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

Lanng S, Thorsteinsson B, Lund-Andersen C, Nerup J, Schiatz PO, Koch C. Diabetes mellitus in Danish cystic fibrosis patients: prevalence and late diabetic complications. Acta Pzdiatr 1994;83: 72–7. Stockholm. ISSN 0803–5253.
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 tolerdnce 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 trcated 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.     

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.     

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.     

Polymorphisms of the TNF-alpha gene and risk of celiac disease in T1DM children

BACKGROUND: Type 1 diabetes mellitus (T1DM) and celiac disease (CD) frequently occur together. Previous reports suggested that the (-308)A variant of the tumor necrosis factor-alpha (TNF-alpha) gene is associated either with T1DM or with CD. The aim of our study was to determine whether (-308)A and (-238)A allelic variants of the TNF-alpha gene might have any impact on the risk of CD in T1DM children. METHODS: Three hundred and one T1DM children were enrolled to the study. The presence of CD was screened with IgA endomysial antibodies (EMA) test. Jejunal biopsy was performed to confirm CD. TNF-alpha-308 and -238 genetic variants were tested using the method of restriction fragment length polymorphism. RESULTS: The prevalence of CD in the enrolled diabetic children was 6.3% (19 out of 301 children). The frequency of the (-308)A TNF-alpha variant was similar in the CD and the non-CD groups, exceeding the Hungarian healthy reference value. The number of (-238)A allele carriers was higher in the CD (4/19) than in the non-CD group (17/277) (p < 0.05). CONCLUSIONS: Our study is limited by the small number of CD patients. On the basis of our findings, carriers of TNF (-308)A allele do not seem to have an increased risk for CD in T1DM. The association between TNF-alpha(-238)A allele carrier state and CD requires further investigation.     

Antioxidant effect of beta-carotene in cystic fibrosis and bronchiectasis: clinical and laboratory parameters of a pilot study

The carotenoids are potent antioxidants with the ability to quench singlet oxygen and other toxic oxygen species. The aim of this pilot study was to investigate the protective effect of β-carotene on oxidant system in patients with cystic fibrosis (CF) and in patients with bronchiectasis (BE) caused by a reason other than CF. Eighteen children with CF and 15 children with BE followed in the Pediatric Chest Disease Unit of Hacettepe University, and 15 healthy children participated in the study. Compared with the controls, significantly lower plasma levels of β-carotene were found in the CF group and significantly lower plasma levels of vitamin E in the CF and BE groups. The standardization of carotenoid levels for total cholesterol did not significantly attenuate these differences. In addition, there were significantly higher levels of malondialdehyde (a marker of lipid peroxidation) and tumour necrosis factor-α (TNF-α) in children with CF and in children with BE than in normal subjects. After 6 mo of β-carotene supplementation, the plasma levels of β-carotene and vitamin E increased and the plasma levels of TNF-α and malondialdehyde decreased in both groups.
Conclusion : Potent antioxidants, β-carotene and vitamin E are deficient in patients with CF and in patients with BE, and they are more susceptible to oxidative damage. These patients may benefit from β-carotene supplementation.     

Proinflammatory cytokines, prostaglandins and zinc in febrile convulsions

BACKGROUND: Some changes in the levels of proinflammatory cytokines, prostaglandins and zinc (Zn) in peripheral blood and cerebrospinal fluid (CSF) have been suggested to occur for the pathogenesis of febrile convulsions (FC). METHODS: In order to test this hypothesis, the levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 alpha, IL-1 beta and prostaglandins (PGE(2), PGF(2 alpha), PGD(2)) in the CSF and plasma and the levels of Zn in serum and CSF were investigated in children during the acute and late phases of FC. Results were compared with control subjects with meningismus. RESULTS: During the acute phase of FC, children had significantly elevated plasma levels of IL-1 beta, CSF levels of TNF-alpha, plasma levels of PGE(2), PGF(2 alpha) and PGD(2) and CSF levels of PGD(2) (P<0.05). A positive correlation between the degree of fever and plasma IL-1 beta levels was observed in both patients and controls. Three months after the acute phase of FC, plasma levels of IL-1 beta had returned to levels seen in controls. Children with FC also had significantly decreased serum Zn levels during the acute phase (P<0.05). However, there was no significant difference between the groups with respect to CSF Zn levels (P>0.05). CONCLUSIONS: During the acute phase of FC, patients had significantly increased plasma IL-1 beta and prostaglandin levels and decreased serum Zn levels. These changes may be responsible for FC pathogenesis.     

IgA bovine serum albumin antibodies are increased in newly diagnosed patients with insulin-dependent diabetes mellitus, but the increase is not an independent risk factor for diabetes

We studied the significance of antibodies to bovine serum albumin (BSA) as a risk factor for insulin-dependent diabetes mellitus (IDDM) in a case-control setting. IgA and IgG antibodies to BSA and ovalbumin were measured from sera of 104 patients with newly diagnosed IDDM and of 111 matched controls by enzyme-linked immunosorbent assay. Patients with diabetes had significantly higher levels of IgA antibodies to BSA ( p = 0.003); IgG antibodies also tended to be higher ( p = 0.08). Levels of IgA antibodies to ovalbumin were similar in the patients and controls, but IgG antibodies were higher in controls ( p = 0.02). When antibodies to BSA, β-lactoglobulin, whole cow's milk and islet cell antibodies were studied as risk determinants of IDDM in a multivariate, logistic regression analysis, IgA antibodies to β-lactoglobulin and to cow's milk were independently associated with the risk ( p = 0.037 and 0.048, respectively), while antibodies to BSA were not a significant risk factor. The results question the role of BSA as a cross-reacting antigen with pancreatic β-cell surface proteins in the aetiology of IDDM.     

Oxygen free radicals and antioxidants in cystic fibrosis: the concept of an oxidant-antioxidant imbalance

Patients with cystic fibrosis frequently exhibit increased oxygen free radical generation from activated neutrophils due to chronic lung inflammation on the one hand and antioxidant deficiencies due to exocrine pancreatic insufficiency on the other, resulting in an oxidant–antioxidant imbalance in favor of the former. As a consequence, free radical attack on unsaturated fatty acids of lipid structures leading to lipid peroxidation and damaging effects on proteins may occur. In the lung, antiproteases are thought to be inactivated by oxygen free radicals released from inflammatory cells. In the cholestatic liver, bile acids may propagate lipid peroxidation. An efficient antioxidant supply is suggested to control tissue injury by restoring the oxidant-antioxidant balance. Mechanisms involved in the generation of oxygen free radicals are described and data on the antioxidant defense system in cystic fibrosis patients are presented, together with evidence of increased lipid peroxidation. Possible implications for disease processes are discussed as well as therapeutic concepts to reconstitute the oxidant-antioxidant balance.     

Combined heterotopic liver–pancreas transplantation as a curative treatment for liver cirrhosis and diabetes mellitus in cystic fibrosis

Cystic fibrosis (CF) is an inherited disease with a defect in epithelial chloride transport that results in a multisystem disease. Although pulmonary disease remains the primary cause of morbidity and mortality, focal biliary cirrhosis and portal hypertension may develop in up to 8% of these patients. Liver transplantation (TX) is an accepted therapy and shows good results. We report on a patient with cystic fibrosis homozygous for the most common CFTR mutation delta F 508 who received a combined heterotopic liver and pancreas transplantation at the age of 18 yr. He suffered from CFRD, which untypically required high doses of insulin. In addition, the patient had pulmonary complications, was chronically colonized with multiresistant Pseudomonas aeruginosa (MBL) and had an allergic bronchopulmonary aspergillosis (ABPA). The patient remained in stable health for 54 months post‐TX and was able to live a nearly normal life. With a follow‐up of five yr, the function of the liver and pancreas allografts was excellent. However, and sadly, his pulmonary function continued to deteriorate from progression of his CF, and he died of respiratory failure due to a severe pneumonia and septicemia at the age of 23 yr and five months.     

Triple diabetes: coexistence of type 1 diabetes mellitus and a novel mutation in the gene responsible for MODY3 in an overweight adolescent

Abstract:  We report an interesting and unique case of an overweight adolescent with a novel mutation of the maturity-onset diabetes of the young (MODY)3 gene [hepatocyte nuclear factor-1 alpha (HNF-1α)] and positive islet cell autoantibodies. The patient is a 17-yr-old Caucasian female, who was diagnosed with type 2 diabetes mellitus, treated with metformin and glipizide, with poor control for 18 months prior to being referred to the Endocrinology clinic. Family history was strongly positive for type 2 diabetes (father, paternal aunts, uncles, and grandmother). All were diagnosed at age 40–50 and treated with oral hypoglycemic agents. The patient's body mass index was 36.4 kg/m². She had no acanthosis nigricans. Initial hemoglobin A1c was 11.9%, with fasting glucose of 234 mg/dL and fasting insulin 10.7 μU/mL. She was started on insulin therapy (0.6 units/kg/d), resulting in good glycemic control. Oral hypoglycemic agents were discontinued. Immunologic studies showed positive islet cell (29 U/mL, normal <1.0) and glutamic acid decarboxylase-65 (0.9 U/mL, normal <0.5) antibodies. Sequencing for HNF-1α gene revealed a nucleotide A to G substitution (ACC to GCC), resulting in a missense mutation, T196A. To our knowledge, T196A has not been previously reported. The coexistence of type 1 diabetes autoimmunity and a mutation in the gene responsible for MODY3 in this overweight patient is intriguing and might explain the early onset of progressive insulinopenia compared with the later age of diabetes onset of the earlier generation in the family.     

Chloride and sodium ion concentrations in saliva and sweat as a method to diagnose cystic fibrosis

ObjectiveCystic fibrosis diagnosis is dependent on the chloride ion concentration in the sweat test (≥ 60 mEq/mL – recognized as the gold standard indicator for cystic fibrosis diagnosis). Moreover, the salivary glands express the CFTR protein in the same manner as sweat glands. Given this context, the objective was to verify the correlation of saliva chloride concentration and sweat chloride concentration, and between saliva sodium concentration and sweat sodium concentration, in patients with cystic fibrosis and healthy control subjects, as a tool for cystic fibrosis diagnosis.MethodsThere were 160 subjects enrolled: 57/160 (35.70%) patients with cystic fibrosis and two known CFTR mutations and 103/160 (64.40%) healthy controls subjects. Saliva ion concentration was analyzed by ABL 835 Radiometer^® equipment and, sweat chloride concentration and sweat sodium concentration, respectively, by manual titration using the mercurimetric procedure of Schales & Schales and flame photometry. Statistical analysis was performed by the chi-squared test, the Mann–Whitney test, and Spearman's correlation. Alpha = 0.05.ResultsPatients with cystic fibrosis showed higher values of sweat chloride concentration, sweat sodium concentration, saliva chloride concentration, and saliva sodium concentration than healthy controls subjects (p-value < 0.001). The correlation between saliva chloride concentration and sweat chloride concentration showed a positive Spearman's Rho (correlation coefficient) = 0.475 (95% CI = 0.346 to 0.587). Also, the correlation between saliva sodium concentration and sweat sodium concentration showed a positive Spearman's Rho = 0.306 (95% CI = 0.158 to 0.440).ConclusionsSaliva chloride concentration and saliva sodium concentration are candidates to be used in cystic fibrosis diagnosis, mainly in cases where it is difficult to achieve the correct sweat amount, and/or CFTR mutation screening is difficult, and/or reference methods for sweat test are unavailable to implement or are not easily accessible by the general population.     

Apolipoproteins and Lipoproteins in Children with Type I Diabetes: Relation to Glycosylated Serum Protein and HbA1

ABSTRACT. Serum levels of cholesterol (C), triglycerides (TG), lipoprotein-C and apolipoproteins (apo) A-I, A-II and B were measured in 30 children with type I diabetes mellitus (16 boys, 14 girls, aged 11–14 years) and in 26 healthy controls (15 boys, 11 girls, aged 10–13 years). For 19 diabetics controls matched for age, sex and relative body weight were selected. The diabetic patients were considered to be in fair metabolic control according to HbA₁ levels and glycosylated serum protein concentrations. Mean serum apo A-I, A-II and B, C, TG, low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) did not differ significantly between diabetic and nondiabetic children. Very low density lipoprotein cholesterol (VLDL-C) was significantly higher in diabetic children than in controls. Serum C and LDL-C levels showed close univariate linear correlations with glycosylated serum protein (LDL-C: r =0.53, p <0.01, C: r =0.58, p <0.01) in diabetics. The ratio LDL/HDL-C was significantly correlated to HbA₁ levels ( r =0.47, p <0.01). By canonical and multiple linear correlation analysis significant relations of a selected set of variables concerning the control and therapy of diabetes (serum glucose, HbA₁, glycosylated serum protein, insulin dose) with a set of lipoprotein variables (C, TG, VLDL-C, HDL-C, LDL-C, apo A-I, A-II, B) could be demonstrated. From these data we conclude that significant relations between atherogenic serum lipids and lipoproteins (C, LDL-C) and the degree of metabolic control exist in diabetic children, even in the absence of marked dyslipoproteinemia. The close relation of LDL-C and total C with glycosylated serum protein in the diabetics might be due to glycosylation of LDL .     

High-resolution computed tomography in young patients with cystic fibrosis: distribution of abnormalities and correlation with pulmonary function tests

Objective

To assess pulmonary abnormalities detected by high-resolution computed tomography (HRCT) in young children with cystic fibrosis (CF) and mild to moderate lung disease.

Study design

High-resolution computed tomography was performed in 60 children, 6 to 10 years old, with mild to moderate lung disease (forced expiratory volume in 1 minute [FEV₁], 52-137; mean, 102; SD, 15% predicted). HRCTs were scored by using a system that evaluates each lobe for severity and extent of CF lung disease. Findings of CF lung disease were tabulated in all subjects and in a subgroup with normal pulmonary function tests. HRCT scores were correlated with FEV₁, forced vital capacity (FVC), and forced expiratory flow between 25% and 75% of expired vital capacity (FEF_25-75) in 57 patients.

Results

Bronchiectasis was present in 35% of subjects, mucous plugging in 15%, and air trapping in 63%. No abnormality was detected in 25%. In 37 subjects with FEV₁, FVC, and FEF_25-75 >85% predicted, bronchiectasis was present in 30%. In 17% of these subjects, bronchiectasis was seen in ≥4 lobes. Correlations between HRCT scores and FEV₁ were significant and showed fair to moderate correlation (r = 0.36-0.46).

Conclusions

High-resolution computed tomography demonstrated a broad range of pulmonary abnormalities in young patients with CF with mild to moderate lung disease. In this study, abnormalities, including bronchiectasis, were common in young children with CF and normal pulmonary function tests.