Non-diabetic Cystic Fibrosis Patients Research Articles

MON-LB114 CGM in Cystic Fibrosis Patients to Predict Cystic Fibrosis-Related Diabetes Onset

Background: Therapeutic progress and improvement on resources enabled the emergence of new comorbidities in cystic fibrosis (CF), such as cystic fibrosis-related diabetes (CFRD). About 20% of adolescents and 40-50% of adults are affected. CFRD and glucose intolerance reduce life expectancy in this population, highlighting the importance of early diagnosis and treatment. Up to 15% of CF patients have hypoglycemia during OGTT and its etiology remains unclear. Some authors associate hypoglycemia with CFRD onset, while others do not agree with this association. Objective: To determine whether abnormal CGM (hypo/hyperglycemia) can predict CFRD onset, pulmonary function and BMI decline in CF patients. Methods: Prospective single center study. All CF patients between 10-19yo from our outpatient clinic were screened for CFRD through OGTT following the World Health Organization (WHO) protocol. The enzymatic colorimetric method was used to classify them as per the ADA. Non-diabetic CF patients performed 3-day CGM, forced expiratory volume in the first second (FEV1), BMI and OGTT. All tests except for CGM were then reassessed after a long follow-up. The WHO’s 2006 curve was used to calculate the z scores for individuals ≤19yo and WHO cut-off values for >19yo. Oral corticoid use during data collection, pregnancy and solid organ transplantation were exclusion criteria. Results: Thirty-nine patients were recruited and 34 completed an average of 3.1 years (±0.51) follow-up. No clinical or laboratory variables could predict diabetes progression or hypoglycemic events. The cohort had an increase in mean BMI (17.80±3.65 vs 18.36±3.49; p=0.025) and a reduction in mean FEV1 (66.91±25.79% vs 56.32±29.57%; p=0.001) between the two evaluations. Patients who developed diabetes showed statistically significant worse FEV1 in the end of the follow-up (22.67±5 vs 59.58±28.9; p=0.041), and lower BMI at both start (14.37±1.23 vs 18.13±3.65; p=0.049) and end (14.81±0.66 vs 18.71±3.46; p=0.029) of follow-up. A logistic regression of the effect of time adjusted for independent variables for progression to CFRD was conducted. A higher possibility of evolution among participants with IGT (odds ratio [OR] 21.67; 95% confidence interval [CI] 7.03-67.36; p<0.01), and a lower possibility among participants with NGT (OR 1.84; 95% CI 1.06-3.19; p=0.031). Conclusion: CGM was not a useful tool to predict early diabetes onset in this population with the current cut-off values. However, the IGT group seems to be the riskiest group. The CF population has particular characteristics and may not have the same diagnostic criteria for DM as the non-CF population. More studies are necessary to determine the appropriate CGM cut-off values for CFRD.

Genetic Dissection of Diabetes: Facing the Giant

Cystic fibrosis (CF) is the most common inherited disorder of childhood and is caused by autosomal recessive mutations in the CF transmembrane conductance regulator ( CFTR ) gene (1). CF is most common among Caucasian individuals, with a prevalence of 1 in 2,500 newborns (2). CF can be diagnosed before birth by genetic testing or by a sweat test in early childhood (3,4). Complications of CF include bowel obstruction due to meconium ileus in newborns, poor growth, sinus infections, biliary disorders, infertility, chronic pulmonary infections, and lung disease that requires lung transplantation as CF worsens (2). Exocrine pancreatic insufficiency is observed in 90% of CF patients. Abnormal chloride channel function results in thick viscous secretions that obstruct pancreatic ducts and lead to the retention of digestive enzymes and to pancreas tissue destruction and fibrosis (5). CF-related diabetes (CFRD) is highly prevalent among CF patients and is thought to result from the progressive destruction of islets of Langerhans by pancreatic fibrosis (5). CFRD affects 2% of children, 19% of adolescents, and 40–50% of adults (6). As CFRD is associated with worse pulmonary function (7), failure to maintain weight (8), and higher mortality rates (6), the World Health Organization has recommended annual screening for CFRD using an oral glucose tolerance test. CFRD is considered a clinical entity distinct from that of type 1 diabetes or type 2 diabetes (T2D) and is included in the category “other specific types of diabetes” by the American Diabetes Association (9). Nondiabetic CF patients already display impaired first-phase of insulin secretion in response to intravenous challenges to glucose and delayed and blunted insulin secretion in response to the oral glucose tolerance test (10–12), and these abnormalities are more pronounced when glycemic status worsens (11–13). Insulin therapy is therefore the recommended treatment for CFRD …

311* Gender differences in insulin levels in a large cohort of non-diabetic cystic fibrosis patients

311* Gender differences in insulin levels in a large cohort of non-diabetic cystic fibrosis patients

MRI appearance of the pancreas in patients with cystic fibrosis: a comparison of pancreas volume in diabetic and non-diabetic patients

We investigated differences in the volume of the pancreas in cystic fibrosis (CF) patients with and without diabetes using MRI to study the natural history of CF-related diabetes (CFRD). We investigated 29 pancreas-insufficient adult CF patients, 13 with CFRD and 16 without diabetes. Patients with CFRD were receiving insulin therapy at the time of study. None of the non-diabetic CF patients had evidence of impaired glucose tolerance. Pancreas volume was estimated by MRI scans using T₁ weighted fat-suppression sequences and assessed by an examiner who was unaware of the patients' diabetes status. Pancreas volume of CF patients was measured and subsequently compared with that of non-CF age-matched Type 1 diabetes (T1DM) patients and healthy controls previously investigated. The two CF groups were matched for age and gender. There were no differences in spirometry values, body mass index or pancreatic exocrine function. The pancreas was visible by MRI in only 3 of 13 (23.1%) patients with CFRD and in 5 of 16 (31.3%) patients without diabetes (p-value = 0.7). In total, the pancreas was not detected by MRI as an anatomical entity in 21 of 29 (72.4%) CF patients, irrespective of their diabetes status. When comparing the four study groups, the pancreas was significantly smaller in CF patients than in T1DM patients and healthy controls.

The size of the spleen by magnetic resonance imaging in patients with cystic fibrosis; with and without diabetes--a novel observational study

Magnetic resonance imaging (MRI) has been shown to be a useful tool to evaluate the volume of the pancreas. There is currently no information about the size of the spleen in cystic fibrosis (CF) patients. We investigated 51 adult volunteers: 28 pancreatic insufficient CF patients [13 with CF-related diabetes (CFRD) and 15 non-diabetic] and 23 male non-CF patients [12 with type 1 diabetes mellitus (T1DM) and 11 healthy control subjects]. Patients with known liver cirrhosis or portal hypertension were excluded. The size of the spleen was measured in all subjects by an investigator unaware of patients' clinical status. For comparison of spleen size in the four study groups only male CF patients were included. For CF patients, spleen size was compared with forced expiratory volume in 1 s (FEV(1)), body mass index (BMI), total number of days of intravenous (IV) antibiotic treatment for pulmonary exacerbations in year previous to study, levels of circulating white blood cells, glycosylated haemoglobin A1c (HbA1c), and exocrine function of the pancreas, as assessed by daily requirement of oral lipase. Amongst the four study groups, spleen size was greatest in the male non-diabetic CF patients (P = 0.01). For CF patients, spleen size was greater in male compared to female patients (P = 0.012). For patients with CFRD, there was an inverse correlation between the spleen size and HbA1c (r = -0.59, P = 0.04) and the daily intake of supplementary lipase (r = -0.63, P = 0.02). The size of the spleen in patients with CFRD, but not in CF patients without CFRD, inversely correlated with the days of IV antibiotic treatment received in the year previous to the study (r = -0.67, P = 0.012). There was no correlation between spleen size and BMI, FEV1 and white blood cell counts in any group. On MRI, the spleen size was greatest in male non-diabetic CF patients in comparison with other groups. The size of the spleen in CFRD patients was smaller when diabetes was poorly controlled, when exocrine pancreatic function was greatly impaired and in those with greater need for IV antibiotics in the year prior to the study.

Management of cystic fibrosis-related diabetes in children and adolescents

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

Reactive hypoglycemia in non-diabetic cystic fibrosis patients

Reactive hypoglycemia in non-diabetic cystic fibrosis patients

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

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

Presence of cystic fibrosis-related diabetes mellitus is tightly linked to poor lung function in patients with cystic fibrosis: data from the European Epidemiologic Registry of Cystic Fibrosis.

Data derived from a cross-sectional analysis of 7,566 patients stratified into six age groups were used to compare lung function, body mass index (BMI), and weight for age in patients with and without cystic fibrosis-related diabetes mellitus (CFDM). The presence of CFDM was tightly linked to poor lung function, regardless of age. The mean value of FEV(1) % predicted in the age groups < 10, 10-< 15, 15-< 20, 20-< 25, 25-< 30, and 30 years or older were 87%, 77%, 69%, 58%, 55%, and 53% in the nondiabetic cystic fibrosis (CF) patients as compared to 79%, 66%, 55%, 49%, 46%, and 44% in the diabetic CF patients. BMI and weight for age were also lower in diabetic than nondiabetic CF patients in all age groups, except for BMI in the youngest patients. The difference in lung function and in nutritional parameters between diabetic and nondiabetic CF patients was not linked to presence or absence of any specific pathogen in the lower respiratory tract. These results confirm and extend those of earlier studies in smaller numbers of patients, and they clearly identify CFDM as a powerful determinant of severe lung disease and reduced survival in patients with CF and diabetes mellitus.

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.

Relative Increase in IgG Antibodies to Pseudomonas aeruginosa 60-kDa GroEL in Prediabetic Patients with Cystic Fibrosis

In recent years research has focused on a possible connection between bacterial infection and development of diabetes mellitus. In this study, serum antibody responses against bacterial antigens in diabetic and nondiabetic patients with cystic fibrosis (CF) were evaluated. The first part of the study included 252 CF patients of whom 46 (18 %) had diabetes. This study showed that precipitating antibodies (precipitins) against Pseudomonas aeruginosa and other bacteria in crossed immunoelectrophoresis, and IgG antibodies against a 60-kD GroEL of P. aeruginosa, were highly variable and positively correlated with age. Patient material matched for age and sex showed no significant difference between diabetic and nondiabetic CF patients in precipitins or IgG antibodies to P. aeruginosa GroEL. Two longitudinal studies of 9 and 5 y using retrospectively selected sera from 29 prediabetic and 29 cross-matched nondiabetic CF patients were performed. As to precipitins against P. aeruginosa, we found no difference between the prediabetic and the nondiabetic group of patients during the study period. The study revealed, however, a significant increase of 24.6 % (p = 0.008) of IgG antibodies against P. aeruginosa 60-kD GroEL, 3-12 mo before the onset of diabetes in patients with CF, compared with an overall increase of 5 % to 6 % per year in both groups during the observation period. This study shows that diabetes in CF appears after a peak of serum IgG antibodies against GroEL and indicates that development of diabetes in CF patients may not only be caused by a progressive fibrosis of the pancreatic tissue, but may be augmented by a short-term specific immunologic reaction, initially triggered by an ongoing and progressive pulmonary infection.

Four-Year Follow-Up of Glucose Tolerance and Beta-Cell Function in Nondiabetic Cystic Fibrosis Patients

Plasma glucose and insulin responses to oral glucose load were investigated and reinvestigated approximately 4 years later in 29 cystic fibrosis children and adolescents with initially normal fasting blood glucose levels. Patients' clinical status was evaluated at the time of both oral glucose tolerance tests. With respect to the basal test, the second one elicited blunted insulin responses and enhanced glycemic levels. Moreover, the prevalence of patients with diabetic glucose tolerance was significantly increased at the second evaluation and insulin secretion was markedly reduced in these patients. Deterioration of glucose tolerance and/or of insulin secretion over time was never accompanied by a significant worsening of clinical and/or nutritional status. In conclusion, in cystic fibrosis subjects with fasting euglycemia (a) both insulin secretion and glucose tolerance deteriorate during a 4-year follow-up, (b) an insulin secretion decrease is more evident in patients who develop diabetic glucose tolerance and (c) these metabolic changes are not significantly linked to a worsening of either nutritional or clinical parameters, even in the patients who develop diabetic glucose tolerance.

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 influenzae and Streptococcus pneumoniae decreased in the diabetic patients, whereas parameters of lung infections with P. aeruginosa and Staphylococcus aureus remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes mellitus in Danish cystic fibrosis patients: prevalence and late diabetic complications

The prevalences of impaired glucose tolerance (IGT), diabetes mellitus and late diabetic complications were studied in all Danish cystic fibrosis (CF) patients. A total of 311 CF patients were identified with an estimated ascertainment rate above 98%. Glucose tolerance was classified in 278 (89%) patients: the prevalences of IGT and diabetes mellitus were 13.7% (38 patients) and 14.7% (41 patients), respectively, with no sex differences. The prevalence of diabetes mellitus increased with age but not with the severity of CF as compared with age- and sex-matched non-diabetic CF patients. Diabetes was diagnosed at a median age of 20 years (range 3-40 years) and the duration of diabetes was 1.7 years (0.1-17 years). Twenty-eight of the diabetic patients (70%) were treated with insulin, on average 20 (4-90) IU per day. Late diabetic complications were identified in 4 patients (10%) with a duration of diabetes mellitus of 1-17 years: background retinopathy (2 patients), diabetic nephropathy (1 patient), microalbuminuria (1 patient) and neuropathy (2 patients). Thus diabetic CF patients are probably not less prone to develop late diabetic complications than patients with other types of diabetes of equally long duration and comparable glycemic control.

Diabetes mellitus in cystic fibrosis: genetic and immunological markers.

Family history, as well as genetic and immunological markers of diabetes mellitus, were studied in cystic fibrosis (CF) patients with and without diabetes mellitus. Positive family history of diabetes mellitus in first-degree relatives was found in only 6 of 210 (3%) CF patients, with no difference between non-diabetic and diabetic patients. The frequency distributions of the HLA types DR3, DR4 and DR3/4, which normally confer susceptibility to insulin-dependent diabetes mellitus and of HLA-DR2, which normally confers resistance to insulin-dependent diabetes mellitus, were not different in non-diabetic CF patients, diabetic CF patients and normal subjects. The genotypic frequencies of tumor necrosis factor-beta and of heat shock protein 70, located within the HLA region on chromosome 6, in CF patients with diabetes were not different from those in patients with insulin-dependent diabetes mellitus, while non-diabetic CF patients and normal subjects shared other patterns. The frequencies of the interleukin-1 beta alleles, located on chromosome 2, were not different in non-diabetic and diabetic CF patients, insulin-dependent diabetic patients and normal subjects. Islet cell cytoplasmic antibodies, measured before, at and after the diagnosis of diabetes in 33 diabetic CF patients and in 32 matched non-diabetic CF patients, were detected in only 2 of 236 (0.8%) serum samples: in a pre-diabetic patient and in a non-diabetic control patient. Birth weights were not different in diabetic and non-diabetic CF patients, arguing against the importance of the intrauterine environment as a determinant in the transmission of diabetes mellitus in CF patients.(ABSTRACT TRUNCATED AT 250 WORDS)

First-phase insulin release in adult cystic fibrosis patients: correlation with clinical and biological parameters.

Adult patients with cystic fibrosis (CF) are at high risk for developing insulin-dependent diabetes mellitus. Therefore, the fast insulin release (FIR) to intravenously administered glucose was measured in 23 adult CF patients. The influence of the clinical parameters and type of gene deletion on the amplitude of the FIR, defined by the sum of the 1st- and 3rd-minute insulin concentrations was analyzed. In 11 of the 18 normoglycemic patients with exocrine pancreatic insufficiency and the 3 nontreated diabetic CF patients studied, an FIR value lower than the 3rd percentile was found. The female patients had higher mean FIR values than the male patients (62.8 +/- 39.6 vs. 27.9 +/- 17.9 mU/l; p < 0.05). No influence of age, body mass index, or pulmonary or liver involvement on the FIR was found. Subjects heterozygous for the delta F508 deletion had a similar insulin response as homozygous patients. The FIR level correlated negatively with the basal glucose level (r = 0.4; p < 0.001). In conclusion, 61% of the adult nondiabetic CF patients with exocrine pancreatic insufficiency presented a loss in acute insulin response, which could not be predicted by clinical or genetic parameters.

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.