Isolated Hypoglyceamia in Children with Cystic Fibrosis: Role of Pancreatic Insufficiency and Glucagon Response.

TheDepartment of Pediatrics, University of Minnesota Children’sHospital, Minneapolis, USACorresponding author:Dr. Stephen MP O’Riordan MRCPI, MDThe Developmental Endocrinology and Research GroupThe Department of Clinical and Molecular GeneticsThe Institute of Child Health, University College London30 Guliford StreetLondon WC1N 1EH.Tel: +44-020-7242-9789, ext. 0732;fax: +44-020-7404-6191;e-mail: s.oriordan@ich.ucl.ac.ukAcknowledgments:PeterHindmarsh,MehulDattani,HilaryHoeyand Nicola Bridges.Conflicts of interest: The authors have declared no conflictsof interest.Editors of the ISPAD Clinical Practice Consensus Guide-lines 2009 Compendium: Ragnar Hanas, Kim Donaghue,Georgeanna Klingensmith, and Peter Swift.This article is a chapter in the

Highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators, such as elexacaftor/tezacaftor/ivacaftor (ETI), herald a new era in therapeutic strategy of cystic fibrosis (CF). ETI's effect on glucose tolerance remains controversial. The study was undertaken to evaluate the effect of ETI treatment on glucose tolerance in youths with CF. All the participants underwent a baseline oral glucose tolerance test (OGTT) before ETI initiation (M0) and 12 months (M12), and at 24 months if possible. The cohort was stratified in two subgroups based on the baseline OGTT: normal glucose tolerance (NGT) and abnormal glucose tolerance (AGT) defined by impaired fasting glucose or impaired glucose tolerance or diabetes not requiring insulin treatment. We included 106 adolescents with CF (age 14.1 ± 1.5 years), 75 with NGT, and 31 with AGT. The baseline characteristics of the two groups were similar except for a higher glucose level at 1- and 2-hour OGTT in the AGT group. ETI induced an increase in body mass index z score and in forced expiratory volume in 1 second (FEV1) (P < .001). After 12 months, participants with NGT did not experience any change of 1-hour and 2-hour glucose. By contrast, those with AGT displayed a reduction of 2-hour glucose at M12 (P = .006). Fifteen out of the 31 (48%) adolescents in the AGT group reversed to NGT but 9 of 75 (17%) in the NGT group progressed to AGT. Three participants with CF-related diabetes at baseline reversed to AGT. One-hour glucose concentrations at or above 8.7 mmol/L (157 mg/dL) during baseline OGTT had 80% sensitivity to identify those with AGT at 12 months (odds ratio 1.51; [1.20-1.92]; P = .001). Twenty participants had a 24-month OGTT that confirmed preserved insulin secretion. ETI may improve glucose tolerance in adolescents with CF by preserving insulin secretion. One-hour glucose during the OGTT helps to detect risk for AGT after ETI treatment.

Abnormal glucose tolerance in cystic fibrosis: Why should patients be screened?

Rationale: Abnormal glucose metabolism is a common complication in people with cystic fibrosis (CF), and those with impaired glucose tolerance (IGT) or CF-related diabetes (CFRD) have increased disease burden. Elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) is safe and effective for people with CF ≥2 years of age with ELX/TEZ/IVA-responsive CFTR (CF transmembrane conductance regulator) mutations; however, efficacy on glycemic control has not been studied. Objectives: To evaluate the impact of ELX/TEZ/IVA on glucose tolerance in people with CF who have IGT or CFRD. Methods: In this phase 3b, open-label study, ELX/TEZ/IVA was administered for 48 weeks to participants ≥12 years of age, heterozygous for F508del and a minimal function CFTR mutation, with either IGT or CFRD. Measurements and Main Results: Sixty-nine participants received ELX/TEZ/IVA. The primary endpoint was change in blood glucose concentration after a 2-hour oral glucose tolerance test from baseline to the average of Week 36 and Week 48; participants had a mean change of -35.0 mg/dl (95% confidence interval [CI], -49.2 to -20.7 mg/dl; P < 0.0001) (-1.9 mmol/L [95% CI, -2.7 to -1.2 mmol/L]). Secondary endpoints were the proportion of participants with improvement in dysglycemia categorization (CFRD, IGT, normal glucose tolerance) at Week 48 and safety. Among participants with abnormal glucose tolerance at baseline, 37.7% (95% CI, 24.8 to 52.1) had improvements in dysglycemia categorization at Week 48. Overall, 35.5% of participants had normal glucose tolerance at Week 48 compared with 13.0% at baseline. Safety was consistent with the established safety profile of ELX/TEZ/IVA. Conclusions: ELX/TEZ/IVA treatment led to clinically meaningful improvements in blood glucose regulation, with significant within-group decreases in blood glucose concentrations after oral glucose tolerance testing and improved dysglycemia categorization in people with CF with early IGT or CFRD. Clinical trial registered with www.clinicaltrials.gov (NCT04599465).

Cystic fibrosis (CF) is an autosomal recessively inherited defect in the cystic fibrosis transmembrane receptor, a cell membrane chloride channel. The deficiency or absence of the channel results in thick, sticky secretions in many organs, including lung, liver, gastrointestinal tract, and pancreas. Eighty-five percent of CF patients have exocrine pancreatic insufficiency. The obstructive nature of the tenacious mucus predisposes to infection, particularly in the respiratory tract.1 CF was once considered a disease of childhood. However, with improvements in medical care during the past few decades, patients with CF are now living well into their third, fourth, or fifth decade of life and have a median life expectancy of 32.2 years.2 As survival has increased, CF-related diabetes (CFRD) has become the leading co-morbidity in this patient population,3–5 occurring in ∼13% of all patients with CF.2 This figure is widely believed to be an underestimate because of the lack of routine screening for diabetes in the CF population.6 CFRD is most commonly diagnosed in patients who are between 18 and 21 years of age.4,7 The 1998 CFRD Consensus Committee identified four glucose tolerance categories for clinical management and research purposes (Table 1).8 The four categories are based on a standard glucose tolerance test: normal glucose tolerance (NGT), impaired glucose tolerance (IGT), CFRD without fasting hyperglycemia (FH), and CFRD with FH. There are important differences in medical nutrition therapy (MNT) for the various categories of glucose intolerance and other circumstances in patients with CFRD. Glycated hemoglobin (A1C) is not useful for diagnosing CFRD because increased red blood cell turnover in CF patients may falsely lower A1C levels. However, it can be useful in monitoring overall blood glucose control in established CFRD patients.8 The American Diabetes Association (ADA) classifies CFRD under …

Oral glucose tolerance test and continuous glucose monitoring to assess diabetes development in cystic fibrosis patients

Oral glucose tolerance test and continuous glucose monitoring to assess diabetes development in cystic fibrosis patients

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.

Alteraciones hidrocarbonadas en pacientes impúberes con fibrosis quística

Hypoglycemia in cystic fibrosis (CF), in the absence of glucose-lowering therapies, has long been identified as an important issue in the management of CF. There is currently still no unifying hypothesis for its etiology. The aims of this study were to perform a 3-h oral glucose tolerance test (OGTT) in participants with CF and (1) document glucose, insulin, glucagon, glucagon-like-peptide-1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP) release patterns within varying glucose tolerance groups during the OGTT; (2) determine the prevalence of hypoglycemic during the OGTT; and (3) define any association between hypoglycemia and patterns of insulin, glucagon, GLP-1, and GIP release. Eligible participants attending an adult CF clinic completed a 3-h OGTT. Hypoglycemia on OGTT was defined as mild (glucose 3.4-3.9 mmol/L), moderate (glucose 3.1-3.3 mmol/L), and severe (glucose ≤ 3 mmol/L). Hormones were measured at fasting, 30, 60, 120, and 180 min. Twenty-four participants completed the study, of which 7 had normal glucose tolerance, 12 had abnormal glucose tolerance, and 5 had cystic fibrosis related diabetes (CFRD). All participants had a delayed insulin response compared with normative data. All glucose tolerance groups showed appropriate and similar suppression of fasting glucagon. Four participants (17%) had mild hypoglycemic, three (13%) had moderate hypoglycemic, and eight (33%) had severe hypoglycemic. No participant with CFRD demonstrated hypoglycemic. Of the 19 participants without CFRD, 15 (79%) experienced hypoglycemic. Participants with hypoglycemic had greater peak glucose and insulin responses than those that did not have hypoglycemic, and this approached significance (p = .0625 for glucose and p = .0862 for insulin). No significant mean differences between GLP-1 and GIP release were found. There was no relationship between hypoglycemic and modulator therapy. Postprandial hypoglycemic was unmasked by the extension of an OGTT to 3 h. Delayed and abnormal insulin release, and ineffective counter-regulatory action of glucagon may have a role in its etiology.

Glucose intolerance in children with cystic fibrosis

Cystic fibrosis (CF) related diabetes is the most common comorbidity in persons with CF. International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines recommend annual oral glucose tolerance testing (OGTT) screening starting at age 10. The OGTT might be recommended in younger children if, as in adults, it provided clinically relevant prognostic information. A database review was performed to determine whether OGTT findings in children with CF predict subsequent clinical course. A retrospective matched-pair cohort study was based on OGTTs performed during 1998-2003. Children aged 6-9 were classified as having normal glucose tolerance (NGT) or abnormal glucose tolerance (AGT). Children with AGT were matched by age and gender to those with NGT. Clinical status was assessed at baseline and 5 yr later. In a separate investigation, diabetes and prior AGT status of children aged 10-18 were used to assess predictions derived from the cohort study. In 1998-2003, 39 of 94 children had AGT. Of these, 31 had sufficient follow-up data to be included. Both at baseline and 5 yr later there was no significant difference in height, weight, body mass index (BMI) or lung function between AGT and NGT. Diabetes developed in 13 AGT (42%) and one NGT (3%) [odds ratio (OR) 11, p = 0.0009]. Age of diabetes onset was 12 ± 1 yr in boys and 11 ± 1 yr in girls, compared to approximately 23 yr in the general CF population. Fifteen current children age 10-18 who had AGT before age 10 have diabetes, close to the prediction of 19. AGT in children with CF age 6-9 yr identifies those at high risk for progression to early onset diabetes.

Natural History of Glucose Intolerance in Patients with Cystic Fibrosis: Ten-Year Prospective Observation Program

Improved exercise capacity (EC) and normal glucose tolerance (NGT) are independently associated with favorable outcomes in CF, however, little information on this relationship exists in patients with CF. Cardiopulmonary exercise tests, oral glucose tolerance tests (OGTT), and HbA1c values measured within a 12-month period were evaluated on 83 pediatric patients diagnosed with CF. Patients were categorized as having NGT, abnormal glucose tolerance (AGT), or CF-related diabetes (CFRD). EC decreased as severity of glucose intolerance increased across NGT, AGT, and CFRD groups (P = 0.02). Compared to patients with NGT, patients with CFRD had lower peak VO2 mL/kg/min (33.0 ± 7.3 vs 41.3 ± 9.4, P = 0.01), lower VO2 % (81 ± 20 vs 93 ± 17, P = 0.03), and higher HbA1c (6.9 ± 1.7 vs 5.4 ± 0.4, P < 0.01). There was a positive association with age and FEV1 % with EC in the 17 patients with CFRD. In the 66 patients without diabetes, peak EC was positively associated with FEV1 % and negatively associated with age, fasting insulin, and insulin 120 min. After accounting for age and FEV1 %, multivariate analyses indicated that insulin and glucose values at 120 min predicted EC. These data provide evidence that poor glucose tolerance is associated with lower EC in pediatric patients with CF. There was a significant relationship between glucose and insulin values obtained by OGTT with EC in a sample of non-diabetic patients with preserved lung function. Future studies are warranted to confirm these findings and investigate the potential role of exercise in the management or prevention of CFRD.

Holter glycémique et dépistage du diabète chez l’enfant atteint de mucoviscidose