Glucose intolerance and diabetes during cystic fibrosis

As a result of the improvement in life-expectancy in cystic fibrosis patients, simultaneous presence of cystic fibrosis and diabetes mellitus is no longer exceptional. In teenagers and young adults with cystic fibrosis, the prevalence of insulin-dependent diabetes mellitus (IDDM) is 7 to 10%. Fifty percent of cystic fibrosis patients have impaired glucose tolerance. These prevalences increase with advancing age. Insulin deficiency is a consistent feature. An endocrine pancreatic deficiency thus exists in addition to the exocrine pancreatic deficiency, as demonstrated by the fall in glucagon and pancreatic polypeptide productions. Development of insulin dependency is associated with deterioration in clinical status and indicates an adverse prognosis. Although in cystic fibrosis patients diabetes mellitus seems to occur as a result of different pathophysiologic mechanisms than those involved in autoimmune IDDM, the risk of degenerative complications is similar in both conditions. It follows that early detection of diabetes mellitus and appropriate insulin treatment are warranted in cystic fibrosis patients.     

Cystic fibrosis-related diabetes mellitus: clinical impact of prediabetes and effects of insulin therapy

In patients with cystic fibrosis (CF), glucose intolerance preceding diabetes (prediabetes) may have adverse effects on nutritional status and respiratory function, which are reversible after the start of insulin therapy. Respiratory function (forced vital capacity and forced expiratory volume in one second) and body mass index (BMI) were compared retrospectively in a French cohort of 14 patients during the 5 y preceding insulin therapy for diabetes and in 14 age- and sex-matched controls with normal oral glucose tolerance tests. In the diabetic group, all three parameters deviated increasingly from the values in the controls; the differences became statistically different during the 6 mo before insulin therapy. The effect was more important in patients for whom diabetes mellitus was diagnosed on the basis of symptoms of hyperglycaemia than in patients for whom it was diagnosed by systematic screening, but still present in the latter. After insulin was started, respiratory function improved and the BMI returned to normal within 1 y. The annual insulin requirement increased from 0.62 during the first year to 1.25 during the fifth year. Glycosylated haemoglobin (HbA_Ic) values ranged from 6.6 to 7.8%. Only 2 episodes of severe hypoglycaemia were recorded over 42 patient-years of follow-up. The insulin regimen most often used was two daily injections of a mixture of short- and intermediate-acting insulin (n = 10) given with an insulin pen.     

Influence of the development of diabetes mellitus on clinical status in patients with cystic fibrosis

The impact of pre-diabetes on clinical status was retrospectively studied in 38 cystic fibrosis (CF) patients with diabetes mellitus (DM) and 38 non-diabetic CF patients (control patients), matched in pairs for age, sex, and chronicPseudomonas aeruginosa lung infection. Quarterly parameters of CF clinical status were collected for 6 years prior to the diagnosis of DM in the index case. Compared to the control patients, decreases in body weight, body mass index (BMI), forced expiratory volume in 1s (FEV₁), and forced vital capacity (FVC) and an increase in the daily intake of pancreatic enzyme capsules were found in the pre-diabetic patients. Statistically significant differences in body weight, BMI, FEV₁, FVC, and intake of pancreatic enzyme capsules between pre-diabetic and control patients emerged 4, 4, 1.25, 3 and 4.5 years prior to the diagnosis of DM, respectively. The number of lung infections did not differ between the two groups of patients. Thus, when DM develops in CF patients, an insidious decline in overall clinical status is observed for years prior to its diagnosis. Whether clinical deterioration in CF leads to DM, or pre-diabetes results in declining CF clinical status is presently unknown. Accumulating evidence suggests that the latter may be the case since insulin therapy seems to improve lung function in CF.     

Diabetes mellitus in cystic fibrosis: effect of insulin therapy on lung function and infections

The effect of insulin therapy on lung function and lung infections was studied in a retrospective case-control design in 18 diabetic cystic fibrosis (CF) patients; 18 non-diabetic CF patients, matched for sex, age and presence of chronic Pseudomonas aeruginosa lung infection. served as controls. Parameters of CF clinical status were collected for six years before and two years after the onset of insulin therapy in the diabetic patients. Before onset of insulin therapy, body mass index (BMI) and forced vital capacity (FVC) in (pre)diabetic patients deviated increasingly from those in control patients. Decreases in BMI and lung function during the past three months before onset of insulin therapy were reverted within three months of insulin therapy. From three months to two years after onset of insulin therapy, differences in BMI and lung function diminished between diabetic and control patients. After two years of insulin therapy, BMI was similar in diabetic and non-diabetic patients and the percentage differences in forced expiratory volume in 1s (FEV₁) and FVC between the two groups were similar to those found six years before the onset of insulin therapy. The finding that insulin therapy improves lung function in diabetic CF patients suggests strongly that the insidious decline in lung function seen during the years before the diagnosis of diabetes mellitus results from the pre-diabetic condition. After onset of insulin therapy, the percentages of sputum examinations positive for Haemophilus infuenzae and Streptococcus pneumoniae decreased in the diabetic patients, whereas parameters of lung infections with P. aeruginosa and Staphylococcus aureus remained unchanged. In conclusion, since insulin therapy improves lung function and reduces the number of infections with H. influenzae and S. pneumoniae in diabetic CF patients, we suggest that insulin therapy should be started when diabetes mellitus is diagnosed.     

Evaluation of growth and changes in body composition following neonatal diagnosis of cystic fibrosis

Early deficits in nutritional status that might require specific treatment and early response to nutritional therapy were studied longitudinally in 25 infants with cystic fibrosis (CF) diagnosed by neonatal screening, using anthropometric and research body composition methodology, and evaluation of pancreatic function. At the time of confirmed diagnosis (mean 5.4 weeks), body mass, length, total body fat (TBF), and total body potassium (TBK) were all significantly reduced. Following diagnosis and commencement of therapy there was a normalization of weight, length, and TBK by 6-12 months of age, indicating catch-up growth. But in some individuals the response was incomplete, and as a group, mean total body fat remained significantly lower than normal at 1 year of age. Seven of 25 (28%) were pancreatic sufficient at diagnosis, and all but one had evidence of declining pancreatic function requiring the institution of pancreatic enzyme therapy during the next 1-9 months. The median age of commencement of enzyme therapy was 10 weeks (range 5 weeks to 11 months). These longitudinal assessments emphasize the dynamic changes occurring in absorptive function, body composition, and nutritional status following neonatal diagnosis of cystic fibrosis and may reflect previously described abnormalities of energy metabolism in this age group. Abnormal body composition is evident in most CF infants following diagnosis by neonatal screening but pancreatic damage may still be evolving. We suggest that early active nutritional therapy and surveillance for changes in pancreatic function are warranted in CF infants diagnosed by neonatal screening.     

Verbesserung der Glukosetoleranz von Patienten mit Zystischer Fibrose unter pseudomonaswirksamer Chemotherpie

Background. For many patients with cystic fibrosis impaired glucose tolerance or even diabetes mellitus is becoming relevant with growing age. The influence of an anti-Pseudomonas chemotherapy on glucose homeostasis of cystic fibrosis patients was investigated. Patients and methods. In fourteen cystic fibrosis patients aged between 7 and 35 years glucose tolerance was tested by standard oral glucose tolerance test in the beginning and at the end of a routine anti-Pseudomonas chemotherapy of fourteen days. Beside the blood glucose serum insulin was determinated. Results. According to the criteria of the American Diabetes Association three of the fourteen patients had an impaired glucose tolerance and another three had diabetes mellitus when tested at the beginning of anti-Pseudomonas chemotherapy. In four of these six patients glucose tolerance was normal at the end of the chemotherapy. Of the remaining two patients one fulfilled the criteria for impaired glucose tolerance and one for diabetes mellitus. In these patients insulin secretion was lower in the second test. Peak insulin was reached earlier while there was no significant improvement of early insulin response. Conclusion. The treatment of chronic airway infection in cystic fibrosis patients with impaired glucose tolerance or diabetes mellitus results in an improvement of glucose homeostasis by a better insulin sensitivity and less by improvement of early insulin response. In developing diagnostic protocols for screening of cystic fibrosis-related diabetes mellitus the impact of the concomitant therapy on glucose homeostasis should be considered.     

Energy expenditure of patients with cystic fibrosis

Resting energy expenditure was measured by open-circuit indirect calorimetry in 71 patients, aged 8.9 to 35.5 years, with cystic fibrosis who had no recent history of acute lung infection. Pulmonary function and nutritional status were studied simultaneously. In most patients, resting energy expenditure was above normal (range 95% to 153% of predicted values for age, sex, and weight as derived from the Harris Benedict equations), and was negatively correlated with pulmonary function (P less than 0.01) and nutritional status (P less than 0.01) when expressed as a percentage of body fat. Pulmonary status was positively correlated with nutritional status (P less than 0.01). We conclude that resting energy expenditure in patients with cystic fibrosis exceeds normal values and that the increase correlates with a deterioration in lung function and nutritional status.     

Diabetes mellitus in patients with cystic fibrosis: effect on survival

Patient data obtained from the cystic fibrosis clinic of the Hospital for Sick Children (Toronto, Canada) over the period 1977 to 1988 were analyzed to compare the diabetic and nondiabetic cystic fibrosis patients. The pulmonary function, nutritional status, and survival data for 713 patients who attended the clinic over the 11-year period are reported. Insulin-dependent diabetes was found to exist in 37 (5.2%) of 713 patients. The patient age at time of diabetes diagnosis ranged from 2 to 34 years, with a mean +/- SD of 20.0 +/- 7.4 years. Patients who died in both the diabetic and nondiabetic groups had worse pulmonary and nutritional status than the surviving patients, but there were no significant differences between the diabetic and nondiabetic groups in those who died or in those who remained alive. Survival analysis showed a similar prognosis in the diabetic and nondiabetic groups. It is concluded that cystic fibrosis patients with diabetes are, for their age, not different from patients without diabetes with respect to pulmonary function, nutritional status, and survival.     

Relation between insulin-like growth factor-I,body mass index, and clinical status in cystic fibrosis

Accepted 26 October 1996
OBJECTIVES—Despite improved nutrition and intensive treatment, subjects with cystic fibrosis have difficulty in maintaining anabolism during intercurrent infections, which can result in reduced body mass index and impaired skeletal growth. Insulin-like growth factor-I (IGF-I) and its binding protein IGFBP3 are sensitive to changes in nutritional status. The aim of this study was to determine the relation between circulating concentrations of these peptides, body mass index, and clinical status in cystic fibrosis.
METHODS—Serum concentrations of IGF-I and IGFBP3 were measured in 197 subjects (108 males, 89 females; mean age 9.69 years, range 0.41-17.9 years) and these data were analysed with respect to body mass index, pubertal stage, and clinical status as assessed by Shwachman score and forced expiratory volume in one second (FEV₁ ).
RESULTS—The mean height SD score of the children studied was −0.2 (SD 1.14) and the body mass index SD score −0.26 (1.4). The body mass index SD score declined with increasing age (r=−0.18) and paralleled changes in IGF-I concentrations, which also declined. The IGF-I SD score (calculated from control data) correlated with age (r=−0.53). The abnormalities were most obvious during late puberty, when IGF-I and IGFBP3 concentrations were significantly reduced compared with those in control subjects matched for pubertal stage. The IGF-I SD score correlated with height SD score (r=0.14) and the decline in IGF-I concentrations with the fall in body mass index SD score (r=0.42). IGF-I SD scores also correlated with the Shwachman score (r=0.33) and FEV₁ (r=0.17).
CONCLUSIONS—The close relation between declining IGF-I and IGFBP3 concentrations and body mass index in patients with cystic fibrosis may simply reflect poor nutritional status and insulin hyposecretion. Nevertheless, IGF-I deficiency could also contribute towards the catabolism observed in these patients, and IGF-I SD scores correlated with other measures of clinical status such as the Shwachman score and FEV₁.

• The fall in body mass index with increasing age in children with cystic fibrosis parallels the decline in concentrations of IGF-I and its principal binding protein, IGFB3 • The close relation between body mass index and IGF-I concentrations in cystic fibrosis may reflect poor nutrition or insulin hyposecretion • Nevertheless, low IGF-I concentrations may contribute directly to the fall in body mass index with increasing age     

Relation between insulin-like growth factor-I, body mass index, and clinical status in cystic fibrosis

OBJECTIVES: Despite improved nutrition and intensive treatment, subjects with cystic fibrosis have difficulty in maintaining anabolism during intercurrent infections, which can result in reduced body mass index and impaired skeletal growth. Insulin-like growth factor-I (IGF-I) and its binding protein IGFBP3 are sensitive to changes in nutritional status. The aim of this study was to determine the relation between circulating concentrations of these peptides, body mass index, and clinical status in cystic fibrosis. METHODS: Serum concentrations of IGF-I and IGFBP3 were measured in 197 subjects (108 males, 89 females; mean age 9.69 years, range 0.41-17.9 years) and these data were analysed with respect to body mass index, pubertal stage, and clinical status as assessed by Shwachman score and forced expiratory volume in one second (FEV1). RESULTS: The mean height SD score of the children studied was -0.2 (SD 1.14) and the body mass index SD score -0.26 (1.4). The body mass index SD score declined with increasing age (r = -0.18) and paralleled changes in IGF-I concentrations, which also declined. The IGF-I SD score (calculated from control data) correlated with age (r = -0.53). The abnormalities were most obvious during late puberty, when IGF-I and IGFBP3 concentrations were significantly reduced compared with those in control subjects matched for pubertal stage. The IGF-I SD score correlated with height SD score (r = 0.14) and the decline in IGF-I concentrations with the fall in body mass index SD score (r = 0.42). IGF-I SD scores also correlated with the Shwachman score (r = 0.33) and FEV1 (r = 0.17). CONCLUSIONS: The close relation between declining IGF-I and IGFBP3 concentrations and body mass index in patients with cystic fibrosis may simply reflect poor nutritional status and insulin hyposecretion. Nevertheless, IGF-I deficiency could also contribute towards the catabolism observed in these patients, and IGF-I SD scores correlated with other measures of clinical status such as the Shwachman score and FEV1.     

Glucose intolerance in cystic fibrosis patients

Diabetes mellitus has evolved as a complication because of increased longevity of patients with cystic fibrosis (CF). CF-related diabetes (CFRD) is associated with increased morbidity and mortality, therefore, prompt diagnosis and aggressive management are important.The prevalence of CFRD increases with age with an age-dependent incidence rate of 5% per year; at 30 years 50% of patients are diabetic. CFRD develops insidiously. Screening by measurements of fasting, random plasma glucose or glycated haemoglobin A(1c), alone or in combination, do not reliably identify CFRD as compared with the 2-hour plasma glucose value measured during an oral glucose tolerance test.Reasons for the development of CFRD are not fully understood. Generally, patients are characterised by the presence of a class I, II or III CF mutation, exocrine pancreatic insufficiency, impaired and delayed insulin secretion, impaired glucagon secretion, normal insulin sensitivity and an increased insulin clearance rate. One can speculate that for endocrine dysfunction to deteriorate from normal to impaired glucose tolerance and then to CFRD, there must be an additional diabetes mellitus-related genetic defect.CFRD leads to deterioration of overall clinical CF status but insulin therapy can revert this. Late diabetic complications may develop as in other types of diabetes although macrovascular complications are rare. CFRD patients have an increased mortality compared to non-diabetic CF patients. Insulin therapy is the preferred treatment.     

Cystic fibrosis related diabetes

Diabetes is a frequent complication seen in cystic fibrosis patients as they reach adulthood. Cystic fibrosis related diabetes (CFRD) is distinguished as a separate entity with features that include progressive loss of islet beta cell mass and insulin deficiency, as well as insulin resistance. Abnormalities in glucose tolerance may be detectable for many years prior to the development of overt diabetes. Therefore oral glucose tolerance testing is the preferred screening method for the identification of those patients at the highest risk for progression to diabetes. Progression to diabetes has been linked to poor outcomes in CF including loss of pulmonary function and increased mortality among females. Given the role that insulin deficiency plays in CFRD, insulin replacement therapy remains the only recommended intervention. In the absence of definitive supportive data, the use of oral antidiabetic agents is not considered standard therapy and needs further study. As with other forms of diabetes, CFRD patients also experience microvascular complications and should be periodically evaluated for manifestations.     

Factors affecting diabetes mellitus onset in cystic fibrosis: evidence from a 10-year follow-up study

This study reports the results of genotype characterization and of a 10-y prospective evaluation of clinical status, glucose tolerance and insulin secretion in 28 originally normoglycaemic patients with cystic fibrosis (CF). The aim of the study was to assess whether any genetic, clinical or metabolic parameters could identify in advance those patients at risk of developing diabetes mellitus over time. During the follow-up 42.8% of patients became diabetic. Neither gender, age nor clinical parameters were significantly different at entry in the patients who eventually developed diabetes compared with those who did not. Insulin secretion during oral glucose tolerance tests (OGTT) deteriorated over time in both groups, whereas a progressive deterioration of glucose tolerance was only evident in the patients who developed diabetes and increased baseline glucose areas were the only predictive parameter of diabetes onset. Genotype analysis revealed significant differences between patients with and without diabetes: ΔF508 homozygosis was more frequent in the first group and N1303K mutation in the second group. In conclusion, in CF: (i) increased glucose areas during OGTT and deterioration of glucose tolerance over time can predict the evolution towards diabetes; and (ii) ΔF508 homozygosis may predispose to the risk of diabetes, whilst N1303K mutation seems to play a protective role.     

Effects of tolbutamide on growth and body composition of nondiabetic children with cystic fibrosis

Previously, we reported that nondiabetic children with cystic fibrosis show a blunted insulin response to a meal stimulus. In the study presented here, using tolbutamide, we determined the effects of augmented insulin secretion/action on height and lean body mass of children with cystic fibrosis. Twelve subjects (mean +/- SEM age, 11.0 +/- 0.5 y) were studied for three 4-mo periods: 1) pretreatment, 2) treatment, consisting of 750 mg/d of tolbutamide, and 3) posttreatment. Before the pretreatment period, insulin response to a meal stimulus was evaluated in relation to three doses of tolbutamide: 0, 250, and 500 mg. Growth was monitored during each period, and incremental changes in lean body mass were calculated from height data. To validate the change in lean body mass based on height measurements, we determined lean body mass in seven subjects during the treatment period by using a criterion method (H218O). Growth velocity (cm/4 mo) significantly increased (p less than 0.05) during the treatment (2.58 +/- 0.31) compared with the pretreatment period (0.88 +/- 0.20). The increase in lean body mass calculated from height was greater during the treatment (1.61 +/- 0.29 kg/4 mo) than during the pretreatment period (0.44 +/- 0.18 kg/4 mo) (p less than 0.05). There was also a significant increase (p less than 0.05) in lean body mass during the treatment as measured with H218O (1.91 +/- 0.65 kg/4 mo). Acute administration of either 250 or 500 mg of tolbutamide reduced (p less than 0.05) the area under the glucose concentration curve in response to a meal compared with the control condition of no tolbutamide.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pancreatic islets in older patients with cystic fibrosis with and without diabetes mellitus: morphometric and immunocytologic studies

Forty patients with cystic fibrosis (CF), including 34 who died above age 10 years without having developed clinical diabetes mellitus and 6 who died with both cystic fibrosis and diabetes mellitus, were studied. The mean age of the female patients with CF but not diabetes was 15.8 +/- 5.6 years; of males without diabetes, 17.2 +/- 6.4 years; of female patients with CF and diabetes mellitus, 20.2 +/- 6.9 years; and of males with CF and diabetes, 21.3 +/- 6.6 years. The mean number of pancreatic islets in microscopic sections for patients with cystic fibrosis but not diabetes was 4.18 +/- 2.76/mm2, and the value for patients with both cystic fibrosis and diabetes mellitus was 2.61 +/- 2.07/mm2. The lowest density of pancreatic islets (1.69 +/- 0.48/mm2) for cystic fibrosis was found in patients with the latest-stage pathologic lesion. Nesidioblastosis (presence of ductuloinsular complexes) was identified in 14 of 38 cystic fibrosis patients, both with and without diabetes mellitus. The pancreatic islets of both diabetic and nondiabetic patients with CF showed hypertrophy; the mean volume of the three largest pancreatic islets for CF only was 0.0117 +/- 0.00657 mm3 and that for cystic fibrosis and diabetes was 0.00795 +/- 0.00599 mm3, both values being larger than normal. Ratios of the amounts of islet endocrine cells, A cells, B cells, and D cells, were determined by peroxidase--anti-peroxidase labeled antibody staining. The B cells composed 43.0% of endocrine cell mass in cystic fibrosis alone and 30.1% in cystic fibrosis with diabetes mellitus, which were lower than normal proportions. The D cell values, 11.9% in cystic fibrosis and 15.1% in cystic fibrosis with diabetes mellitus, on the other hand, were greater than normal ratios.     

Glucose tolerance in cystic fibrosis.

Glucose tolerance was evaluated in 356 living and dead patients with cystic fibrosis who were recorded at the Danish Cystic Fibrosis Centre. Twenty two patients (6%) were treated elsewhere, 25 (7%) were unable, unwilling or too young (age less than 2 years) to participate; 309 patients (87%) were therefore eligible for the study of whom 99 (32%) were dead and 210 (68%) were alive. Of the dead patients, 13 also had diabetes mellitus (13%). Of the living patients (median age 14 years, range 2-40), nine (4%) were known to have diabetes and all were being treated with insulin. In the remaining 201 patients an oral glucose tolerance test (1.75 g/kg body weight, maximum 75 g) was carried out. A total of 155 patients (74%) had normal glucose tolerance, 31 (15%) had impaired glucose tolerance, and 15 (7%) had diabetes mellitus according to the WHO criteria. The percentage of glycated haemoglobin (HbA1c) (reference range 4.1-6.4%) increased significantly as glucose tolerance decreased: when glucose tolerance was normal the median was 5.2%; when it was impaired the figure was 5.5%; in patients whose diabetes was diagnosed by the oral glucose tolerance test it was 5.9%; and in patients already known to have diabetes mellitus it was 8.6%. The incidence and prevalence of impaired glucose tolerance and diabetes mellitus increased with age. From the age of 15 to 30 years the decrease in the prevalence of normal glucose tolerance was almost linear. Within this age span the proportion of patients with cystic fibrosis with normal glucose tolerance was reduced by roughly 5%/year. Only 35% (95% confidence interval (CI) 22 to 48%) of the patients with cystic fibrosis who were alive at the age of 25 years had normal glucose tolerance; 32% (95% CI 14 to 49%) were diabetic. The prevalence of glucose intolerance in cystic fibrosis is rapidly increasing with age; its potentially harmful effect on the prognosis of cystic fibrosis is of increasing importance as the length of survival of these patients increases.     

Pancreatic Islets in Older Patients with Cystic Fibrosis with and without Diabetes Mellitus: Morphometric and Immunocytologic Studies

Forty patients with cystic fibrosis (CF), including 34 who died above age 10 years without having developed clinical diabetes mellitus and 6 who died with both cystic fibrosis and diabetes mellitus, were studied. The mean age of the female patients with CF but not diabetes was 15.8± 5.6 years; of males without diabetes, 17.2± 6.4 years; of female patients with CF and diabetes mellitus, 20.2± 6.9 years; and of males with CF and diabetes, 21.3± 6.6 years. The mean number of pancreatic islets in microscopic sections for patients with cystic fibrosis but not diabetes was 4.18± 2.76/mm², and the value for patients with both cystic fibrosis and diabetes mellitus was 2.61± 2.07/mm². The lowest density of pancreatic islets (1.69± 0.48/mm²) for cystic fibrosis was found in patients with the latest-stage pathologic lesion. Nesidioblastosis (presence of ductuloinsular complexes) was identified in 14 of 38 cystic fibrosis patients, both with and without diabetes mellitus. The pancreatic islets of both diabetic and nondiabetic patients with CF showed hypertrophy; the mean volume of the three largest pancreatic islets for CF only was 0.0117± 0.00657³ mm and that for cystic fibrosis and diabetes was 0.00795± 0.00599 mm³, both values being larger than normal. Ratios of the amounts of islet endocrine cells, A cells, B cells, and D cells, were determined by peroxidase-anti-peroxidase labeled antibody staining. The B cells composed 43.0% of endocrine cell mass in cystic fibrosis alone and 30.1% in cystic fibrosis with diabetes mellitus, which were lower than normal proportions. The D cell values, 11.9% in cystic fibrosis and 15.1% in cystic fibrosis with diabetes mellitus, on the other hand, were greater than normal ratios.     

Low-dose insulin therapy in patients with cystic fibrosis and early-stage insulinopenia prevents deterioration of lung function: a 3-year prospective study

Cystic fibrosis related diabetes (CFRD) is an insulinopenic condition. We aimed to detect insulinopenia early and to evaluate the impact of low dose insulin on nutritional status and forced expiratory volume in first second (FEV1). Out of 142 cystic fibrosis patients (CFpts) older than 10 years, 28 with abnormal oral glucose tolerance test in spite of normal fasting glycemia were found to have decreased first phase insulin release and started low dose insulin therapy (median age 15.4 years). Sex and age matched CFpts with normal glucose tolerance (NGT) were observed for comparison. Whereas nutritional status improved following 3 years of insulin administration, FEV1 stabilized in insulin-treated insulinopenic subjects (73.8 +/- 4.3% vs. 73.5 +/- 4.4%), but decreased in the parallel group with NGT who remained without insulin treatment (71.1 +/- 3.8% vs. 61.0 +/- 4.0%; p = 0.001). We conclude that low dose insulin improves nutritional status and stabilizes pulmonary functions. Regular estimation of stimulated insulin secretion in CFpts may allow optimizing treatment.     

Association of Epstein-Barr virus infection and pulmonary exacerbations in patients with cystic fibrosis.

We observed severe pulmonary exacerbations during primary Epstein-Barr virus (EBV) infection in adolescent patients with cystic fibrosis. Since EBV is not a known respiratory tract pathogen in cystic fibrosis, we studied retrospectively all EBV-susceptible patients ages 6 to 18 years with chronic Pseudomonas respiratory tract colonization hospitalized for a pulmonary exacerbation during an 18-month period. Patients with serologic evidence of primary EBV infection (n = 5) were compared to control patients without EBV (n = 7). Before admission the groups had similar pulmonary function tests, clinical scores and frequency of hospitalization. On admission patients with EBV had significant weight loss, lower pulmonary function tests and lower clinical scores compared with controls. All remained significantly different 6 months after admission. Frequency of exacerbations requiring hospitalization increased after EBV infection but remained unchanged in controls. Primary EBV infection can be associated with severe pulmonary exacerbations and subsequent deterioration in clinical course in cystic fibrosis patients.     

Longitudinal evaluation of glucose tolerance and insulin secretion in non-diabetic children and adolescents with cystic fibrosis: results of a two-year follow-up

Thirty-two patients with cystic fibrosis and repeatedly normal fasting blood glucose underwent oral glucose tests and islet-cell antibody assessments on two occasions approximately two years apart. Fourteen patients underwent two iv glucose tolerance tests also. Although in the group as a whole mean glucose areas in response to the oral test remained substantially unmodified over the two-year period, the prevalence of glucose tolerance abnormalities increased from 37.5 to 50%. Insulin output in response to both oral and iv tolerance tests decreased over time. Worsening of insulin secretion and/or of glucose tolerance was never accompanied by deteriorating clinical status. Islet-cell antibodies were detected in no patients, even in those who developed a diabetic glucose tolerance. These results support, on a longitudinal basis, the view of a progressive impairment of B-cell function in cystic fibrosis, which may precede the onset of metabolic abnormalities and is not triggered by autoimmunity.