Advertisement

Characterization of patients with cystic fibrosis presenting an indeterminate glucose tolerance (INDET)

  • Adèle Coriati
    Affiliations
    Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada

    Department of Nutrition, Université de Montréal, Montréal, Québec H3T 1A8, Canada
    Search for articles by this author
  • Sophie Ziai
    Affiliations
    Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada

    Department of Nutrition, Université de Montréal, Montréal, Québec H3T 1A8, Canada
    Search for articles by this author
  • Mirna Azar
    Affiliations
    Department of Medicine, Université de Montréal, Montréal, Québec H3T1J4, Canada
    Search for articles by this author
  • Yves Berthiaume
    Affiliations
    Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada

    Cystic Fibrosis Clinic of the Centre hospitalier de l'Université de Montréal, Montréal, Québec H2W 1T8, Canada

    Department of Medicine, Université de Montréal, Montréal, Québec H3T1J4, Canada
    Search for articles by this author
  • Rémi Rabasa-Lhoret
    Correspondence
    Corresponding author at: Institut de recherches cliniques de Montréal, 110 avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada. Tel.: +1 514 987 5762; fax: +1 514 987 5670.
    Affiliations
    Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada

    Department of Nutrition, Université de Montréal, Montréal, Québec H3T 1A8, Canada

    Cystic Fibrosis Clinic of the Centre hospitalier de l'Université de Montréal, Montréal, Québec H2W 1T8, Canada

    Department of Medicine, Université de Montréal, Montréal, Québec H3T1J4, Canada
    Search for articles by this author
Open ArchivePublished:March 26, 2015DOI:https://doi.org/10.1016/j.jcf.2015.03.001

      Abstract

      Background

      CFRD is preceded and associated with a significantly increased morbidity and mortality. We aimed to characterize a large newly established glucose tolerance subgroup named INDET (indeterminate; 1-h oral glucose tolerance test (OGTT) > 11.0 but 2 h-OGTT < 7.8 mmol/L) in adult patients with cystic fibrosis (CF).

      Methods

      All CF participants (n = 252, ≥18 yrs without CFRD) underwent a 2 h-OGTT with glucose and insulin sample measurements every 30 min. They were then classified as having either normal, impaired, or INDET glucose tolerance, or de novo CFRD. Other clinical characteristics were collected such as the BMI and pulmonary function.

      Results

      All groups were of similar age (P = 0.629) and BMI (P = 0.813). We found that the INDETs displayed decreased lung function comparable to de novo CFRD. OGTT-derived glucose or insulin secretion/sensitivity parameters cannot fully explain this observation.

      Conclusions

      Prospective studies are required to establish if the INDET-CF group can identify clinically relevant outcomes.

      Keywords

      1. Introduction

      Cystic Fibrosis (CF) is the most common autosomal genetic disease in Caucasians. In CF, viscous secretions accumulate in lung tissues and lead to chronic respiratory infections, inflammation, respiratory failure and eventually death [
      • Grasemann H.
      • Ratjen F.
      Early lung disease in cystic fibrosis.
      ]. With the advances in medicine, the longevity of patients with CF has increased. However, this has led to the emergence of new complications such as the most common one, CF-related diabetes (CFRD) [
      • Elborn J.S.
      Personalised medicine for cystic fibrosis: treating the basic defect.
      ,
      • Simmonds N.J.
      • Cullinan P.
      • Hodson M.E.
      Growing old with cystic fibrosis — the characteristics of long-term survivors of cystic fibrosis.
      ]. More than 40% of adult patients will eventually develop CFRD while an identical proportion will present milder glucose abnormalities [
      • Moran A.
      • Dunitz J.
      • Nathan B.
      • Saeed A.
      • Holme B.
      • Thomas W.
      Cystic fibrosis-related diabetes: current trends in prevalence, incidence, and mortality.
      ]. CFRD is preceded by a long phase of postprandial glucose intolerance. This period is characterized by an unexplained accelerated decrease in weight and pulmonary function as compared to CF patients who remain non-diabetic [
      • Hameed S.
      • Morton J.R.
      • Jaffé A.
      • Field P.I.
      • Belessis Y.
      • Yoong T.
      • et al.
      Early glucose abnormalities in cystic fibrosis are preceded by poor weight gain.
      ,
      • Lanng S.
      • Thorsteinsson B.
      • Nerup J.
      • Koch C.
      Influence of the development of diabetes mellitus on clinical status in patients with cystic fibrosis.
      ]. CFRD's main feature is reduced insulin secretion that is present early in life in almost all pancreatic exocrine insufficient CF patients [
      • Hammana I.
      • Coderre L.
      • Potvin S.
      • Costa M.
      • Berthiaume Y.
      • Lavoie A.
      • et al.
      Dichotomy between postprandial glucose and lipid profiles in adults with cystic fibrosis: a pilot study.
      ,
      • Costa M.
      • Potvin S.
      • Hammana I.
      • Malet A.
      • Berthiaume Y.
      • Jeanneret A.
      • et al.
      Increased glucose excursion in cystic fibrosis and its association with a worse clinical status.
      ]. Hyperglycemia is a direct consequence of lower insulin secretion and the rate of both pulmonary function and weight decline is inversely related to the severity of both the degree of hyperglycemia as well as the severity of insulin deficiency [
      • Milla C.
      • Billings J.
      • Moran A.
      Diabetes is associated with dramatically decreased survival in female but not male subjects with cystic fibrosis.
      ,
      • Milla C.
      • Warwick W.
      • Moran A.
      Trends in pulmonary function in patients with cystic fibrosis correlate with the degree of glucose intolerance at baseline.
      ]. This could be explained by the fact that hyperglycemia could favor oxidative stress and pathogen growth while reduced insulin would favor a sub-clinical catabolic state [
      • Milla C.
      • Warwick W.
      • Moran A.
      Trends in pulmonary function in patients with cystic fibrosis correlate with the degree of glucose intolerance at baseline.
      ].
      The standard method used to diagnose CFRD is the oral glucose tolerance test (OGTT). However, classical OGTT thresholds used to diagnose abnormal glucose tolerance, which are based on the risk for retinopathy in type 2 diabetes, are questioned in CF [
      • Canadian Diabetes Association Clinical Practice Guidelines Expert Committee
      Canadian Diabetes Association 2013 clinical practice guidelines for the prevention and management of diabetes in Canada.
      ]. Thresholds associated with risk for accelerated weight and lung function loss would be more relevant. CF patients present a specific OGTT pattern characterized by early glucose excursion with rapid normalization as well as major defects in early insulin secretion. OGTT intermediate time points rather than fasting glucose (G0) and 2-h values (G2) could thus provide more pertinent information to identify dysglycemia-associated risks. The American Diabetes Association (ADA) and the Cystic Fibrosis Foundation (CFF) proposed a new CF-specific subgroup of glucose tolerance, considered as indeterminate (INDET), with normal G2 but elevated 1-h OGTT glucose (G1) values (G1 > 11.0 but G2-OGTT < 7.8 mmol/L) [
      • Moran A.
      • Brunzell C.
      • Cohen R.C.
      • Katz M.
      • Marshall B.C.
      • Onady G.
      • et al.
      Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society.
      ]. In fact, in a pediatric CF population, higher G1, but not G2, was associated with worse pulmonary function [
      • Brodsky J.
      • Dougherty S.
      • Makani R.
      • Rubenstein R.C.
      • Kelly A.
      Elevation of 1-hour plasma glucose during oral glucose tolerance testing is associated with worse pulmonary function in cystic fibrosis.
      ]. Recent studies showed that INDETs are at high risk of developing CFRD [
      • Schmid K.
      • Fink K.
      • Holl R.W.
      • Hebestreit H.
      • Ballmann M.
      Predictors for future cystic fibrosis-related diabetes by oral glucose tolerance test.
      ,
      • Ode K.L.
      • Frohnert B.
      • Laguna T.
      • Phillips J.
      • Holme B.
      • Regelmann W.
      • et al.
      Oral glucose tolerance testing in children with cystic fibrosis.
      ]. To date, there are no studies evaluating characteristics (weight, lung function, insulin and glucose) of a large INDET subgroup of CF adult patients. Our hypothesis was that INDETs would display distinct pulmonary, nutritional and insulin secretion profiles.

      2. Materials and methods

      2.1 Subjects

      This is a cross-sectional analysis of baseline data from the Montreal Cystic Fibrosis Cohort (MCFC). Non-diabetic adult patients with CF (>18 years) underwent an OGTT screening with additional intermediate sampling and clinical measurements were taken systematically. The institutional research ethics committee approved the protocol and all subjects received a signed copy of the written consent form. All subjects (n = 252) for whom data were available as of January 2014 were included in this analysis.
      The inclusion/exclusion criteria were previously described in detail [
      • Coriati A.
      • Belson L.
      • Ziai S.
      • Haberer E.
      • Gauthier M.S.
      • Mailhot G.
      • et al.
      Impact of sex on insulin secretion in cystic fibrosis.
      ]. All subjects taking medication or had health conditions that could significantly interfere with glucose metabolism were excluded from analysis. Such conditions include: haemoptysis, fever, ongoing or recent (within 1 month) intravenous antibiotic treatment, pregnancy, overnight tube feeding, CFTR modulators and oral steroids. If a patient had any sign of infection confirmed by a trained pneumologist, the test was postponed to the next medical appointment, 3 to 6 months later. However, patients where allowed to take medications related to usual CF disease management (e.g. enzyme and vitamin supplementations, etc.). Patients with CF diagnosed with de novo CFRD underwent a second OGTT to confirm the diagnosis.

      2.2 Anthropometric data

      Genotype status was obtained from medical files. Pulmonary function was measured by spirometry on the day of the OGTT using predicted %FEV1 (Medgraphic 1870, St. Paul, MN, USA) as a variable. Pancreatic insufficiency was defined by current enzyme supplementation. Body weight was measured using an electronic scale (Tanita Corporation Arlington heights, IL, USA) and standing height by a wall stadiometer. BMI was calculated using weight in kilograms divided by height in square meter (kg/m2).

      2.3 Oral glucose tolerance test

      All subjects underwent a 2-h OGTT and both glucose and insulin levels were measured as described previously [
      • Coriati A.
      • Belson L.
      • Ziai S.
      • Haberer E.
      • Gauthier M.S.
      • Mailhot G.
      • et al.
      Impact of sex on insulin secretion in cystic fibrosis.
      ]. CF Patients included in the study were classified according to conventional criteria (ADA and CFF), based on their OGTT plasma glucose values, as having NGT (G0 ≤ 7.0 mmol/L and G2 ≤ 7.7 mmol/L), INDET (G0 ≤ 7.0 mmol/L and G2 ≤ 7.7 mmol/L, but G1 ≥ 11.1 mmol/L), impaired glucose tolerance (IGT; G0 ≤ 7.0 mmol/L and G2 ≥ 7.8 mmol/L, and ≤ 11.0 mmol/L) or de novo CFRD (G2 ≥ 11.1 mmol/L) [
      • Schmid K.
      • Fink K.
      • Holl R.W.
      • Hebestreit H.
      • Ballmann M.
      Predictors for future cystic fibrosis-related diabetes by oral glucose tolerance test.
      ].

      2.4 Biochemical measurements

      Plasma glycated hemoglobin (HbA1c) and inflammatory markers plasma fibrinogen and C-reactive protein (CRP) concentrations were determined as described previously [
      • Ode K.L.
      • Frohnert B.
      • Laguna T.
      • Phillips J.
      • Holme B.
      • Regelmann W.
      • et al.
      Oral glucose tolerance testing in children with cystic fibrosis.
      ].

      2.5 Glucose levels, insulin secretion and insulin sensitivity

      Insulin and glucose values during the OGTT were used to evaluate insulin sensitivity (Stumvoll index) and secretion, glucose levels as well as the disposition index using validated indices, as described previously [
      • Coriati A.
      • Belson L.
      • Ziai S.
      • Haberer E.
      • Gauthier M.S.
      • Mailhot G.
      • et al.
      Impact of sex on insulin secretion in cystic fibrosis.
      ].

      2.6 Statistical methods

      Values are expressed as median or mean ± SEM or SD. AUCs were calculated using the software GraphPad Prism for Windows. Statistical significance between the glucose tolerance groups was determined by 2-way ANOVA repeated measures and by Mann–Whitney T-Test as well as by Chi2 logistic regression for genotype status comparisons. SPSS for Windows was used for all statistical analyses (Version 17.0 SPSS, Chicago, IL) and a probability value ≤ 0.05 was considered as statistically significant.

      3. Results

      Patients included in this study were 25.9 ± 7.9 years old with a BMI of 21.8 ± 3.0 kg/m2 and a %FEV1 of 72.9 ± 21.4%. Pancreatic insufficiency was present in 80.8% of the patients and 46.4% of the CF cohort was homozygote for the ΔF508 mutation (Table 1).
      Table 1Physical and biochemical cohort characteristics and glucose homeostasis of adult patients with CF (n = 252).
      Total

      (N = 252)
      NGT

      (N = 99)
      INDET

      (N = 45)
      IGT

      (N = 66)
      De novo CFRD

      (N = 42)
      P value
      Sex (% women)46.446.535.659.138.10.056
      Age (years)25.9 ± 7.925.4 ± 7.326.4 ± 10.225.5 ± 7.427.1 ± 7.10.629
      Weight (kg)60.2 ± 11.161.1 ± 11.260.4 ± 11.559.4 ± 11.259.3 ± 10.30.723
      BMI (kg/m2)21.8 ± 3.021.9 ± 2.921.6 ± 2.721.8 ± 3.221.4 ± 3.10.813
      FEV1 (%)72.9 ± 21.475.9 ± 20.6 a66.6 ± 21.2b75.6 ± 21.1a67.6 ± 22.7b0.038
      CRP (mg/L)6.3 ± 7.05.7 ± 7.98.3 ± 6.45.7 ± 6.66.8 ± 6.00.279
      Pancreatic enzyme (% yes)80.873.577.883.397.60.010
      Chi2.
      ΔF508 homozygous (%)46.444.948.944.450.00.841
      Chi2.
      ΔF508 heterozygous (%)41.941.840.041.345.2
      Others11.713.311.114.34.8
      NGSP-HbA1c (%)5.8 ± 0.65.5 ± 0.4a5.7 ± 0.4a5.7 ± 0.5a6.4 ± 0.8b0.001
      IFCC-HbA1c (mmol/mol)4037393946
      Fasting plasma glucose (mmol/L)5.5 ± 0.85.2 ± 0.4a5.5 ± 0.5 b5.3 ± 0.7ab6.4 ± 1.2c0.001
      Fasting plasma insulin (μU/mL)10.7 ± 5.110.9 ± 5.410.4 ± 4.710.2 ± 4.711.3 ± 5.70.702
      1 h-OGTT plasma glucose (mmol/L)11.3 ± 3.18.8 ± 1.4a12.8 ± 1.5b11.7 ± 2.0c15.1 ± 3.5d0.001
      1 h-OGTT plasma insulin (μU/mL)53.3 ± 36.158.6 ± 34.4a61.8 ± 39.4a50.2 ± 38.6ab36.9 ± 25.7b0.004
      2 h-OGTT plasma glucose (mmol/L)8.1 ± 3.35.7 ± 1.1a6.3 ± 1.0a9.1 ± 0.9b13.9 ± 2.7c0.001
      2 h-OGTT plasma insulin (μU/mL)51.2 ± 37.446.0 ± 27.8a44.1 ± 22.2a64.3 ± 51.7b49.8 ± 37.9ab0.009
      Insulin sensitivity index0.074 ± 0.0300.088 ± 0.020a0.086 ± 0.016a0.064 ± 0.025b0.041 ± 0.026c0.001
      Abbreviation: FEV1, forced expiratory volume expired in 1 s. Mean and SDs are shown (±); P value was determined by 2-way ANOVA repeated measures and by Mann–Whitney T-Test to individually compare FEV1 between glucose tolerance groups (tolerance groups that do not share the same letter are statistically different from each other); NGT: normal glucose tolerance, INDET: indeterminate glucose tolerance, IGT: impaired glucose tolerance, CFRD: CF-related diabetes; NGSP: national glycohemoglobin standardization program; IFCC: international federation of chemical chemistry.
      Values in bold represent significant P values.
      low asterisk Chi2.
      When stratified by glucose tolerance, results showed that all groups were of similar age, BMI, genotype profile and inflammatory marker status (Table 1). Surprisingly, despite a tendency for a lower proportion of women in the INDET group (INDET 35.6%; NGT 46.5%; IGT 59.1% and CFRD 38.1%), this did not translate into a lower mean BMI for this sex category. In fact, we compared BMIs of women and men within as well as between glucose tolerance groups. We found no significant difference when comparing either men (P = 0.991) or women (P = 0.390) between glucose tolerance groups. Also, there was no difference when comparing men and women within each glucose tolerance group (P > 0.05). When comparing pulmonary function status, we found that there was a significant difference between groups (P = 0.038; Table 1). We noticed that, contrary to both the NGTs and the IGTs who display similar pulmonary function status, the INDETs were comparable to the de novo CFRDs as they presented lower pulmonary function NGT vs. INDET (P = 0.024), NGT vs. de novo CFRD (P = 0.023), INDET vs. IGT (P = 0.035), IGT vs. de novo CFRD (P = 0.045), NGT vs. IGT (P = 0.824) and INDET vs. de novo CFRD (P = 0.996). Also, we observed that this lowered pulmonary function observed in INDETs is not influenced by a subgroup of patients with significantly lower values (Suppl. Fig. 1).
      We then compared glucose and insulin homeostasis between groups. When examining the plasma glucose excursion during the OGTT, we observed that the INDETs displayed a trend, specifically at G1, more similar to the de novo CFRDs than the NGTs (Fig. 1A ). G0 of the INDETs was similar to the IGTs, but significantly lower than in the de novo CFRDs (P ≤ 0.001). G1 was statistically different in all groups and the INDET's average value is higher than IGTs and NGTs, but lower than in the de novo CFRD group (P ≤ 0.001). On the other hand, the insulin excursion curve of the INDETs was more closely comparable to the NGTs (Fig. 1B). Average 1-h OGTT insulin values (I1) of the INDETs were similar to the NGTs and IGTs, but higher than the de novo CFRDs (P = 0.004). When closely comparing insulin and glucose excursions between INDETs and IGTs, we noticed that during the first 30 min of the OGTT, INDETs had comparable levels of insulin as IGTs, but glucose excursion was higher in INDETs. During the next 30 min, insulin levels in INDETs continued to rise, however the rate of increase in insulin levels for IGTs was lower. Glucose levels continued to rise after 60 min in IGTs whereas in INDETs, their levels started decreasing reaching similar values as NGTs at the end of the OGTT. These observations suggest that during the first 30 min of the OGTT, the INDETs could be more insulin resistant (similar insulin secretion but higher glucose values) than IGTs but that their ability to secrete more insulin in the next 30 min allows a better glucose profile during the last OGTT hour. In contrast to what the first 30 min glucose and insulin profile suggest, overall estimated insulin sensitivity is higher for INDETs than IGTs (P ≤ 0.001) (Table 1). The disposition index (insulin secretion adjusted for insulin sensitivity) indicates that the INDET group displayed higher insulin sensitivity associated with higher insulin secretion as compared to the de novo CFRDs, but similar to the NGTs (Fig. 2). It should be noted that overall insulin sensitivity estimation using OGTT needs to be taken with caution as this surrogate measurement has not been fully validated in CF. Altogether, these observations suggest that none of the glucose or insulin indexes studied can explain the low, but comparable to the de novo CFRDs, pulmonary function observed in INDETs.
      Figure thumbnail gr1
      Fig. 1Plasma A) glucose and B) insulin excursions after a 1.75 g of glucose/kg of a 2 h-OGTT between glucose tolerance groups. Black dotted curve, normal glucose tolerance (NGT); black solid curve, de novo CF-related diabetes (CFRD); gray solid curve, impaired glucose tolerance (IGT); gray dotted curve, indeterminate glucose tolerance (INDET). (n = 252 adult patients with CF in total). Two-way ANOVA with repeated measures to determine the interaction between tolerance groups and A) glucose or B) insulin plasma values during OGTT (P < 0.001). Tolerance groups that do not share the same letter are statistically different from each other in which the P values represent the Mann–Whitney Student's T-Test (P < 0.05). *: for the de novo CFRD curve. Data are represented as ±SEM.
      Figure thumbnail gr2
      Fig. 2Disposition index: total insulin secretion index adjusted for insulin sensitivity index between glucose tolerance groups. AUC0–120 during OGTT reflects total insulin secretion index and insulin sensitivity index represent the Stumvoll index. NGT: normal glucose tolerance, INDET: indeterminate glucose tolerance, IGT: impaired glucose tolerance, CFRD: CF-related diabetes. n = 252 adult patients with CF in total. Data are represented as ±SEM.

      4. Conclusions

      Using a well-characterized large adult CF cohort, our data provided an important observation with potential clinical implications. We found that despite a similar age and BMI between glucose tolerance groups, INDETs displayed reduced pulmonary function at a similar level as newly diagnosed CFRDs. Because of the observed association between the pre-diabetic status and accelerated weight and lung function, it is important to study patients with INDET. However, not a lot of data is available about the INDET-CF status beside its association with future CFRD onset [
      • Schmid K.
      • Fink K.
      • Holl R.W.
      • Hebestreit H.
      • Ballmann M.
      Predictors for future cystic fibrosis-related diabetes by oral glucose tolerance test.
      ]. The exact causal factors responsible for the association between the INDET status and lower pulmonary function are unknown. Several non-CF studies have shown that the G1 can be an important predictive indicator of unfavorable health conditions in obesity and cardiovascular disease [
      • Moran A.
      • Brunzell C.
      • Cohen R.C.
      • Katz M.
      • Marshall B.C.
      • Onady G.
      • et al.
      Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society.
      ,
      • Brodsky J.
      • Dougherty S.
      • Makani R.
      • Rubenstein R.C.
      • Kelly A.
      Elevation of 1-hour plasma glucose during oral glucose tolerance testing is associated with worse pulmonary function in cystic fibrosis.
      ,
      • Manco M.
      • Miraglia Del Giudice E.
      • Spreghini M.R.
      • Cappa M.
      • Perrone L.
      • Brufani C.
      • et al.
      1-hour plasma glucose in obese youth.
      ,
      • Abdul-Ghani M.A1.
      • Abdul-Ghani T.
      • Ali N.
      • Defronzo R.A.
      One-hour plasma glucose concentration and the metabolic syndrome identify subjects at high risk for future type 2 diabetes.
      ,
      • Bianchi C.
      • Miccoli R.
      • Trombetta M.
      • Giorgino F.
      • Frontoni S.
      • Faloia E.
      • et al.
      Elevated 1-hour postload plasma glucose levels identify subjects with normal glucose tolerance but impaired β-cell function, insulin resistance, and worse cardiovascular risk profile: the GENFIEV study.
      ]. A recent report in CF suggests that G1 is probably “the most sensitive test”, but acknowledges the need for more evidence [
      • Waugh N.
      • Royle P.
      • Craigie I.
      • Ho V.
      • Pandit L.
      • Ewings P.
      • et al.
      Screening for cystic fibrosis-related diabetes: a systematic review.
      ].
      Our study is the first to provide detailed OGTT glucose and insulin values. Evidence supports a potential role for lower insulin (e.g. catabolic state) as well as higher glucose values (e.g. increased oxidative stress and pathogen growth) as important underlying factors explaining accelerated clinical deterioration associated with the pre-diabetic period [
      • Milla C.
      • Warwick W.
      • Moran A.
      Trends in pulmonary function in patients with cystic fibrosis correlate with the degree of glucose intolerance at baseline.
      ]. However, when comparing to the other glucose tolerance groups, none of the various parameters related to glucose excursion as well as insulin secretion and sensitivity could explain the observed lower pulmonary function in INDETs, suggesting that other factors could be involved. Nonetheless, because of their lower pulmonary function, indentifying INDETs is very useful. Hence, this group definitively requires further characterization in order to understand underlying factors. Interestingly, INDETs display similar weight than other tolerance groups while presenting lower pulmonary function. Conversly, it was previously reported that patients with high G1 benefit from insulin treatment to stabilize their BMI [
      • Moran A.
      • Pekow P.
      • Grover P.
      • Zorn M.
      • Slovis B.
      • Pilewski J.
      • et al.
      Insulin therapy to improve BMI in cystic fibrosis-related diabetes without fasting hyperglycemia: results of the cystic fibrosis related diabetes therapy trial.
      ]. Prospective data will thus be essential to investigate the temporal sequence of accelerated weight and/or lung function in INDETs.
      The present study has several limitations. Firstly, our observation is limited to patients with a homogenous French-Canadian background with a relatively good nutritional status, which could partly explain the lack of difference in pulmonary function between NTGs and IGTs. Our results are however strengthened by the use of a large well-characterized adult cohort in which both insulin and glucose values are available. Secondly, prospective studies are needed to establish the importance of G1 in predicting clinically relevant trends. Because of the complexity of the interactions among insulin insufficiency, infection-related hyperglycemia, and inflammation, it is probable that a single factor, glucose or insulin, might not explain a large proportion of the future risk for clinical deterioration. Thirdly, despite the lower proportion of women in the INDET group, we observed no difference in BMIs between men and women. Hence, we suggest that 1) our subgroups of men and women in each glucose tolerance groups might not be large enough to detect a difference or that 2) women with CF are healthier than men. Also, women with the worst clinical status have probably developed CFRD at the pediatric age, which excludes them from our observational cohort. Further studies should explore the INDET proportion of female patients as well as their nutritional status. Finally, over 59% of IGT patients also present a G1 > 11.0 mmol/L. However, when comparing IGT-CF patients with and without high G1, there was no difference in pulmonary function between these two subgroups (75.7% vs 75.2%, respectively; P = 0.667). Although a subgroup of IGT patients shared high G1 levels with INDET patients, it remains that they are two different clinical categories of CF patients with different overall OGTT glucose profiles and potentially other unidentified markers. Of those unidentified factors, bioclinical and inflammatory for instance, some might explain the observed differences in pulmonary function.
      In conclusion, adult INDET-CF patients present a lower pulmonary function at the level observed in the de novo CFRDs. Prospective studies are required to further identify clinically relevant outcomes.
      The following is the supplementary data related to this article.
      Figure thumbnail gr3
      Supplementary Fig. 1Scattergram of measured forced expiratory volume in 1 s as a percentage of predicted (%FEV1) against every glucose tolerance group in patients with CF. NGT: normal glucose tolerance, INDET: indeterminate glucose tolerance, IGT: impaired glucose tolerance, CFRD: CF-related diabetes. n = 252 adult patients with CF in total. Medians are represented for each glucose tolerance group.

      Funding

      This study is supported by the J-A DeSève chair for clinical research to RRL and by an operating team grant from the Canadian Cystic Fibrosis Foundation (#18608) to RRL and YB. AC holds the Michel Bélanger PhD scholarship from the Institut de Recherches Cliniques de Montréal (IRCM). RRL hold a scholarship from the Fonds de Recherche en Santé du Québec and SZ has a doctoral Banting and Best scholarship from the Canadian Institutes of Health Research.

      Declaration of interests

      No potential conflict of interest to declare.

      Author contributions

      R.R-L. and A.C. designed the study. A.C. wrote the manuscript. A.C. formatted the manuscript for the submission. A.C. analyzed data, conducted the literature search and drafted the manuscript. A.C. and S.Z. recruited subjects and collected data. M.A., S.Z., Y.B. and R.R-L. reviewed and edited the manuscript. As the corresponding author and guarantor of this article, R.R-L. takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript.

      Acknowledgments

      We thank the CF and diabetes clinic nurses for OGTT coordination.

      References

        • Grasemann H.
        • Ratjen F.
        Early lung disease in cystic fibrosis.
        Lancet Respir Med. Apr 2013; 1: 148-157https://doi.org/10.1016/S2213-2600(13)70026-2
        • Elborn J.S.
        Personalised medicine for cystic fibrosis: treating the basic defect.
        Eur Respir Rev. Mar 2013; 22: 3-5https://doi.org/10.1183/09059180.00008112
        • Simmonds N.J.
        • Cullinan P.
        • Hodson M.E.
        Growing old with cystic fibrosis — the characteristics of long-term survivors of cystic fibrosis.
        Respir Med. Apr 2009; 103: 629-635https://doi.org/10.1016/j.rmed.2008.10.011
        • Moran A.
        • Dunitz J.
        • Nathan B.
        • Saeed A.
        • Holme B.
        • Thomas W.
        Cystic fibrosis-related diabetes: current trends in prevalence, incidence, and mortality.
        Diabetes Care. 2009; 32: 1626-1631https://doi.org/10.2337/dc09-0586
        • Hameed S.
        • Morton J.R.
        • Jaffé A.
        • Field P.I.
        • Belessis Y.
        • Yoong T.
        • et al.
        Early glucose abnormalities in cystic fibrosis are preceded by poor weight gain.
        Diabetes Care. Feb 2010; 33: 221-226https://doi.org/10.2337/dc09-1492
        • Lanng S.
        • Thorsteinsson B.
        • Nerup J.
        • Koch C.
        Influence of the development of diabetes mellitus on clinical status in patients with cystic fibrosis.
        Eur J Pediatr. Sep 1992; 151: 684-687
        • Hammana I.
        • Coderre L.
        • Potvin S.
        • Costa M.
        • Berthiaume Y.
        • Lavoie A.
        • et al.
        Dichotomy between postprandial glucose and lipid profiles in adults with cystic fibrosis: a pilot study.
        J Cyst Fibros. Mar 2009; 8: 128-134https://doi.org/10.1016/j.jcf.2008.11.002
        • Costa M.
        • Potvin S.
        • Hammana I.
        • Malet A.
        • Berthiaume Y.
        • Jeanneret A.
        • et al.
        Increased glucose excursion in cystic fibrosis and its association with a worse clinical status.
        J Cyst Fibros. Nov 30 2007; 6: 376-383
        • Milla C.
        • Billings J.
        • Moran A.
        Diabetes is associated with dramatically decreased survival in female but not male subjects with cystic fibrosis.
        Diabetes Care. Sep 2005; 28: 2141-2144
        • Milla C.
        • Warwick W.
        • Moran A.
        Trends in pulmonary function in patients with cystic fibrosis correlate with the degree of glucose intolerance at baseline.
        Am J Respir Crit Care Med. Sep 2000; 162: 891-895
        • Canadian Diabetes Association Clinical Practice Guidelines Expert Committee
        Canadian Diabetes Association 2013 clinical practice guidelines for the prevention and management of diabetes in Canada.
        Can J Diabetes. 2013; 37: S1-S212
        • Moran A.
        • Brunzell C.
        • Cohen R.C.
        • Katz M.
        • Marshall B.C.
        • Onady G.
        • et al.
        Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society.
        Diabetes Care. Dec 2010; 33: 2697-2708https://doi.org/10.2337/dc10-1768
        • Brodsky J.
        • Dougherty S.
        • Makani R.
        • Rubenstein R.C.
        • Kelly A.
        Elevation of 1-hour plasma glucose during oral glucose tolerance testing is associated with worse pulmonary function in cystic fibrosis.
        Diabetes Care. Feb 2011; 34: 292-295https://doi.org/10.2337/dc10-1604
        • Schmid K.
        • Fink K.
        • Holl R.W.
        • Hebestreit H.
        • Ballmann M.
        Predictors for future cystic fibrosis-related diabetes by oral glucose tolerance test.
        J Cyst Fibros. Jan 2014; 13: 80-85https://doi.org/10.1016/j.jcf.2013.06.001
        • Ode K.L.
        • Frohnert B.
        • Laguna T.
        • Phillips J.
        • Holme B.
        • Regelmann W.
        • et al.
        Oral glucose tolerance testing in children with cystic fibrosis.
        Pediatr Diabetes. 2010 Nov; 11: 487-492https://doi.org/10.1111/j.1399-5448.2009.00632.x
        • Coriati A.
        • Belson L.
        • Ziai S.
        • Haberer E.
        • Gauthier M.S.
        • Mailhot G.
        • et al.
        Impact of sex on insulin secretion in cystic fibrosis.
        J Clin Endocrinol Metab. May 2014; 99: 1767-1773
        • Manco M.
        • Miraglia Del Giudice E.
        • Spreghini M.R.
        • Cappa M.
        • Perrone L.
        • Brufani C.
        • et al.
        1-hour plasma glucose in obese youth.
        Acta Diabetol. Dec 2012; 49: 435-443https://doi.org/10.1007/s00592-012-0384-3
        • Abdul-Ghani M.A1.
        • Abdul-Ghani T.
        • Ali N.
        • Defronzo R.A.
        One-hour plasma glucose concentration and the metabolic syndrome identify subjects at high risk for future type 2 diabetes.
        Diabetes Care. Aug 2008; 31: 1650-1655https://doi.org/10.2337/dc08-0225
        • Bianchi C.
        • Miccoli R.
        • Trombetta M.
        • Giorgino F.
        • Frontoni S.
        • Faloia E.
        • et al.
        Elevated 1-hour postload plasma glucose levels identify subjects with normal glucose tolerance but impaired β-cell function, insulin resistance, and worse cardiovascular risk profile: the GENFIEV study.
        J Clin Endocrinol Metab. 2013 May; 98: 2100-2105https://doi.org/10.1210/jc.2012-3971
        • Waugh N.
        • Royle P.
        • Craigie I.
        • Ho V.
        • Pandit L.
        • Ewings P.
        • et al.
        Screening for cystic fibrosis-related diabetes: a systematic review.
        Health Technol Assess. 2012; 16 ([1–179]): iii-ivhttps://doi.org/10.3310/hta16240
        • Moran A.
        • Pekow P.
        • Grover P.
        • Zorn M.
        • Slovis B.
        • Pilewski J.
        • et al.
        Insulin therapy to improve BMI in cystic fibrosis-related diabetes without fasting hyperglycemia: results of the cystic fibrosis related diabetes therapy trial.
        Diabetes Care. Oct 2009; 32: 1783-1788https://doi.org/10.2337/dc09-0585