fibrosis in the Highly Effective Modulator Era. Clin Chest Med 2022; 43:727-742. [PMID: 36344077 DOI: 10.1016/j.ccm.2022.06.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Attainment and maintenance of good nutrition has been an important aspect of management in cystic fibrosis (CF) for decades. In the era of highly effective modulator therapy for CF, the quality of the nutrients we recommend is increasingly important. Our therapy must support our patients' health for many years beyond what we previously thought. Preventing cardiovascular disease, reducing hyperlipidemia, and optimizing lean body mass for active, longer lives now join the long-standing goal of promoting lung function through nutrition. This chapter summarizes recent developments in nutrition in people with CF, with an eye to the evolution of our practice.
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Affiliation(s)
- Alexandra Wilson
- Cystic Fibrosis Clinical Research, Clinical Research Services, National Jewish Health, 1400 Jackson Street, K333, Denver, CO 80206, USA
| | - Kimberly Altman
- Gunnar Esiason Adult Cystic Fibrosis and Lung Center, Columbia University Medical Center, New York Presbyterian Hospital, New York, NY, USA
| | - Terri Schindler
- Pediatric Pulmonology, University Hospitals Cleveland Medical Center, Rainbow Babies and Children's Hospital
| | - Sarah Jane Schwarzenberg
- Department of Pediatrics; University of Minnesota Masonic Children's Hospital, Academic Office Building, 2450 Riverside Avenue South AO-201, Minneapolis, MN 55454, USA.
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26
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Collins S. The experience of living with and managing cystic fibrosis related diabetes: a qualitative review. J Res Nurs 2022; 27:735-753. [PMID: 36530741 PMCID: PMC9755567 DOI: 10.1177/17449871221116970] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/27/2023] Open
Abstract
Background Improved survival rates for people with cystic fibrosis have led to increased rates of co-morbidity, of which diabetes is the most common. Cystic fibrosis related diabetes affects 19% of adolescents and up to 50% of adults, although little is known about their experiences of this co-morbidity. Aims To investigate the experiences of living with and managing cystic fibrosis related diabetes among adolescents and adults. Methods Systematic review and thematic analysis of qualitative evidence. Results Six studies, rated good quality, were included in the review and four main themes emerged from the data: knowledge and understanding; emotional and social impact; balancing both conditions; acceptance and adjustment. Although the main themes reflect adolescent and adult experiences, there were subtle variations in their sub-themes. Participants' overriding story was of journeying towards acceptance and integration of cystic fibrosis related diabetes into their lives. This included their unpreparedness for the likely onset of cystic fibrosis related diabetes and their struggles to balance the competing demands of living with and managing cystic fibrosis and diabetes. Conclusions The diagnosis of cystic fibrosis related diabetes and its incorporation into daily life is challenging for many people with cystic fibrosis. Review findings indicate opportunities for cystic fibrosis related diabetes interventions pre-diagnosis, at diagnosis, and during ongoing management, which need integrating into routine cystic fibrosis care.
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Affiliation(s)
- Sarah Collins
- Cystic Fibrosis Specialist Dietitian, Royal Brompton & Harefield Hospitals, London, UK
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27
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Kumar S, Pallin M, Soldatos G, Teede H. Comparison of continuous glucose monitoring to reference standard oral glucose tolerance test for the detection of dysglycemia in cystic Fibrosis: A systematic review. J Clin Transl Endocrinol 2022; 30:100305. [PMID: 36200022 PMCID: PMC9529501 DOI: 10.1016/j.jcte.2022.100305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/30/2022] [Accepted: 09/26/2022] [Indexed: 11/27/2022] Open
Abstract
Aims Increasing evidence for benefit of early detection of cystic fibrosis related diabetes (CFRD) coupled with limitations of current diagnostic investigations has led to interest and utilisation of continuous glucose monitoring (CGM). We conducted a systematic review to assess current evidence on CGM compared to reference standard oral glucose tolerance test for the detection of dysglycemia in people with cystic fibrosis without confirmed diabetes. Methods MEDLINE, Embase, CENTRAL, Evidence-Based Medicine Reviews, grey literature and six relevant journals were searched for studies published after year 2000. Studies reporting contemporaneous CGM metrics and oral glucose tolerance test results were included. Outcomes on oral glucose tolerance tests were categorised into a) normal, b) abnormal (indeterminate and impaired) or c) diabetic as defined by American Diabetes Association criteria. CGM outcomes were defined as hyperglycemia (≥1 peak sensor glucose ≥ 200 mg/dL), dysglycemia (≥1 peak sensor glucose ≥ 140-199 mg/dL) or normoglycemia (all sensor glucose peaks < 140 mg/dL). CGM hyperglycemia in people with normal or abnormal glucose tolerances was used to define an arbitrary CGM-diagnosis of diabetes. The Quality Assessment of Diagnostic Accuracy Studies tool was used to assess risk of bias. Primary outcome was relative risk of an arbitrary CGM-diagnosis of diabetes compared to the oral glucose tolerance test. Results We identified 1277 publications, of which 19 studies were eligible comprising total of 416 individuals with contemporaneous CGM and oral glucose tolerance test results. Relative risk of an arbitrary CGM-diagnosis of diabetes compared to oral glucose tolerance test was 2.92. Studies analysed were highly heterogenous, prone to bias and inadequately assessed longitudinal associations between CGM and relevant disease-specific sequela. Conclusions A single reading > 200 mg/dL on CGM is not appropriate for the diagnosis of CFRD. Prospective studies correlating CGM metrics to disease-specific outcomes are needed to determine appropriate cut-points.
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Affiliation(s)
- Shanal Kumar
- Monash Centre for Health Research and Implementation, Monash University
- Diabetes and Vascular Medicine Unit, Monash Health
| | | | - Georgia Soldatos
- Monash Centre for Health Research and Implementation, Monash University
- Diabetes and Vascular Medicine Unit, Monash Health
| | - Helena Teede
- Monash Centre for Health Research and Implementation, Monash University
- Diabetes and Vascular Medicine Unit, Monash Health
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28
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Yu XQ, Zhu Q. New-onset diabetes secondary to acute pancreatitis: An update. World J Clin Cases 2022; 10:10862-10866. [PMID: 36338218 PMCID: PMC9631135 DOI: 10.12998/wjcc.v10.i30.10862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/27/2022] [Accepted: 09/16/2022] [Indexed: 02/05/2023] Open
Abstract
Diabetes is a condition of persistent hyperglycemia caused by the endocrine disorder of the pancreas. Therefore, all pancreatic diseases have the risk of diabetes. In particular, increasing attention has been paid recently to new-onset diabetes secondary to acute pancreatitis (AP). The complications of secondary diabetes have caused a lot of trouble for patients and have garnered increasing attention. At present, the pathophysiological mechanism of new-onset diabetes caused by AP is not clear. This review summarizes the current understanding of new-onset diabetes secondary to AP.
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Affiliation(s)
- Xian-Qiang Yu
- Department of General Surgery, Women's and Children’s Hospital Affiliated to Qingdao University, Qingdao 266034, Shandong Province, China
| | - Qian Zhu
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
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29
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Aksit MA, Ling H, Pace RG, Raraigh KS, Onchiri F, Faino AV, Pagel K, Pugh E, Stilp AM, Sun Q, Blue EE, Wright FA, Zhou YH, Bamshad MJ, Gibson RL, Knowles MR, Cutting GR, Blackman SM. Pleiotropic modifiers of age-related diabetes and neonatal intestinal obstruction in cystic fibrosis. Am J Hum Genet 2022; 109:1894-1908. [PMID: 36206743 PMCID: PMC9606479 DOI: 10.1016/j.ajhg.2022.09.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 09/12/2022] [Indexed: 01/25/2023] Open
Abstract
Individuals with cystic fibrosis (CF) develop complications of the gastrointestinal tract influenced by genetic variants outside of CFTR. Cystic fibrosis-related diabetes (CFRD) is a distinct form of diabetes with a variable age of onset that occurs frequently in individuals with CF, while meconium ileus (MI) is a severe neonatal intestinal obstruction affecting ∼20% of newborns with CF. CFRD and MI are slightly correlated traits with previous evidence of overlap in their genetic architectures. To better understand the genetic commonality between CFRD and MI, we used whole-genome-sequencing data from the CF Genome Project to perform genome-wide association. These analyses revealed variants at 11 loci (6 not previously identified) that associated with MI and at 12 loci (5 not previously identified) that associated with CFRD. Of these, variants at SLC26A9, CEBPB, and PRSS1 associated with both traits; variants at SLC26A9 and CEBPB increased risk for both traits, while variants at PRSS1, the higher-risk alleles for CFRD, conferred lower risk for MI. Furthermore, common and rare variants within the SLC26A9 locus associated with MI only or CFRD only. As expected, different loci modify risk of CFRD and MI; however, a subset exhibit pleiotropic effects indicating etiologic and mechanistic overlap between these two otherwise distinct complications of CF.
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Affiliation(s)
- Melis A Aksit
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Hua Ling
- Department of Genetic Medicine, Center for Inherited Disease Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Rhonda G Pace
- Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Karen S Raraigh
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Frankline Onchiri
- Children's Core for Biostatistics, Epidemiology and Analytics in Research, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - Anna V Faino
- Children's Core for Biostatistics, Epidemiology and Analytics in Research, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - Kymberleigh Pagel
- The Institute for Computational Medicine, The Johns Hopkins University, Baltimore, MD 21218, USA
| | - Elizabeth Pugh
- Department of Genetic Medicine, Center for Inherited Disease Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Adrienne M Stilp
- Department of Biostatistics, University of Washington, Seattle, WA 98195, USA
| | - Quan Sun
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Elizabeth E Blue
- Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA
| | - Fred A Wright
- Department of Statistics, North Carolina State University, Raleigh, NC 27797, USA; Bioinformatics Research Center, North Carolina State University, Raleigh, NC 27797, USA; Department of Biological Sciences, North Carolina State University, Raleigh, NC 27797, USA
| | - Yi-Hui Zhou
- Bioinformatics Research Center, North Carolina State University, Raleigh, NC 27797, USA
| | - Michael J Bamshad
- Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA; Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Center for Clinical and Translational Research, Seattle Children's Hospital, Seattle, WA 98105, USA
| | - Ronald L Gibson
- Center for Clinical and Translational Research, Seattle Children's Hospital, Seattle, WA 98105, USA; Department of Pediatrics, Division of Pulmonary & Sleep Medicine, University of Washington School of Medicine/Seattle Children's Hospital, Seattle, WA, USA
| | - Michael R Knowles
- Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Garry R Cutting
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Scott M Blackman
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
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30
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Nyirjesy SC, Peleckis AJ, Eiel JN, Gallagher K, Doliba A, Tami A, Flatt AJ, De Leon DD, Hadjiliadis D, Sheikh S, Stefanovski D, Gallop R, D’Alessio DA, Rubenstein RC, Kelly A, Rickels MR. Effects of GLP-1 and GIP on Islet Function in Glucose-Intolerant, Pancreatic-Insufficient Cystic Fibrosis. Diabetes 2022; 71:2153-2165. [PMID: 35796669 PMCID: PMC9501647 DOI: 10.2337/db22-0399] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/01/2022] [Indexed: 01/07/2023]
Abstract
Impaired insulin and incretin secretion underlie abnormal glucose tolerance (AGT) in pancreatic insufficient cystic fibrosis (PI-CF). Whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can enhance pancreatic islet function in cystic fibrosis (CF) is not known. We studied 32 adults with PI-CF and AGT randomized to receive either GLP-1 (n = 16) or GIP (n = 16) during glucose-potentiated arginine (GPA) testing of islet function on two occasions, with either incretin or placebo infused, in a randomized, double-blind, cross-over fashion. Another four adults with PI-CF and normal glucose tolerance (NGT) and four matched control participants without CF underwent similar assessment with GIP. In PI-CF with AGT, GLP-1 substantially augmented second-phase insulin secretion but without effect on the acute insulin response to GPA or the proinsulin secretory ratio (PISR), while GIP infusion did not enhance second-phase or GPA-induced insulin secretion but increased the PISR. GIP also did not enhance second-phase insulin in PI-CF with NGT but did so markedly in control participants without CF controls. These data indicate that GLP-1, but not GIP, augments glucose-dependent insulin secretion in PI-CF, supporting the likelihood that GLP-1 agonists could have therapeutic benefit in this population. Understanding loss of GIP's insulinotropic action in PI-CF may lead to novel insights into diabetes pathogenesis.
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Affiliation(s)
- Sarah C. Nyirjesy
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Amy J. Peleckis
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Jack N. Eiel
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Kathryn Gallagher
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Andriana Doliba
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Abigail Tami
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Anneliese J. Flatt
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Diva D. De Leon
- Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Denis Hadjiliadis
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Saba Sheikh
- Division of Pulmonary Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Darko Stefanovski
- New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Kennett Square, PA
| | - Robert Gallop
- Department of Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA
- Department of Mathematics, West Chester University of Pennsylvania, West Chester, PA
| | - David A. D’Alessio
- Division of Endocrinology and Metabolism, Department of Medicine, Duke University School of Medicine, Durham, NC
| | - Ronald C. Rubenstein
- Division of Allergy and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO
| | - Andrea Kelly
- Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Michael R. Rickels
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
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Granger E, Keogh RH, Frost F. The long-term effects of insulin use in incident cystic fibrosis-related diabetes: a target trial emulated using longitudinal national registry data. ERJ Open Res 2022; 8:00170-2022. [PMID: 36382232 PMCID: PMC9638829 DOI: 10.1183/23120541.00170-2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 07/14/2022] [Indexed: 11/09/2022] Open
Abstract
Introduction Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis and is associated with deleterious clinical outcomes. Insulin is recommended as a treatment by international guidelines. However, there are scarce clinical trial data to support the use of insulin, and little is known about the long-term outcomes of treatment. The aim of this study was to compare the long-term impacts of insulin use versus non-use in CFRD. Methods We used data from the national UK Cystic Fibrosis Registry and adopted a target trial framework. Eligible individuals included those 12 years and older with a new diagnosis of CFRD. Outcomes were change in % predicted forced expiratory volume in 1 s (FEV1 %) and body mass index z-scores (BMI) over a 5-year follow-up period. Treatment strategies were to receive insulin or not for the duration of follow-up. Treatment effect estimates were obtained using two methods to control for confounding: inverse-probability-of-treatment weighted estimation of marginal structural models and the G-formula. Results We identified 1613 individuals diagnosed with CFRD between 2008 and 2016 and included 1196 and 1192 in the FEV1 % and BMI outcome analyses respectively. We found no evidence of an effect of insulin on FEV1 % over the 5-year study period. Similarly, we found no overall effect of insulin on BMI; however, there was some evidence for a positive treatment effect in patients with lower baseline BMI. Conclusion Using well-established national registry data, we found no evidence of long-term treatment effects for insulin on FEV1 % or BMI in people with incident CFRD. This target trial using registry data to estimate the effects of insulin use on clinical outcomes in incident cystic fibrosis-related diabetes found no evidence of a long-term benefit (up to 5 years) of insulin use on lung function or BMIhttps://bit.ly/3B8azKz
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Auxological and Endocrinological Features in Children and Adolescents with Cystic Fibrosis. J Clin Med 2022; 11:jcm11144041. [PMID: 35887806 PMCID: PMC9323690 DOI: 10.3390/jcm11144041] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 07/07/2022] [Accepted: 07/12/2022] [Indexed: 02/01/2023] Open
Abstract
Cystic fibrosis (CF) is a multisystem autosomal recessive disease caused by mutations that lead to deficient or dysfunctional CF transmembrane conductance regulator (CFTR) proteins. Patients typically present malnutrition resulting from the malabsorption of fundamental nutrients and recurring lung infections, with a progressive worsening of the respiratory function. For these reasons, the clinical management of CF requires a multidisciplinary team. From an endocrinological point of view, patients often present major complications, such as diabetes, bone disease, thyroid disorders, delayed growth and puberty, hypogonadism and infertility, which negatively affect their quality of life and, in some cases, significantly reduce life expectancy. These complications can arise as a direct result of CFTR dysfunction and/or as a consequence of a deterioration in the function of the organs affected. The objective of this review is to analyze all the possible endocrinological complications that can occur in patients with CF by evaluating the most recent papers in the literature.
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Rakotoarisoa L, Weiss L, Lefebvre F, Porzio M, Ravoninjatovo B, Abely M, Boucher ID, Dubois S, Troussier F, Gilles R, Prevotat A, Kessler L. Comparison of Continuous Glucose Monitoring in Cystic Fibrosis Patients With or Without Pancreatic Exocrine Insufficiency. Horm Metab Res 2022; 54:407-412. [PMID: 35272389 DOI: 10.1055/a-1794-5496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
This study aimed to compare continuous glucose monitoring (CGM) in cystic fibrosis (CF) according to pancreatic exocrine status.CGM and oral glucose tolerance testing (OGTT) were realized annually over five years in people with CF (pwCF) aged≥10 years without cystic fibrosis-related diabetes (CFRD). CGM parameters in patients with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and newly diagnosed CFRD were compared according to presence of pancreatic sufficiency (PS) or insufficiency (PI).Overall, 547 OGTTs and 501 CGMs were performed in 147 CF patients, comprising 122 PI and 25 PS. In PS patients, 84% displayed NGT, 12% IGT, and 4% CFRD vs. 58%, 32%, and 10% (p=0.05) in PI. Among participants displaying normal OGTT, time in glucose range (70-140 mg/dl) was significantly increased, 97% (93, 99) vs. 92% (85, 96), p<0.001, and time above glucose range > 140 mg/dl significantly decreased, 1% (0, 2) % vs. 6% (2, 13), in patients with PS compared to those with PI. No significant differences were highlighted in patients with IGT.CGM revealed significant different glucose tolerance abnormalities in PI versus PS, which were undetected by standard 2-hour OGTT glucose.
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Affiliation(s)
- Luc Rakotoarisoa
- Department of Diabetology, University Hospital Strasbourg, Strasbourg, France
- Inserm UMR 1260, Regenerative Nanomedicine, University of Strasbourg, Strasbourg, France
| | - Laurence Weiss
- CRCM, University Hospital Strasbourg, Strasbourg, France
| | | | - Michele Porzio
- CRCM, University Hospital Strasbourg, Strasbourg, France
| | | | - Michel Abely
- CRCM, University Hospital Centre Reims, Reims, France
| | | | - Séverine Dubois
- Diabetology, University Hospital Centre Angers, Angers, France
| | | | | | - Anne Prevotat
- Allergology, Lille University Hospital Center, Lille, France
| | - Laurence Kessler
- Department of Diabetology, University Hospital Strasbourg, Strasbourg, France
- Inserm UMR 1260, Regenerative Nanomedicine, University of Strasbourg, Strasbourg, France
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Characterization of glucose metabolism in youth with vs. without cystic fibrosis liver disease: A pilot study. J Clin Transl Endocrinol 2022; 28:100296. [PMID: 35342717 PMCID: PMC8942823 DOI: 10.1016/j.jcte.2022.100296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 03/02/2022] [Accepted: 03/15/2022] [Indexed: 11/24/2022] Open
Abstract
Severe CF-liver disease may exaggerate glucose abnormalities in patients with CFRD. CF-liver disease may decrease insulin clearance that fosters insulin resistance. Patients with CFRD and liver disease may warrant treatment other than insulin. Background Diabetes and liver disease are life-threatening complications of cystic fibrosis (CF). CF-liver disease is a risk factor for CF related diabetes (CFRD) development, but the underlying mechanisms linking the two co-morbidities are not known. The objective of this pilot study was to characterize glucose metabolism in youth with CF with and without liver disease. Methods In this two-center cross-sectional study, 20 youth with CF with and without liver disease underwent a 3-hour oral glucose tolerance test. Subjects were categorized by liver disease (LD) status [no LD, mild LD, severe LD] and diabetes status. Measures of glucose excursion, islet cell secretory responses, insulin sensitivity and clearance were obtained. Results Participants with severe LD had the highest fasting, peak, and glucose area under the curve over 3 h (AUC3h) among individuals with CFRD (interaction p < 0.05). In parallel with glycemic changes, prandial β-cell secretory response (AUC C-peptide 3h) was lower in those with severe LD compared to mild or no LD (p < 0.01). There was a trend of higher HOMA-IR in those with severe LD (p = 0.1) as well as lower fasting insulin clearance in those with mild and severe LD compared to no LD (p = 0.06) and lower prandial insulin clearance in severe LD among those with CFRD (interaction p = 0.1). Conclusion In this small cohort, subjects with severe LD tended to have more impaired glycemia, insulin secretion, insulin sensitivity and clearance. Larger studies are imperative to define the pathogenesis to inform clinical care guidelines in terms of CFRD screening, diagnosis, and treatment options.
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Zorron M, Marson FAL, Morcillo AM, Gonçalves AC, El Beck MDS, Ribeiro JD, Ribeiro AF. Can continuous glucose monitoring predict cystic fibrosis-related diabetes and worse clinical outcome? J Bras Pneumol 2022; 48:e20210307. [PMID: 35475864 PMCID: PMC9064635 DOI: 10.36416/1806-3756/e20210307] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 01/11/2022] [Indexed: 12/01/2022] Open
Abstract
Objective: To determine whether abnormal continuous glucose monitoring (CGM) readings (hypoglycemia/hyperglycemia) can predict the onset of cystic fibrosis-related diabetes (CFRD) and/or clinical impairment (decline in BMI and/or FEV1) in pediatric patients with cystic fibrosis (CF). Methods: This was a longitudinal prospective cohort study involving CF patients without diabetes at baseline. The mean follow-up period was 3.1 years. The patients underwent 3-day CGM, performed oral glucose tolerance test (OGTT), and had FEV1 and BMI determined at baseline. OGTT, FEV1, and BMI were reassessed at the end of the follow-up period. Results: Thirty-nine CF patients (10-19 years of age) had valid CGM readings at baseline, and 34 completed the follow-up period (mean = 3.1 ± 0.5 years). None of the study variables predicted progression to CFRD or were associated with hypoglycemic events. CGM could detect glucose abnormalities not revealed by OGTT. Patients with glucose levels ≥ 140 mg/dL, as compared with those with lower levels, on CGM showed lower BMI values and z-scores at baseline-17.30 ± 3.91 kg/m2 vs. 19.42 ± 2.07 kg/m2; p = 0.043; and −1.55 ± 1.68 vs. −0.17 ± 0.88; p = 0.02, respectively-and at the end of follow-up-17.88 ± 3.63 kg/m2 vs. 19.95 ± 2.56 kg/m2; p = 0.039; and −1.65 ± 1.55 vs. −0.42 ± 1.08; p = 0.039. When comparing patients with and without CFRD, the former were found to have worse FEV1 (in % of predicted)-22.67 ± 5.03 vs. 59.58 ± 28.92; p = 0.041-and a greater decline in FEV1 (−36.00 ± 23.52 vs. −8.13 ± 17.18; p = 0.041) at the end of follow-up. Conclusions: CGM was able to identify glucose abnormalities not detected by OGTT that were related to early-stage decreases in BMI. CGM was ineffective in predicting the onset of diabetes in this CF population. Different diagnostic criteria for diabetes may be required for individuals with CF.
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Affiliation(s)
- Mariana Zorron
- . Departamento de Pediatria, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas (SP) Brasil
| | | | - André Moreno Morcillo
- . Departamento de Pediatria, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas (SP) Brasil
| | - Aline Cristina Gonçalves
- . Departamento de Pediatria, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas (SP) Brasil
| | - Mayra de Souza El Beck
- . Departamento de Pediatria, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas (SP) Brasil
| | - José Dirceu Ribeiro
- . Departamento de Pediatria, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas (SP) Brasil
| | - Antonio Fernando Ribeiro
- . Departamento de Pediatria, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas (SP) Brasil
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Khare S, Desimone M, Kasim N, Chan CL. Cystic fibrosis-related diabetes: Prevalence, screening, and diagnosis. J Clin Transl Endocrinol 2022; 27:100290. [PMID: 34917485 PMCID: PMC8669384 DOI: 10.1016/j.jcte.2021.100290] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 11/30/2021] [Accepted: 12/01/2021] [Indexed: 12/30/2022] Open
Abstract
Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity in patients with cystic fibrosis (CF). Prevalence of CFRD increases with age and is greater with severe mutations. Other risk factors associated with CFRD are female sex, pancreatic insufficiency, liver disease, need for gastrostomy tube feedings, history of bronchopulmonary aspergillosis, and poor pulmonary function. CFRD is related to worse clinical outcomes and increased mortality. Early diagnosis and treatment have been shown to improve clinical outcomes. Screening for CFRD is recommended with an annual oral glucose tolerance test (OGTT) starting at age 10 years. Diagnosis of CFRD is made by standard American Diabetes Association (ADA) criteria during baseline health. CFRD can also be diagnosed in individuals with CF during acute illness, while on enteral feeds, and after transplant. In this review we will discuss the epidemiology of CFRD and provide an overview of the advantages and pitfalls of current screening and diagnostic tests for CFRD.
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Affiliation(s)
- Swapnil Khare
- Division of Endocrinology, Diabetes and Metabolism, Indiana University-Purdue University, Indianapolis, IN, United States
| | - Marisa Desimone
- Division of Endocrinology, Diabetes and Metabolism SUNY, Upstate Medical University, Syracuse, NY, United States
| | - Nader Kasim
- Division of Pediatric Endocrinology, Michigan State University, Helen Devos Children's Hospital/Spectrum Health, Grand Rapids, MI, United States
| | - Christine L. Chan
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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Understanding Cystic Fibrosis Comorbidities and Their Impact on Nutritional Management. Nutrients 2022; 14:nu14051028. [PMID: 35268004 PMCID: PMC8912424 DOI: 10.3390/nu14051028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/23/2022] [Accepted: 02/25/2022] [Indexed: 11/17/2022] Open
Abstract
Cystic fibrosis (CF) is a chronic, multisystem disease with multiple comorbidities that can significantly affect nutrition and quality of life. Maintaining nutritional adequacy can be challenging in people with cystic fibrosis and has been directly associated with suboptimal clinical outcomes. Comorbidities of CF can result in significantly decreased nutritional intake and intestinal absorption, as well as increased metabolic demands. It is crucial to utilize a multidisciplinary team with expertise in CF to optimize growth and nutrition, where patients with CF and their loved ones are placed in the center of the care model. Additionally, with the advent of highly effective modulators (HEMs), CF providers have begun to identify previously unrecognized nutritional issues, such as obesity. Here, we will review and summarize commonly encountered comorbidities and their nutritional impact on this unique population.
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Chan CL, Pyle L, Vigers T, Zeitler PS, Nadeau KJ. The Relationship Between Continuous Glucose Monitoring and OGTT in Youth and Young Adults With Cystic Fibrosis. J Clin Endocrinol Metab 2022; 107:e548-e560. [PMID: 34537845 PMCID: PMC8764335 DOI: 10.1210/clinem/dgab692] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Indexed: 01/13/2023]
Abstract
CONTEXT Early glucose abnormalities in people with cystic fibrosis (PwCF) are commonly detected by continuous glucose monitoring (CGM). Relationships between these CGM abnormalities and oral glucose tolerance testing (OGTT) in PwCF have not been fully characterized. OBJECTIVE This work aimed to determine the relationship between CGM and common OGTT-derived estimates of β-cell function, including C-peptide index and oral disposition index (oDI) and to explore whether CGM can be used to screen for OGTT-defined prediabetes and cystic fibrosis-related diabetes (CFRD). METHODS PwCF not on insulin and healthy controls aged 6 to 25 years were enrolled in a prospective study collecting OGTT and CGM. A subset underwent frequently sampled OGTTs (fsOGTT) with 7-point glucose, insulin, and C-peptide measurements. Pearson correlation coefficient was used to test the association between select CGM and fsOGTT measures. Receiver operating curve (ROC) analysis was applied to CGM variables to determine the cutoff optimizing sensitivity and specificity for detecting prediabetes and CFRD. RESULTS A total of 120 participants (controls = 35, CF = 85), including 69 with fsOGTTs, were included. CGM coefficient of variation correlated inversely with C-peptide index (Cpeptide30-Cpeptide0/Glucose30-Glucose0) (r = -0.45, P < .001) and oDIcpeptide (C-peptide index)(1/cpep0) (r = -0.48, P < .0001). In PwCF, CGM variables had ROC - areas under the curve ranging from 0.43 to 0.57 for prediabetes and 0.47 to 0.6 for CFRD. CONCLUSION Greater glycemic variability on CGM correlated with reduced β-cell function. However, CGM performed poorly at discriminating individuals with and without OGTT-defined CFRD and prediabetes. Prospective studies are now needed to determine how well the different tests predict clinically relevant nonglycemic outcomes in PwCF.
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Affiliation(s)
- Christine L Chan
- Department of Pediatrics, Pediatric Endocrinology, Children’s Hospital Colorado and University of Colorado Anschutz Medical Center, Aurora, Colorado 80045, USA
| | - Laura Pyle
- Department of Biostatistics, Colorado School of Public Health, Aurora, Colorado 80045, USA
| | - Tim Vigers
- Department of Pediatrics, Pediatric Endocrinology, Children’s Hospital Colorado and University of Colorado Anschutz Medical Center, Aurora, Colorado 80045, USA
- Department of Biostatistics, Colorado School of Public Health, Aurora, Colorado 80045, USA
| | - Philip S Zeitler
- Department of Pediatrics, Pediatric Endocrinology, Children’s Hospital Colorado and University of Colorado Anschutz Medical Center, Aurora, Colorado 80045, USA
| | - Kristen J Nadeau
- Department of Pediatrics, Pediatric Endocrinology, Children’s Hospital Colorado and University of Colorado Anschutz Medical Center, Aurora, Colorado 80045, USA
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Lee AJ, Huffmyer JL, Thiele EL, Zeitlin PL, Chatterjee D. The Changing Face of Cystic Fibrosis: An Update for Anesthesiologists. Anesth Analg 2022; 134:1245-1259. [PMID: 35020677 DOI: 10.1213/ane.0000000000005856] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Cystic fibrosis (CF) is the most common fatal genetic disease in North America. While CF is more common among Whites, it is increasingly being recognized in other races and ethnicities. Although there is no cure, life expectancy has steadily improved, with the median survival exceeding 46 years in the United States. There are now more adults than children with CF in the United States. CF is caused by mutations in a gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein, expressed in many epithelial cells. More than 2100 CFTR mutations have been linked to CF, and newer CFTR modulator drugs are being used to improve the production, intracellular processing, and function of the defective CFTR protein. CF is a multisystem disease that affects primarily the lungs, pancreas, hepatobiliary system, and reproductive organs. Anesthesiologists routinely encounter CF patients for various surgical and medical procedures, depending on the age group. This review article focuses on the changing epidemiology of CF, advances in the classification of CFTR mutations, the latest innovations in CFTR modulator therapies, the impact of the coronavirus disease pandemic, and perioperative considerations that anesthesiologists must know while caring for patients with CF.
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Affiliation(s)
- Amy J Lee
- From the Department of Anesthesiology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado
| | - Julie L Huffmyer
- Department of Anesthesiology, University of Virginia Health, Charlottesville, Virginia
| | - Eryn L Thiele
- Department of Anesthesiology, University of Virginia Health, Charlottesville, Virginia
| | - Pamela L Zeitlin
- Department of Pediatrics, National Jewish Health, Denver, Colorado
| | - Debnath Chatterjee
- From the Department of Anesthesiology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado
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Kasim N, Khare S, Sandouk Z, Chan C. Impaired glucose tolerance and indeterminate glycemia in cystic fibrosis. J Clin Transl Endocrinol 2021; 26:100275. [PMID: 34868882 PMCID: PMC8626567 DOI: 10.1016/j.jcte.2021.100275] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/22/2021] [Accepted: 11/11/2021] [Indexed: 11/30/2022] Open
Abstract
Oral glucose tolerance testing is used for screening, diagnosis, and risk stratification of cystic fibrosis related diabetes. Abnormal glucose tolerance in cystic fibrosis has prognostic utility with regards to progression towards overt diabetes, pulmonary function, weight loss, and mortality. Further research is needed to delineate the significance of impaired glucose tolerance and indeterminate glycemia within the CF population. Lower thresholds for indeterminate glycemia may be needed within the cystic fibrosis population. Oral glucose tolerance testing (OGTT) is the primary method to screen for and diagnose cystic fibrosis-related diabetes (CFRD). Diagnostic thresholds as currently defined are based on microvascular complications seen in type 2 diabetes. Abnormal glucose tolerance (AGT) refers to OGTT glucose elevations outside the normal range and encompasses both impaired and indeterminate glucose tolerance. Current guidelines define impaired glucose tolerance (IGT) as a 2-hour glucose of 140–199 mg/dL (7.8–11 mmol/L) and indeterminate glucose tolerance (INDET) as any mid-OGTT glucose ≥ 200 mg/dL (11.1 mmol/L) with a normal fasting and 2 h glucose. There is growing evidence that AGT also has associations with CF-centered outcomes including pulmonary decline, hospitalizations, and weight loss. Here we aim to review the historical emergence of glucose tolerance testing, review relevance to risk stratification for CFRD, discuss alternate cutoffs for identifying AGT earlier, and highlight the need for larger, future studies to inform our understanding of the implications of IGT and INDET on CF health.
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Affiliation(s)
- Nader Kasim
- Division of Pediatric Endocrinology and Diabetes, Helen Devos Children’s Hospital, Grand Rapids, MI, USA
- Corresponding author at: 35 Michigan St. NE, Suite 1800, Grand Rapids, MI 49546, USA.
| | - Swapnil Khare
- Department of Endocrinology, Diabetes and Metabolism, Indiana University, Indianapolis, IN, USA
| | - Zahre Sandouk
- Metabolism, Endocrinology and Nutrition Division, Internal Medicine Department, University of Michigan, Ann Arbor, MI, USA
| | - Christine Chan
- Department of Pediatrics, Division of Endocrinology, Children’s Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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Sandouk Z, Khan F, Khare S, Moran A. Cystic fibrosis related diabetes (CFRD) prognosis. J Clin Transl Endocrinol 2021; 26:100278. [PMID: 34926166 PMCID: PMC8652010 DOI: 10.1016/j.jcte.2021.100278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 10/29/2021] [Accepted: 11/12/2021] [Indexed: 11/17/2022] Open
Abstract
Poor nutritional status and decreased lean body mass. Decline in pulmonary function. Increased mortality from lung disease. Microvascular complications. Macrovascular complications (not currently a significant complication but this may change with modulators). Cystic fibrosis related diabetes (CFRD) occurs in at least 40–50% of adults with CF. With other forms of diabetes, microvascular and macrovascular disease are the major causes of morbidity and mortality. Macrovascular disease is rare in CF. While microvascular disease does occur in this population, there are CF-specific diabetes complications that have a more important impact on prognosis. The additional diagnosis of diabetes in CF is associated with decreased lung function, poor nutritional status, and an overall increase in mortality from lung disease. These negative findings start even before the clinical diagnosis of CFRD, during the period when patients experience abnormal glucose tolerance related to insulin insufficiency. The main mechanisms by which CFRD negatively affects prognosis are thought to be a combination of 1) protein catabolism, decreased lean body mass and undernutrition resulting from insulin insufficiency, and 2) an increased pro-inflammatory and pro-infectious state related to intermittent hyperglycemia. With the introduction of CFTR modulators, the care of CF patients has been revolutionized and many aspects of CF health such as BMI and lung function are improving. The impact of these drugs on the adverse prognosis related to the diagnosis of diabetes in CF, as well as the potential to delay or prevent onset of CFRD remain to be determined.
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42
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Bengtson CD, He J, Kim MD, Salathe MA. Cystic Fibrosis-related Diabetes Is Associated with Worse Lung Function Trajectory despite Ivacaftor Use. Am J Respir Crit Care Med 2021; 204:1343-1345. [PMID: 34469275 DOI: 10.1164/rccm.202104-1060le] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
| | - Jianghua He
- The University of Kansas Medical Center Kansas City, Kansas
| | - Michael D Kim
- The University of Kansas Medical Center Kansas City, Kansas
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43
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Al-Selwi Y, Shaw JA, Kattner N. Understanding the Pancreatic Islet Microenvironment in Cystic Fibrosis and the Extrinsic Pathways Leading to Cystic Fibrosis Related Diabetes. CLINICAL MEDICINE INSIGHTS-ENDOCRINOLOGY AND DIABETES 2021; 14:11795514211048813. [PMID: 34675737 PMCID: PMC8524685 DOI: 10.1177/11795514211048813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/23/2021] [Indexed: 11/16/2022]
Abstract
Cystic fibrosis (CF) is an autosomal recessive chronic condition
effecting approximately 70 000 to 100 000 people globally and is
caused by a loss-of-function mutation in the CF transmembrane
conductance regulator. Through improvements in clinical care, life
expectancy in CF has increased considerably associated with rising
incidence of secondary complications including CF-related diabetes
(CFRD). CFRD is believed to result from β-cell loss as well as
insufficient insulin secretion due to β-cell dysfunction, but the
underlying pathophysiology is not yet fully understood. Here we review
the morphological and cellular changes in addition to the
architectural remodelling of the pancreatic exocrine and endocrine
compartments in CF and CFRD pancreas. We consider also potential
underlying proinflammatory signalling pathways impacting on endocrine
and specifically β-cell function, concluding that further research
focused on these mechanisms may uncover novel therapeutic targets
enabling restoration of normal insulin secretion.
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Affiliation(s)
- Yara Al-Selwi
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - James Am Shaw
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.,Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Nicole Kattner
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
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Van den Bossche S, De Broe E, Coenye T, Van Braeckel E, Crabbé A. The cystic fibrosis lung microenvironment alters antibiotic activity: causes and effects. Eur Respir Rev 2021; 30:30/161/210055. [PMID: 34526313 DOI: 10.1183/16000617.0055-2021] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 04/23/2021] [Indexed: 01/08/2023] Open
Abstract
Chronic airway colonisation by Pseudomonas aeruginosa, a hallmark of cystic fibrosis (CF) lung disease, is associated with increased morbidity and mortality and despite aggressive antibiotic treatment, P. aeruginosa is able to persist in CF airways. In vitro antibiotic susceptibility assays are poor predictors of antibiotic efficacy to treat respiratory tract infections in the CF patient population and the selection of the antibiotic(s) is often made on an empirical base. In the current review, we discuss the factors that are responsible for the discrepancies between antibiotic activity in vitro and clinical efficacy in vivo We describe how the CF lung microenvironment, shaped by host factors (such as iron, mucus, immune mediators and oxygen availability) and the microbiota, influences antibiotic activity and varies widely between patients. A better understanding of the CF microenvironment and population diversity may thus help improve in vitro antibiotic susceptibility testing and clinical decision making, in turn increasing the success rate of antibiotic treatment.
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Affiliation(s)
| | - Emma De Broe
- Laboratory of Pharmaceutical Microbiology, Ghent University, Ghent, Belgium
| | - Tom Coenye
- Laboratory of Pharmaceutical Microbiology, Ghent University, Ghent, Belgium
| | - Eva Van Braeckel
- Dept of Respiratory Medicine, Cystic Fibrosis Reference Centre, Ghent University Hospital, Ghent, Belgium.,Dept of Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium
| | - Aurélie Crabbé
- Laboratory of Pharmaceutical Microbiology, Ghent University, Ghent, Belgium
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45
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Kelly A, Sheikh S, Stefanovski D, Peleckis AJ, Nyirjesy SC, Eiel JN, Sidhaye A, Localio R, Gallop R, De Leon DD, Hadjiliadis D, Rubenstein RC, Rickels MR. Effect of Sitagliptin on Islet Function in Pancreatic Insufficient Cystic Fibrosis With Abnormal Glucose Tolerance. J Clin Endocrinol Metab 2021; 106:2617-2634. [PMID: 34406395 PMCID: PMC8660013 DOI: 10.1210/clinem/dgab365] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Indexed: 01/21/2023]
Abstract
PURPOSE Impaired incretin secretion may contribute to the defective insulin secretion and abnormal glucose tolerance (AGT) that associate with worse clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). The study objective was to test the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitor-induced increases in intact incretin hormone [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] concentrations augment insulin secretion and glucagon suppression and lower postprandial glycemia in PI-CF with AGT. METHODS 26 adults from Children's Hospital of Philadelphia and University of Pennsylvania CF Center with PI-CF and AGT [defined by oral glucose tolerance test glucose (mg/dL): early glucose intolerance (1-h ≥ 155 and 2-h < 140), impaired glucose tolerance (2-h ≥ 140 and < 200 mg/dL), or diabetes (2-h ≥ 200)] were randomized to a 6-month double-blind trial of DPP-4 inhibitor sitagliptin 100 mg daily or matched placebo; 24 completed the trial (n = 12 sitagliptin; n = 12 placebo). Main outcome measures were mixed-meal tolerance test (MMTT) responses for intact GLP-1 and GIP, insulin secretory rates (ISRs), glucagon suppression, and glycemia and glucose-potentiated arginine (GPA) test-derived measures of β- and α-cell function. RESULTS Following 6-months of sitagliptin vs placebo, MMTT intact GLP-1 and GIP responses increased (P < 0.001), ISR dynamics improved (P < 0.05), and glucagon suppression was modestly enhanced (P < 0.05) while GPA test responses for glucagon were lower. No improvements in glucose tolerance or β-cell sensitivity to glucose, including for second-phase insulin response, were found. CONCLUSIONS In glucose intolerant PI-CF, sitagliptin intervention augmented meal-related incretin responses with improved early insulin secretion and glucagon suppression without affecting postprandial glycemia.
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Affiliation(s)
- Andrea Kelly
- Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Correspondence: Andrea Kelly, MD, MSCE, Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.
| | - Saba Sheikh
- Division of Pulmonary Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphias, PA, USA
| | - Darko Stefanovski
- Department of Biostatistics, University of Pennsylvania School of Veterinary Medicine, Kennett Square, PA, USA
| | - Amy J Peleckis
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Sarah C Nyirjesy
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Jack N Eiel
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Aniket Sidhaye
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Russell Localio
- Department of Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
| | - Robert Gallop
- Department of Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
- Department of Mathematics, West Chester University of Pennsylvania, West Chester, PA, USA
| | - Diva D De Leon
- Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Denis Hadjiliadis
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Ronald C Rubenstein
- Division of Pulmonary Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphias, PA, USA
- Division of Allergy and Pulmonary Medicine, Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, USA
| | - Michael R Rickels
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
- Michael R. Rickels, MD, MS, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA.
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46
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Hart PA, Bradley D, Conwell DL, Dungan K, Krishna SG, Wyne K, Bellin MD, Yadav D, Andersen DK, Serrano J, Papachristou GI. Diabetes following acute pancreatitis. Lancet Gastroenterol Hepatol 2021; 6:668-675. [PMID: 34089654 PMCID: PMC8277724 DOI: 10.1016/s2468-1253(21)00019-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/26/2020] [Accepted: 01/12/2021] [Indexed: 02/07/2023]
Abstract
Diabetes represents a group of diseases involving persistent hyperglycaemia. Exocrine disorders of the pancreas are increasingly recognised to cause or precede the onset of diabetes, which in this context is referred to as pancreatogenic or type 3c diabetes. Diabetes, as a sequela of acute pancreatitis, is observed across the spectrum of severity in acute pancreatitis and can be associated with other clinical complications. The pathophysiology of acute pancreatitis-related diabetes is poorly understood, and observations suggest that it is probably multifactorial. In this Review, we discuss the epidemiology, pathophysiology, and management considerations of diabetes following acute pancreatitis, and highlight knowledge gaps in this topic.
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Affiliation(s)
- Phil A Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
| | - David Bradley
- Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Darwin L Conwell
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Kathleen Dungan
- Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Somashekar G Krishna
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Kathleen Wyne
- Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Melena D Bellin
- Department of Pediatrics and Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Dhiraj Yadav
- Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Dana K Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Jose Serrano
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Georgios I Papachristou
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
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47
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Coderre L, Debieche L, Plourde J, Rabasa-Lhoret R, Lesage S. The Potential Causes of Cystic Fibrosis-Related Diabetes. Front Endocrinol (Lausanne) 2021; 12:702823. [PMID: 34394004 PMCID: PMC8361832 DOI: 10.3389/fendo.2021.702823] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/06/2021] [Indexed: 12/16/2022] Open
Abstract
Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity, affecting more than 50% of adult CF patients. Despite this high prevalence, the etiology of CFRD remains incompletely understood. Studies in young CF children show pancreatic islet disorganization, abnormal glucose tolerance, and delayed first-phase insulin secretion suggesting that islet dysfunction is an early feature of CF. Since insulin-producing pancreatic β-cells express very low levels of CFTR, CFRD likely results from β-cell extrinsic factors. In the vicinity of β-cells, CFTR is expressed in both the exocrine pancreas and the immune system. In the exocrine pancreas, CFTR mutations lead to the obstruction of the pancreatic ductal canal, inflammation, and immune cell infiltration, ultimately causing the destruction of the exocrine pancreas and remodeling of islets. Both inflammation and ductal cells have a direct effect on insulin secretion and could participate in CFRD development. CFTR mutations are also associated with inflammatory responses and excessive cytokine production by various immune cells, which infiltrate the pancreas and exert a negative impact on insulin secretion, causing dysregulation of glucose homeostasis in CF adults. In addition, the function of macrophages in shaping pancreatic islet development may be impaired by CFTR mutations, further contributing to the pancreatic islet structural defects as well as impaired first-phase insulin secretion observed in very young children. This review discusses the different factors that may contribute to CFRD.
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Affiliation(s)
- Lise Coderre
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montréal, QC, Canada
| | - Lyna Debieche
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montréal, QC, Canada
- Département de médecine, Université de Montréal, Montréal, QC, Canada
| | - Joëlle Plourde
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montréal, QC, Canada
- Département de médecine, Université de Montréal, Montréal, QC, Canada
| | - Rémi Rabasa-Lhoret
- Division of Cardiovascular and Metabolic Diseases, Institut de recherche clinique de Montréal, Montréal, QC, Canada
- Département de nutrition, Université de Montréal, Montréal, QC, Canada
- Cystic Fibrosis Clinic, Centre Hospitalier de l’Université de Montréal (CHUM), Montréal, QC, Canada
| | - Sylvie Lesage
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montréal, QC, Canada
- Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, QC, Canada
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48
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HOMA indices as screening tests for cystic fibrosis-related diabetes. J Cyst Fibros 2021; 21:123-128. [PMID: 34090803 DOI: 10.1016/j.jcf.2021.05.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 04/19/2021] [Accepted: 05/17/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND We assessed the diagnostic performances of homeostasis model assessment indices (HOMA) of β-cell function (HOMA-%β) and of insulin resistance (HOMA-IR) for cystic fibrosis related diabetes (CFRD) screening. METHODS Data were collected from a prospective cohort of 228 patients with CF (117 adults and 111 children). Fasting insulin and glucose levels were measured to calculate HOMA-%β and HOMA-IR. HOMA-%β <100 indicated insulin secretion deficiency and HOMA-IR >1 insulin resistance. Both were used to calculate sensitivity, specificity, and positive and negative predictive values (PPV and NPV). Two-hour oral glucose tolerance tests (2h-OGTT) defined CFRD. Analyses were conducted separately for children and adults. Performances of HOMA-%β and HOMA-IR were calculated at inclusion, for each year of follow-up and for pooled data over the follow-up period. RESULTS Sensitivity, specificity, NPV and PPV were respectively: 88%, 45%, 98% and 11% for HOMA-%β and 42%, 48%, 91% and 6% for HOMA-IR in the pooled data of children; and 83%, 18%, 90% and 10% for HOMA-%β, and 39%, 80%, 92% and 18% for HOMA-IR in the pooled data of adults. Combining HOMA-%β and HOMA-IR did not improve performances. CONCLUSION Within both age groups, HOMA-%β <100 provided good sensitivity and NPV. HOMA-IR >1 had low sensitivity. Calculation of the HOMA-%β could be an interesting first-line screening approach to exclude CFRD and thus avoid unnecessary OGTT in patients for whom value is ≥100. However, HOMA-%β<100 does not support the diagnosis of CFRD and should be complemented by OGTT.
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49
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Semaniakou A, Chappe F, Anini Y, Chappe V. VIP reduction in the pancreas of F508del homozygous CF mice and early signs of Cystic Fibrosis Related Diabetes (CFRD). J Cyst Fibros 2021; 20:881-890. [PMID: 34034984 DOI: 10.1016/j.jcf.2021.05.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 04/30/2021] [Accepted: 05/04/2021] [Indexed: 12/19/2022]
Abstract
Vasoactive intestinal peptide (VIP), a 28-amino acid neuropeptide with potent anti-inflammatory, bronchodilatory and immunomodulatory functions, is secreted by intrinsic neurons innervating all exocrine glands, including the pancreas, in which it exerts a regulatory function in the secretion of insulin and glucagon. Cystic fibrosis-related diabetes (CFRD) is the most common co-morbidity associated with cystic fibrosis (CF), impacting approximately 50% of adult patients. We recently demonstrated a 50% reduction of VIP abundance in the lungs, duodenum and sweat glands of C57Bl/6 CF mice homozygous for the F508del-CFTR disease-causing mutation. VIP deficiency resulted from a reduction in VIPergic and cholinergic innervation, starting before signs of CF disease were observed. As VIP functions as a neuromodulator with insulinotropic effect on pancreatic beta cells, we sought to study changes in VIP in the pancreas of CF mice. Our goal was to examine VIP content and VIPergic innervation in the pancreas of 8- and 17-week-old F508del-CFTR homozygous mice and to determine whether changes in VIP levels would contribute to CFRD development. Our data showed that a decreased amount of VIP and reduced innervation are found in CF mice pancreas, and that these mice also exhibited reduced insulin secretion, up-regulation of glucagon production and high random blood glucose levels compared to same-age wild-type mice. We propose that low level of VIP, due to reduced innervation of the CF pancreas and starting at an early disease stage, contributes to changes in insulin and glucagon secretion that can lead to CFRD development.
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Affiliation(s)
- Anna Semaniakou
- Department of Physiology & Biophysics, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
| | - Frederic Chappe
- Department of Physiology & Biophysics, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
| | - Younes Anini
- Department of Physiology & Biophysics, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada; Obstetrics and Gynecology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
| | - Valerie Chappe
- Department of Physiology & Biophysics, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
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50
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Wilbert F, Grünert SC, Heinzmann A, Bode SFN. Cystic fibrosis in disguise - the wolf in sheep's clothing, a case report. BMC Pediatr 2021; 21:174. [PMID: 33853553 PMCID: PMC8048214 DOI: 10.1186/s12887-021-02636-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 03/29/2021] [Indexed: 11/13/2022] Open
Abstract
Background Childhood hypoglycemia in combination with hepatomegaly is suspicious for inborn errors of metabolism. Cystic fibrosis typically presents with failure to thrive, pulmonary and gastrointestinal symptoms. Hepatic involvement and hypoglycemia can occur in a significant number of patients, although hepatomegaly is uncommon. Case presentation A 28 months old boy was presented with recurrent upper airways infections, progressive lethargy and weight loss. Clinically hepatomegaly was the main presenting feature and hypoglycemia (minimum 1.4 mmol/l) was noted as were elevated transaminases. The patient did not produce enough sweat to analyze it. Infectious causes for hepatitis were excluded and a broad metabolic work-up initiated. A therapy with starch was initiated to control hypoglycemia. In further course loose stools were reported and pancreatic elastase was found to be reduced. A further sweat test yielded pathological chloride concentration and genetic testing confirmed the diagnosis of cystic fibrosis. Conclusions Cystic fibrosis is a systemic disease and less common presentations need to be considered. Even in the age of CF-newborn screening in many countries CF needs to be ruled out in typical and atypical clinical presentations and diagnostics need to be repeated if inconclusive.
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Affiliation(s)
- Friederike Wilbert
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Centre - University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Sarah C Grünert
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Centre - University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Andrea Heinzmann
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Centre - University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Sebastian F N Bode
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Centre - University of Freiburg, Faculty of Medicine, Freiburg, Germany. .,Department of Pediatrics and Adolescent Medicine, Ulm University Medical Centre, Ulm, Germany.
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