Early detection of impaired glucose tolerance in patients with cystic fibrosis and predisposition factors

INTRODUCTION: The number of patients with glucose tolerance alterations associated with cystic fibrosis (CF) has increased, probably due to the greater survival rate among sufferers of this disease. We studied impaired glucose tolerance (IGT) in patients with CF and investigated whether its appearance has any relationship with age, sex, genetic mutation and/or the degree of clinical involvement. We assessed the parameters that might allow early detection. PATIENTS AND METHODS: In 28 patients with CF (14 M, 14 F; aged 22 months to 18 years), sex, genetic mutation, nutritional status and the degree of pancreatic and pulmonary involvement were recorded. The metabolic study included glycosylated hemoglobin (HbA1c) determination, oral glucose tolerance test (OGTT) and intravenous glucose tolerance tests (IVGTT). RESULTS: In the patients with CF, 35.71% showed impaired glucose tolerance (IGT) and 3.57% had diabetes mellitus. The patients with IGT and CF were 3.2 years older than those with normal glucose tolerance (NGT; p<0.05), but no significant differences were found regarding sex, anthropometric measurements, percentage of pulmonary gammagraphic involvement, Shwachman-Kulczycki test or HbA1c. In the OGTT, the patients homozygous for the deltaF508 mutation had higher blood glucose values than the heterozygous group (p=0.03), but these values were not higher than those in patients with other mutations. During the OGTT, blood insulin values at 30' were reduced in patients with IGT compared to patients with NGT (p<0.02) and the insulin peak occurred at 100.9+/-24.3 min compared to 65.3+/-21.8, respectively (p<0.05). In the IVGTT, 82.14% of the patients had reduced insulin levels at 1 and 3 min (I1'+3'). No differences in the blood glucose levels during the OGTT were found between patients with normal I1'+3' values and patients with reduced values. CONCLUSIONS: A high percentage of patients with CF also present with IGT. This increases with age and is more common among patients homozygous for the deltaF508 mutation and is not related to clinical status. Alterations in the kinetics of insulin secretion play an important role in the appearance of IGT and CF. We suggest that the OGTT is a more sensitive method than IVGTT for identifying early alterations in CF-related 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.     

Research of factors for glucose intolerance in mucoviscidosis]

Glucose tolerance has been assessed in cystic fibrosis (CF) children using HbA1C and plasma glucose and insulin determinations during an oral glucose tolerance test (OGTT), along with the determination of HLA-DR and islet-cell (ICA) and anti-insulin (IAA) antibodies. Of 49 patients (25 males, 24 females), aged 2 to 21 years (mean = 10.9 years), 29 had normal glucose tolerance (WHO criteria) during OGTT, 14 had impaired glucose tolerance (IGT) and 6 had an isolated hyperglycemia at 120 min. Fasting plasma glucose and HbA1C were significantly higher in IGT than in normoglycemic patients. However, these two parameters showed poor individual predictive value of disturbance in glucose tolerance. Of 14 patients with abnormal OGTT, 7 were aged below 10 years, with 2 as young as 5 years; 8 patients were females. HLA antigens characteristic of type I diabetes tended to be found less frequently in CF patients than in the general population: 9% were DR3, 7% were DR4 and none was DR3/DR4. There were no HLA differences according to glucose tolerance. ICA and IAA were respectively detected in only one patient. Stimulated plasma insulin was low but did not correlate with glucose tolerance. In conclusion, impaired glucose tolerance is common in cystic fibrosis and can be found early in life. Although insulin secretion is decreased in this population, it does not seem to be the only factor responsible for impaired glucose intolerance. The absence of the genetical and immunological characteristics of type I diabetes confirms that glucose intolerance in cystic fibrosis is due to other pathogenetic mechanisms.     

Hyperglycaemia and insulinopenia in a neonate with cystic fibrosis

Abnormal glucose tolerance is a frequent late complication of cystic fibrosis (CF), but the prevalence of CF-related diabetes mellitus (CFRD) in children less than 10 y old is less than 2%. The youngest child with CFRD reported to date was 6 mo of age. Insulinopenia is the primary cause of abnormal glucose tolerance/CFRD, but it is unknown whether it may begin in the neonatal period. We describe a case of a neonate with CF who presented with hyperglycaemia in the diabetic range and marked insulinopenia. Insulinopenia and impaired glucose tolerance were permanent findings at 6 and 15 mo of age. CONCLUSION: This case suggests that abnormal glucose tolerance/diabetes may occur much earlier in the course of CF, even during neonatal age. Careful follow-up and further studies in CF infants could reveal that the real incidence of glucose intolerance and diabetes in this age group has been underestimated.     

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.     

Insulin resistance is associated with decreased clinical status in cystic fibrosis

Patients with cystic fibrosis (CF) frequently have impaired glucose tolerance and progression to diabetes (DM) with clinical features of both insulin-dependent and non-insulin-dependent diabetes. One feature of non-insulin-dependent DM is decreased insulin sensitivity, also known as insulin resistance. The goal of this study was to determine whether patients with CF exhibit insulin resistance and to determine the potential effect of insulin resistance on clinical status. We also sought to determine whether insulin resistance is associated with a specific CF genotype. We studied 18 patients with CF (8 with normal glucose tolerance, 5 with impaired glucose tolerance, 5 with DM), and 20 lean control subjects matched for age, weight, and sex. All control subjects had normal glucose tolerance. The clinical status for each CF patient was determined according to a modified National Institutes of Health scoring system. Each subject underwent a three-step hyperinsulinemic euglycemic clamp (insulin doses of 10, 40, 120 mU/m ² per minute). Results from the 120 mU/m ² per minute infusion defined maximal glucose disposal rate (defined in milligrams per kilogram body weight per minute) at steady state with peripheral insulin levels 195 ± 20 mU/ml. Subjects with CF demonstrated insulin resistance (control subjects = 13.6 ± 1.1, patients with CF = 10.2 ± 1.6 mg/kg per minute; p = 0.003). When each subgroup was compared separately with control subjects, all subgroups were statistically insulin resistant (glucose disposal rate, patients with CF and normal glucose tolerance = 10.8; those with impaired glucose tolerance = 8.4; those with DM = 10.1 mg/kg per minute), and the patients with CF with impaired glucose tolerance were the most insulin resistant. When plotted versus glucose disposal rate, a striking positive correlation between worsened clinical status and insulin resistance ( r = 0.85) is demonstrated. Furthermore, there is no correlation between insulin resistance and fasting blood glucose, subject age, or percent ideal body weight (all r values not significant). In conclusion, patients with CF exhibit insulin resistance that is associated with worsened clinical status. We believe it is the combination of insulin resistance and decreased insulin secretion that is responsible for the high incidence of CF-related diabetes. (J Pediatr 1997;130:948-56)     

Carbohydrate tolerance in cystic fibrosis is closely linked to pancreatic exocrine function

We evaluated carbohydrate tolerance in nine thin cystic fibrosis (CF) patients and in six controls, measuring responsiveness to the following insulinotropic secretagogues: oral glucose, IV glucose, and IV tolbutamide. Glucose responses segregated patients into two groups: Group I with normal carbohydrate tolerance associated with normal to slightly increased insulin responses, and Group II with impaired carbohydrate tolerance associated with insulinopenia. This latter group included one patient with frank diabetes. The CF patients demonstrated a significant positive correlation between insulin secretion, in response to each secretagogue, and pancreatic exocrine function as measured by serum pancreatic amylase isoenzyme concentration. Pancreatic alpha-cell function, as reflected by basal plasma glucagon concentrations, also correlated well with exocrine function in the CF patients, excluding the diabetic individual. The enteroinsular axis of the CF group was intact as reflected by normal plasma gastric inhibitory polypeptide concentrations in Group I and by elevated levels, basally and in response to oral glucose, in the insulinopenic Group II patients. Furthermore, those patients with impaired tolerance demonstrated a greater magnitude of insulinopenia compared to controls following IV glucose and possibly IV tolbutamide, than following oral glucose. Thus, these data suggest that loss of carbohydrate tolerance in patients with CF, like that seen with classical chronic pancreatitis, 1) parallels the loss of exocrine function, 2) is associated with appropriate enteroinsular signaling, and 3) can be detected earlier or more easily following testing with direct IV secretagogues than following oral glucose stimulation.     

Monitorización continua de glucosa para cribado de alteraciones hidrocarbonadas en fibrosis quística

BackgroundDiabetes mellitus (DM) is an increasing complication of cystic fibrosis (CF). It is associated with enhance morbidity. Continuous glucose monitoring system (CGMS) could detect glucose disorders earlier than other screening tests usually used.AimsTo compare oral glucose tolerance test (OGTT), HbA_1c and CGMS in patients with CF and recent disorders of glucose homeostasis and to analyse changes in nutritional status and/or pulmonary function.Patients and methodsThirteen patients with CF (11–22 years, 7 males) were studied using OGTT, HbA_1c and CGMS. All of them had newly diagnosed glucose disturbances. They were not receiving steroid therapy or had an underlying illness. In all subjects we compared: HbA_1c levels (%), fasting and 2-hours glucose OGTT (mg/dl) and glucose CGMS values (overall, fasting, 2-hours post mean-meals and excursions >140 mg/dl at any time). Furthermore, body mass index, forced expiratory volume in the first second (%) and forced vital capacity (%) were evaluated in the previous year and at the time of the study. We also analysed exocrine pancreatic function and CF-mutation.ResultsMean age at diagnosis of glucose disturbance was 16.4 years. All patients had insufficient exocrine pancreatic function and 11/13 presented ΔF508 CF-mutation. Only one patient was diagnosed with DM using OGGT and 7/13 (53.8%) with CGMS. A total 77% of patients had poor nutritional status and/or pulmonary function at time of diagnosing the glucose disorder. Only 4 patients had abnormal HbA_1c levels.ConclusionsCGMS allows a better detection of glucose disorders than OGTT. Glucose homeostasis abnormalities are associated with a decrease in nutritional status and/or pulmonary function. HbA_1c does not aid in the early diagnose of glucose disorders.     

Glycosylated haemoglobin and glucose intolerance in cystic fibrosis.

Sixty four patients, age range 1-20 years, with cystic fibrosis had their tolerance to glucose assessed according to their glycosylated haemoglobin (HbA1) concentrations. Raised concentrations were found in 24 (37.5%). Oral glucose tolerance tests were performed on 21 patients with raised HbA1 and 13 patients with normal HbA1 concentrations. C peptide responses were also measured to assess islet cell function. Patients with normal HbA1 had normal glucose tolerance and C peptide response. Seven of 21 patients with raised HbA1 concentrations were glucose intolerant. The remaining 14 patients with raised HbA1 concentrations had normal glucose tolerance but a reduced C peptide response, suggesting impaired islet cell function. There were no appreciable differences in the incidence of chest infections, respiratory function, and chest x-ray scores among patients with normal HbA1 concentrations, raised HbA1 concentrations, and normal oral glucose tolerant tests, and patients who were glucose intolerant. No correlation was found between HbA1 concentration and age or Shwachman score. Measuring HbA1 concentrations periodically is useful in detecting and monitoring glucose intolerance in patients with cystic fibrosis.     

Continuous glucose monitoring system in the screening of early glucose derangements in children and adolescents with cystic fibrosis

BACKGROUND: In cystic fibrosis (CF), diabetes mellitus (DM) is associated with progression of pulmonary disease and nutritional impairment. AIM: To compare oral glucose tolerance test (OGTT) and continuous glucose monitoring system (CGMS) in patients with CF with early glucose derangements. PATIENTS AND METHODS: Thirty-two patients with CF (5-20 years) with intermediate glucose values > 7.7 mmol/l during OGTT received a CGMS registration. Patients were classified into those with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and DM, according to glucose values at 120 min of OGTT and during CGMS. Furthermore BMI z-scores, forced expiratory volume in 1 second (FEV1%), number of respiratory infections/year, enzyme supplementation, and HbA1c were evaluated. RESULTS: OGTT and CGMS derangements were in agreement in 43.7% of the patients. BMI z-scores, FEV1%, number of respiratory infections/ year, enzyme supplementation, and HbA1c did not differ among the three groups. HbA1c, correlated positively with 120 min OGTT (r = 0.34; p = 0.059), CGMS area (r = 0.35; p = 0.048) and the number of respiratory infections, and negatively with FEV1%. CONCLUSIONS: Intermediate glucose values during OGTT should be considered as a screening test in patients with CF. CGMS can be useful in studying the early occurrence of glucose derangements in selected patients.     

Abnormal glucose tolerance in Egyptian beta-thalassemic patients: possible association with genotyping

BACKGROUND: Type 1 diabetes mellitus (DM) is a frequent complication in patients with beta-thalassemia. It is believed to be due to the damage inflicted by iron overload of the pancreatic beta cells. Liver disorders and genetic influences seem to be additional predisposing factors. OBJECTIVE: To study the prevalence of diabetes and impaired glucose tolerance (IGT) in transfusion-dependent Egyptian beta-thalassemic patients and to evaluate the possible role of genotyping in the pathogenesis of diabetes associated with beta-thalassemia. RESEARCH DESIGN and METHODS: A total of 56 transfusion-dependent beta-thalassemic patients aged 10-31 (mean age=15.9 +/- 5.7 yr), 32 males and 24 females, including 48 thalassemia major and eight thalassemia intermedia; compared to 15 age- and sex-matched controls. All were subjected to history and examination, laboratory investigations: complete blood count (CBC), serum ferritin, liver function tests, hepatitis B and C markers, fasting blood glucose, oral glucose tolerance test (OGTT) and fasting C-peptide. Genotyping for 16 mutations was assessed in thalassemic patients with abnormal glucose tolerance. RESULTS: The prevalence of diabetes was 10.4% (5 of 48) and IGT was 14.6% (7 of 48) among thalassemia major, whereas, none of thalassemia intermedia had abnormal glucose tolerance. Fasting C-peptide was lower in beta-thalassemic patients compared to controls (p <0.001); the level was significantly higher in patients complicated by diabetes or IGT compared with other thalassemic patients (p <0.001). Chronic hepatitis C was detected in all patients (100%) with abnormal glucose tolerance. Genotyping showed that IVS II nt 745 was detected in 77.7% of cases with abnormal glucose tolerance. CONCLUSIONS: Abnormal glucose tolerance is common in multiply transfused beta-thalassemia major patients, which could be attributed to progressive and early loss of beta-cell mass, along with persistent insulin resistance. Chronic hepatitis C may play a role in the development of abnormal glucose tolerance. An association between diabetes and genotyping IVS II nt 745 was found. Patients with this particular genotype are advised to check their blood glucose every 6 months to detect early occurrence of diabetes.     

Hyperglycemia and hypoinsulinemia in patients with Fanconi-Bickel syndrome

Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by the combination of hepatorenal glycogen accumulation and Fanconi-type nephropathy. Mutations in GLUT2, the gene for facilitative glucose transporter protein 2 (GLUT2), cause FBS. AIM: To evaluate glucose and insulin responses to oral glucose load in patients with FBS. METHODS: Ten children (7.3 +/- 4.8 years) diagnosed with FBS in early infancy underwent a standard oral glucose tolerance test (OGTT); plasma glucose (PG) and serum insulin concentrations were measured at 30-min intervals for 2 hours. HbA1c, insulin-like growth factor-I, and fasting lipid profiles were also measured. RESULTS: Mean fasting and 2-h PG concentrations were 3.8 +/- 0.9 mmol/l and 8.6 +/- 3.0 mmol/1, respectively. 2-hour PG levels were above 11.1 mmol/l in two patients (20%) and between 7.75 and 11.1 mmol/ in four patients (40%). HbA1c was normal in all the patients with a mean of 5.4 +/- 0.3%. Mean fasting and peak serum insulin levels were 8.7 +/- 0.8 pmol/ and 98.6 +/- 43.0 pmol/l, respectively, and did not differ between the patients with normal and abnormal OGTT. Patients with abnormal OGTT were younger (4.8 +/- 3.2 vs 11.0 +/- 4.8 yr; p = 0.04). Fasting PG increased with age (r = 0.80, p < 0.01). Total and LDL cholesterol as well as triglyceride concentrations were elevated. CONCLUSIONS: Most but not all patients with FBS have impaired glucose tolerance/diabetes range hyperglycemia after OGTT while maintaining normal HbA1c. Patients with FBS are relatively hypoinsulinemic. Both fasting hypoglycemia and post-OGTT hyperglycemia seem to improve with age.     

Low prevalence of glucose intolerance in racially mixed children with cystic fibrosis

Alves C, Lima DS, Cardeal M, Santana A. Low prevalence of glucose intolerance in racially mixed children with cystic fibrosis. Objective: To evaluate glucose tolerance in racially mixed Brazilian youth with cystic fibrosis (CF). Methods: Cross‐sectional study conducted between August and September 2007, at a reference service for CF, evaluating: glycated hemoglobin (HbA1c), blood glucose, and insulin levels, before and 2 h after a glucose overload. Results: There were 46 patients aged between 6 yr and 16 yr and 2 months (median: 9 yr and 10 months) of whom 64% were boys. Of these, 26% were Whites; 54.4% Mulattoes; and 19.6% Blacks. HbA1c was normal in all patients. Only one participant (12‐yr old) had glucose intolerance. Insulin levels ranged from 1 to 23 µIU/mL (median: 4.5 µIU/mL) at baseline and from 3.2 to 192.1 µIU/mL (median: 11 µIU/mL) after a glucose overload. Insulin resistance evaluated by the HOMA index, stratified by sex and age, was present in three patients. The ΔF508 mutation was present in only 4.3% of the sample, all of them being heterozygous. Conclusions: The low prevalence of carbohydrate intolerance in this population is probably a result of their young age. Another possibility is the low frequency of the ΔF508 mutation. Although not conclusive, these data suggest that in addition to age, the genotype:phenotype ratio may influence the development of glucose intolerance in patients with CF.     

Insulin resistance in a young man with cystic fibrosis

An 18-year-old man had cystic fibrosis (CF) and insulin-resistant carbohydrate intolerance characterized by (1) obesity, basal hyperinsulinemia, and hyperglucagonemia; (2) impaired oral glucose tolerance; (3) hyperinsulinemia in response to oral and intravenous (IV) administration of glucose and to IV administration of tolbutamide; (4) exaggerated gastric inhibitory polypeptide secretion following orally administered glucose; and (5) diminished sensitivity to insulin administered IV compared with other patients with CF. Both parents also demonstrate basal and stimulated hyperinsulinemia in response to orally administered glucose. The long-term outlook for patients with CF is improving, and more patients are surviving childhood. Thus, it should be recognized that an insulin-resistant form of carbohydrate intolerance may develop in patients with CF with obesity and/or genetic risk factors.     

HLA type,islet cell antibodies,and glucose intolerance in cystic fibrosis.

Impaired glucose tolerance, assessed by a raised glycated haemoglobin (HbA1) concentration, was found in 24 (39%) out of 61 patients with cystic fibrosis with an age range of 1-23 years. No correlation between age and HbA1 concentration was found indicating that factors other than progressive pancreatic fibrosis may be important in the aetiology. HLA typing, islet cell antibodies, and autoantibody screen were completed. Eighteen (75%) out of 24 patients with cystic fibrosis who had an impaired glucose tolerance had HLA-DR3 or HLA-DR4 antigens compared with 23 (62%) out of 37 patients with normal glucose tolerance. Islet cell antibodies were present in seven (15%) out of 46 patients with cystic fibrosis; the prevalence in a normal population is 0.5%. Five (25%) of the 20 patients with a raised HbA1 concentration were positive for islet cell antibodies compared with two (8%) out of the 26 with normal glucose tolerance. Six (86%) out of seven patients who were positive for islet cell antibodies had HLA-DR3 or HLA-DR4 antigens. There was no general autoantibody production. Islet cell antibodies may play a part in the development of glucose intolerance in some patients with cystic fibrosis by being produced in those who are genetically predisposed as part of an immune response to damaged pancreatic tissue.     

Oral glucose tolerance testing in children with cystic fibrosis

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

Diabetes mellitus associated with cystic fibrosis

The prevalence of overt diabetes mellitus and carbohydrate intolerance was studied in 448 patients with cystic fibrosis (CF). Insulin-dependent diabetes (IDDM) developed in 7.6% of patients (13 male and 21 female). Survival was significantly lower (P less than 0.01) in the IDDM-CF group, with fewer than 25% surviving to age 30 years, whereas nearly 60% of the nondiabetic CF population reached this age. A significant deterioration in CF clinical status, based on NIH score, became apparent 2 years before onset of overt IDDM (P less than 0.05 at 2 years prior, P less than 0.01 at IDDM diagnosis). Total glycosylated hemoglobin (HbA1) was significantly (P less than 0.001) higher for the total CF population (7.3% +/- 1.2%) than for the general non-CF population (6.5% +/- 0.7%), and in the IDDM-CF group (P less than 0.05) compared with normoglycemic CF control patients. Female patients had a higher mean HbA1 after 12 years of age than their male counterparts did (P less than 0.02). HBA1 did not predict the development of IDDM, but there was a weak inverse relationship between HbA1 and both NIH clinical score (r = -0.41, P less than 0.02) and standard pulmonary function tests (forced vital capacity, r = -0.25, P less than 0.01) in the general CF population. Therefore, impaired carbohydrate tolerance in CF is associated with progressive clinical deterioration.     

Reduced pancreatic insulin release and reduced peripheral insulin sensitivity contribute to hyperglycaemia in cystic fibrosis

Traditional opinion holds that patients with cystic fibrosis (CF) develop impaired glucose tolerance or diabetes due to insulinopenia caused by fibrosis of the pancreas. However, studies on the dynamics of insulin secretion and peripheral insulin action have yielded confliciting results. We studied 18 patients with CF (9 , 9 , age 15–29 years) and 17 healthy control subjects (8 , 9 , 20–32 years). Oral glucose tolerance tests and combined i.v.-glucose-tolbutamide-tests were performed on separate days in fasting subjects. Bergman's Minimal Model was used to quantitate both peripheral insulin sensitivity (S_I) and insulin-independent glucose disposal (glucose effectiveness; S_G). Based on National Diabetes Data Group criteria, 4 patients were classified as diabetic 922%; CF-DM), 3 patients (17%) had impaired glucose tolerance (CF-IGT) while glucose metabolism was normal in 11 patients (61%; CF-NGT). Irrespective of the degree of glucose tolerance, the insulin response to oral glucose was not reduced but delayed, up to 60 min in the CF-IGT/DM group. First-phase insulin release (0–10 min) after i.v.-glucose was significantly lower in CF patients (29% of healthy controls;P<0.0001), with no difference between the CF-NGT and CF-IGT/DM groups. Insulin release following tolbutamide injection was only marginally reduced in CF patients (64% of controls). In contrast, S_I was significantly reduced in the subgroup of CF patients with abnormal glucose metabolism (CF-IGT/DM: 0.97±0.16·10^–4 l/min/pmol; control group: 1.95±0.25;P<0.05).Conclusion The early insulin release is reduced in response to i.v.-glucose, while in the oral glucose tolerance test, insulin secretion is quantitatively preserved, but delayed. Reduced peripheral insulin sensitivity is a major factor for impaired glucose tolerance and diabetes mellitus in CF patients.     

Early decline of pancreatic function in cystic fibrosis patients with class 1 or 2 CFTR mutations

BACKGROUND: Most cystic fibrosis (CF) patients develop steatorrhea and require pancreatic enzyme replacement therapy. However, there are few data regarding the decline of exocrine pancreatic function within the first years of life in relation to CF genotype. We assessed the decline of pancreatic function in CF infants carrying class 1 or 2 CFTR mutations who were diagnosed in a neonatal screening program. MATERIALS AND METHODS: Twenty-eight CF patients were included in the study and 27 completed the study. In all subjects, fecal pancreatic elastase-1 concentrations and fecal fat excretion were scheduled to be determined at diagnosis, at 6 months of age and subsequently at 6-month intervals. RESULTS: In all CF patients, fecal pancreatic elastase-1 concentrations of the first assay after diagnosis (3 to 4 months of age) were lower than the cut-off level for normals of <200 microg/g stool. Steatorrhea was found in 81.5% of these subjects. At the age of 6 months, all screened CF subjects had fecal pancreatic elastase-1 concentrations <100 microg/g and at the age of 12 months all were pancreatic insufficient. At that time, having proved pancreatic insufficiency in all studied subjects, we stopped the scheduled further assessment. CONCLUSION: CF patients require careful monitoring of pancreatic status from diagnosis onwards. In patients carrying class 1 or 2 CFTR mutations, pancreatic insufficiency develops in the first months of life. The proper assessment of pancreatic insufficiency and intestinal malabsorption is crucial for the early introduction of pancreatic enzymes.     

Glucose homeostasis in mucoviscidosis

In patients with cystic fibrosis (CF) of the pancreas an endocrine imbalance especially of insulin secretion due to progressive structural abnormalities of the pancreas must be expected. 30-75 percent of CF-patient exhibit impaired oral glucose tolerance tests (oGTT). Deterioration of the glucose homeostasis leads to a secondary diabetes mellitus that mimics a type II diabetes in the early stage, in the later course of disease it resembles a type I diabetes with absolute insulinopenia. In this study glucose homeostasis was investigated after an oral glucose load with 1.75 g glucose/kg bodyweight. Glucose, C-peptide and insulin were measured during 180 minutes. 32 nondiabetic CF-patients were studied. 16 patients revealed an impaired oral glucose tolerance according to the criteria of the National Diabetes Data Group. 6 patients showed a normal glucose tolerance and 10 patients with normal fasting and 120 minute glucose concentrations were hyperglycemic at midtest determinations. Impaired oGTTs were observed in malnourished CF-patients in a higher rate than in normal weight patients. A delayed and exceeded C-peptide and insulin response to the oral glucose load was determined with deteriorating glucose tolerance. Glucose values did not drop to fasting values at the 180 minute determination in cases of impaired oral glucose tolerance.