S. Ziai

Agreement of bioelectric impedance analysis and dual-energy X-ray absorptiometry for body composition evaluation in adults with cystic fibrosis

Malnutrition in cystic fibrosis (CF) is associated with increased mortality and can lead to fat-free (FFM) and fat mass (FM) loss. Dual-energy X-ray absorptiometry (DXA) is used and validated to measure FFM and FM. DXAs high cost has led to the utilization of less costly techniques such as bioelectrical impedance analysis (BIA). The aim of this study was to determine the agreement of FFM, FM and %FM measurements taken with DXA and BIA in adults with CF. We measured FFM, FM and %FM in 34 adults with CF with a leg-to-leg BIA and an iDXA and determined agreement using Bland-Altman analysis. While DXA and BIA measurements were well correlated (r > 0.8), mean biases between both methods were between 8 and 11%. BIA underestimated FM and %FM and overestimated FFM. In a clinical research setting where these measurements are used to phenotype patients, BIA cannot replace DXA.

LDL-cholesterol and insulin are independently associated with body mass index in adult cystic fibrosis patients

BACKGROUND The median life expectancy of cystic fibrosis (CF) patients has increased dramatically over the last few years and we now observe a subset of patients with a body mass index (BMI) exceeding 25 kg/m(2). The aim of this study was to characterize these individuals and to identify factors associated with higher BMI. METHODS This is a cross sectional study including 187 adult CF subjects. Percent predicted forced expiratory volume in 1s (%FEV(1)), blood lipid profiles as well as fasting glucose and insulin levels were evaluated. Subjects also had an oral glucose tolerance test (OGTT) and the area under the curve (AUC) for glucose and insulin was calculated. CF subjects were then stratified according to the following BMI categories: underweight: BMI≤18.5 kg/m(2); normal weight: 18.5 kg/m(2)<BMI<25 kg/m(2); and overweight or obese: BMI≥25 kg/m(2). RESULTS Overweight subjects were older and less likely to have enzyme supplementation compared to the other two groups. Furthermore, this group exhibits higher levels of fasting insulin, total and LDL-cholesterol as well as insulin AUC. Further analyses demonstrated that BMI correlated with %FEV(1), fasting insulin, insulin AUC, total cholesterol, LDL-cholesterol and the ratio of HDL-cholesterol to total cholesterol and that %FEV(1), insulin AUC and LDL-cholesterol were independent associated with BMI. DISCUSSION Overweight CF subjects have higher fasting insulin and insulin AUC as well as total and LDL-cholesterol. Furthermore, we also demonstrated that LDL-cholesterol, insulin AUC are independently associated with BMI in a population of adult CF subjects.

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

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 2h-OGTT<7.8 mmol/L) in adult patients with cystic fibrosis (CF). METHODS All CF participants (n=252, ≥18 yrs without CFRD) underwent a 2h-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.

Hypertriglyceridemia is associated with insulin levels in adult cystic fibrosis patients

BACKGROUND Recent studies have identified hypertriglyceridemic cystic fibrosis patients (CF-TG). However, whether hypertriglyceridemia is associated with an altered metabolic profile remains unknown. OBJECTIVE To characterize CF-TG and determine whether triglycerides (TG) levels are associated with metabolic alterations. METHODS 210 adult CF subjects from the Montreal Cystic Fibrosis Cohort without known diabetes were included in the analysis. All subjects underwent an OGTT to assess glucose tolerance, insulin secretion (insulin AUC) and insulin sensitivity (Stumvoll index). Fasting lipid profiles, pulmonary function (%FEV1) and BMI were determined. Hypertriglyceridemia (TG>1.7mmol/L) was observed in 20 CF patients. These subjects were matched for age, sex and glucose tolerance category with 20 CF patients (CF-normal-TG) and 20 healthy controls that had TG levels below 1.7mmol/L. Pearson correlations were performed in the complete study sample (n=210) to examine the associations between TG levels and other parameters. RESULTS The prevalence of hypertriglyceridemia was 9.5%. Compared to CF-normal-TG, CF-TG subjects displayed significantly higher %FEV1, insulin AUC (AUC0-120, AUC0-30, AUC30-120), cholesterol levels and a higher ratio of total cholesterol to HDL-cholesterol. Pearson analysis demonstrated that TG levels were associated with BMI, %FEV1, fasting insulin, insulin AUC0-120 and AUC30-120, Stumvoll index, cholesterol levels and the ratio of total cholesterol to HDL-cholesterol. All these correlations remained significant after correction for BMI except %FEV1. CONCLUSION TG levels are associated with a mild alteration of the metabolic profile. Whether these changes will increase the long-term risk of CF patients in developing cardiometabolic complications remains to be investigated.

Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis

Cystic fibrosis-related diabetes (CFRD) is the most frequent complication of cystic fibrosis (CF) and associated with increased mortality. Why patients have an accelerated loss of lung function before the diagnosis of CFRD remains poorly understood. We reported that patients with or without CFRD had increased glucose excursions when compared to healthy peers. Studies have demonstrated that patients with CF have increased glucose fluctuations and hyperglycemia and that this may affect the clinical course of CF and lead to lymphocyte dysfunction. T-helper 17 (Th17) lymphocytes produce and secrete the pro-inflammatory cytokine IL-17. The Th17 pathway is involved in CF lung inflammation, β-cell destruction in type 1 diabetes (T1D) and Th17 cells of patients with type 2 diabetes have increased production of IL-17 when compared to healthy peers. Also, regulatory T-cells (Tregs) have been shown to be dysfunctional and produce IL-17 in T1D. Furthermore, vitamin D can affect inflammation in CF, diabetes and the differentiation of lymphocytes. In this review, we discuss the potential roles of hyperglycemia on Th17 cells, Tregs and IL-17 as a potential cause for accelerated lung function decline before CFRD and how this could be modulated by vitamin D or by directly intervening in the IL-17A pathway.

Diagnosis of cystic fibrosis-related glucose abnormalities: Can we shorten the standard oral glucose tolerance test?

Adult patients with cystic fibrosis (APCF) are at high risk of developing impaired glucose tolerance (IGT) and CF-related diabetes (CFRD) and thus an annual screening with a 2-h oral glucose tolerance test (OGTT) is recommended. This population would greatly benefit from a simplified and harmless alternative to the standard OGTT. Thus, we aimed to compare the diagnostic values of HbA1c and glycemias at interval time points during the 2-h OGTT for IGT and CFRD detection in APCF. To do so, we conducted a cross-sectional analysis of 194 APCF with normal fasting plasma glucose values (≤ 7.0 mmol · L(-1)) who underwent a 2-h OGTT. Receivers operating characteristic area under the curves (ROC-AUC) were analyzed to assess the diagnostic value of HbA1c and intermediate OGTT glycemias using 2-h OGTT glycemia as reference. For both IGT and CFRD diagnoses, ROC-AUC values obtained from glycemia at 90 min were significantly higher than HbA1c and remaining intermediate glycemias (p < 0.001). The best 90-min OGTT cut-off values for these diagnoses were >9.3 mmol · L(-1) (IGT) and ≥ 11.5 mmol · L(-1) (CFRD). A 90-min OGTT glycemia might be a simplified alternative to 2-h OGTT glycemia for earlier glucose tolerance abnormalities diagnosis in APCF. This finding should be confirmed in other APCF cohorts and its predictive value should be established prospectively.

Variation of glucose tolerance in adult patients with cystic fibrosis: What is the potential contribution of insulin sensitivity?

BACKGROUND Reduced insulin secretion is a key factor to explain high prevalence of glucose intolerance in patients with cystic fibrosis (CF). However, the role of insulin sensitivity remains unclear. The aim of this study is to investigate the association of insulin secretion and sensitivity with the evolution of glucose tolerance. METHODS A total of 152 patients without known diabetes from the Montreal CF cohort underwent two 2-h oral glucose tolerance tests (OGTT) at baseline and again after 21.2±5.5months. Pulmonary function and anthropometric measurements were also collected at each visit. At both visits, based on their OGTT results, patients were categorized in glucose tolerance groups (normal glucose tolerance, impaired glucose tolerance or CF-related diabetes) and stratified in 3 groups according to the variation of their glucose tolerance: stable, improved or deteriorated. RESULTS At baseline, patients in the deteriorated group had a better sensitivity to insulin than those in the improved group (P=0.029). At follow-up glucose tolerance remained stable in 55.3%, improved in 14.5% and deteriorated in 30.3% of patients. During follow-up, insulin secretion remained stable in all 3 groups. While insulin sensitivity remained stable in patients without changes in glucose tolerance it worsened in patients who deteriorated glucose tolerance (P<0.001) and improved in patients who improved their glucose tolerance (P=0.003). CONCLUSION In a context of significantly reduced insulin secretion, variations of insulin sensitivity are associated with variations of glucose tolerance in adult patients with CF.

Normal total and high molecular weight adiponectin levels in adults with cystic fibrosis.

Cystic fibrosis related diabetes (CFRD) is an important complication of CF that increases mortality. Adiponectin, an adipokine secreted from adipose tissue, plays an important role in fatty acid and glucose metabolism. Lower total adiponectin (TA) levels have been linked to the risk of developing type 2 diabetes. However, studies show that the high molecular weight isoform (HMW), thought to be more active than TA, might be a better indicator of insulin sensitivity. Our aim was to determine the association between HMW and insulin sensitivity in CF subjects and determine if other factors might modulate its levels. Thirteen control subjects and 47 CF adults (16 with normal glucose tolerance, 16 prediabetic and 15 with CFRD) underwent an oral glucose tolerance test. Blood samples were taken at time 0, 30, 60, 90 and 120 min. Body mass index, fibrinogen, glucose and insulin, TA and HMW were measured in every subject. Regression analysis was used to determine the association between TA, HMW and glucose (fasting glucose, 2h glucose and glucose AUC) as well as insulin (fasting insulin, insulin AUC, and Stumvoll insulin sensitivity index) parameters. TA and HMW levels were similar between CF patients and controls and were not associated to insulin sensitivity. TA was negatively associated to insulin AUC (p=0.0108) and 2h glucose (p=0.0116) in controls while these relationships were either weakly negative (p=0.0208) or weakly positive (p=0.0105) in CF patients. Also, HMW was negatively associated to insulin (p=0.00301) and glucose AUC (p=0.0546) in controls whereas these associations were positive in CF patients (p=0.0388, p=0.0232 respectively). In conclusion, our exploratory study on HMW adiponectin demonstrated similar levels of TA and HMW between CF patients and controls and different relationships between forms of adiponectin to glucose metabolism and insulin in CF.

Glucose Fluctuations are Not Modulated by the Proportion of Calories from Macronutrients or Spontaneous Total Energy Expenditure in Adults with Cystic Fibrosis

OBJECTIVES To determine the modifiable factors affecting glucose variability in people with cystic fibrosis (CF). CF-related diabetes (CFRD) is the most common complication of CF, and its presence increases morbidity and mortality in patients. Patients with CF (with and without CFRD) have potentially harmful glucose fluctuations and glucose excursions when compared to healthy adults. Carbohydrate intake and exercise have been shown to affect glycemia. Therefore, our hypothesis was that the proportion of energy from carbohydrates and total energy expenditure (TEE) would influence glucose fluctuations in adults with CF. METHODS A cross-sectional study involved 36 patients with CF, in whom continuous glucose monitoring systems were installed. Glucose fluctuations were then quantified using 3 indexes: mean amplitude of glucose excursions, standard deviation and coefficient of variation. Patients filled out a 3-day food diary to quantify energy intake and the proportions of calories from carbohydrates, fats and proteins, and they wore Sensewear Armbands to estimate spontaneous TEE and footsteps walked. Glucose tolerance status was determined using oral glucose tolerance tests. RESULTS Patients with CF with normal and impaired glucose tolerance had fewer glucose fluctuations than patients with CFRD (p<0.05). However, linear regression models used to determine whether nutrition or energy expenditure affects glucose fluctuations demonstrated that energy, the proportion of carbohydrates, of fat and of protein, TEE or the number of footsteps walked did not affect glucose fluctuation indexes (p>0.05). CONCLUSIONS TEE and the proportion of energy from carbohydrates did not affect glucose fluctuations in adults with CF.

The association between leptin and insulin levels in adults with cystic fibrosis

UNLABELLED Cystic fibrosis (CF)-related diabetes is an important complication of CF caused by a decrease in insulin secretion that is associated with weight loss, poor nutritional status and increased mortality. Leptin, a hormone secreted from white adipose tissue, has an important role in energy homoeostasis by inhibiting food intake and increasing energy expenditure. Leptin secretion can be increased by nutrient signals such as insulin. AIMS Considering that leptin plays a role in energy homoeostasis and that CF is associated to poor weight gain and decreased insulin secretion, leptin levels in CF patients with different glucose tolerances were investigated and compared with those of healthy control subjects. METHODS Two-hour oral glucose tolerance tests (OGTT) were performed in 82 patients with CF and various glucose tolerances as well as in 17 healthy control subjects during which blood was withdrawn every 30 min to measure glucose and insulin. Fasting leptin, fibrinogen and fat mass were also measured, and body mass index (kg/m(2)) calculated for all participants. Early and late insulin secretion was separated by calculating the area under the curve from time 0 to 30 min and 30 to 120 min of the OGTT (AUC(0-30) and AUC(30-120)). RESULTS Leptin levels were comparable between CF patients and healthy control subjects. Interestingly, correlations were observed between leptin levels and insulin (AUC(0-120) and AUC(30-120)) after adjusting for gender and fat mass (P<0.05). CONCLUSION This study suggests a potential role of insulin in regulating leptin levels in adults with stable CF.