Type 1 diabetes mellitus and asthma: A follow-up study

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Growth factors and metabolic markers in cord blood: relationship to birth weight and length.

Low birth weight and length for gestational age are associated with a high risk of short stature and metabolic syndrome in adulthood. The mechanisms that link prenatal growth to adult stature and metabolic syndrome have not yet been entirely clarified. The aim of our study was to evaluate the relationship between standardized anthropometric measures at birth and insulin-like growth factor (IGF)-I, IGF-II, insulin, adiponectin, and non-esterified fatty acid (NEFA) cord blood levels in the general population. One hundred fifty-eight random newborn subjects (77F, 81M) from Genoa, Italy, were analyzed. Anthropometric parameters were measured and standardized according to standard Italian tables. Insulin values were treated as categorical, since in several cases the results fell below detection cut-off. Mean birth weight was 3,214.23∓488.99 gr and mean length was 49.82∓2.17 cm. Females had higher mean IGF-I (p=0.04), and were more likely to have insulin values either <2 μU/ml or >4.5μU/ml (p= 0.04) compared to males. Weight and length SD scores (SDS) were higher in subjects with elevated insulin levels (p=0.002). A moderate correlation was found between weight and IGF-II (r=0.354). Multivariable analysis demonstrated that standardized birth weight was associated with IGFII and insulin values. Our data highlight the importance of IGF-II in fetal growth and suggest that gender differences should be taken into consideration when evaluating prenatal growth.

Molecular cytogenetic characterization of the first reported case of an inv dup (4p)(p15.1-pter) with a concomitant 4q35.1-qter deletion and normal parents.

Inverted duplications associated with terminal deletions are complex anomalies described in an increasing of chromosome ends. We report on the cytogenetic characterization of the first de novo inv dup del(4) with partial 4p duplication and 4q deletion in a girl with clinical signs consistent with "recombinant 4 syndrome". This abnormality was suspected by banding, but high-resolution molecular cytogenetic investigations allowed us to define the breakpoints of the rearrangement. The terminal duplicated region extending from 4p15.1 to the telomere was estimated to be 29.27 Mb, while the size of the terminal deletion was 3.114 Mb in the 4q35.1 region. Until now, 10 patients with duplicated 4p14-p15 and deleted 4q35 chromosome 4 have been described. In all cases the abnormal chromosome 4 was derived from a pericentric inversion inherited from one of the parents. In conclusion, we have identified the first case of inv dup del(4) with normal parents suggesting that, often, terminal duplications or terminal deletions mask complex rearrangements.

Retinopathy screening in patients with type 1 diabetes diagnosed in young age using a non-mydriatic digital stereoscopic retinal imaging.

BACKGROUND: Diabetic retinopathy seriously impairs patients' quality of life, since it represents the first cause of blindness in industrialized countries. AIM: To estimate prevalence of retinopathy in young Type 1 diabetes patients using a non-mydriatic digital stereoscopic retinal imaging (NMDSRI), and to evaluate the impact of socio-demographic, clinical, and metabolic variables. SUBJECTS AND METHODS: In 247 young patients glycated hemoglobin (HbA1c), gender, age, pubertal stage, presence of diabetic ketoacidosis (DKA), HLA-DQ heterodimers of susceptibility for Type 1 diabetes, and ß-cell autoimmunity at clinical onset were considered. At retinopathy screening, we evaluated age, disease duration, pubertal stage, body mass index (BMI-SDS), insulin requirement, HbA1c levels, other autoimmune diseases, diabetes-related complications, serum concentrations of cholesterol and triglycerides, systolic and diastolic blood pressure. RESULTS: Retinopathy was found in 26/247 patients: 25 showed background retinopathy, and 1 had a sight-threatening retinopathy. A significant relationship between retinopathy and female gender (p=0.01), duration of disease ≥15 yr (p<0.0001), serum triglycerides levels >65 mg/dl (p=0.012) and mean HbA1c ≥7.5% or >9% (p=0.0014) were found at the multivariate logistic analysis. CONCLUSIONS: Metabolic control is the most important modifiable factor and promotion of continuous educational process to reach a good metabolic control is a cornerstone to prevent microangiopathic complications. Symptoms appear when the complication is already established; a screening program with an early diagnosis is mandatory to prevent an irreversible damage.

The ALBA project: an evaluation of needs, management, fears of Italian young patients with type 1 diabetes in a school setting and an evaluation of parents' and teachers' perceptions.

OBJECTIVE: To determine how Italian parents and school personnel of 6-13-year-old children with type 1 diabetes (T1D) manage during school hours, including insulin administration, management of hypoglycemia, and glucagon use. A further aim was an investigation into the responsibilities and training of school personnel regarding diabetes. RESEARCH DESIGN AND METHODS: After an initial qualitative phase, semi-structured questionnaires were completed by a sample of parents and teachers. RESULTS: 220 parent and 52 teacher questionnaires were completed. 43.6% of parents said diabetes had negatively influenced school activities. Children either self-administer insulin, or have help from a parent, since there is very rarely a nurse present (3.6%) or a teacher who will take responsibility for the treatment (2.9%). Most parents (55.9%) stated either that the school had no refrigerator to store glucagon or that they did not know if the school was so equipped. A small percentage of teachers considered their schools to be equipped to manage an emergency (23%) and said they would use glucagon directly in an emergency (14.9%). Only 40.4% of teachers said that they had received any specific training. CONCLUSIONS: The study shows that people who are not directly involved have superficial knowledge of the different aspects of diabetes, even though no parents reported episodes of neglect/incorrect management. There is no legislation which clearly defines the role of the school in the care of children with T1D, and teachers are not trained to help them. Training sessions for school personnel and greater legislative clarity about the 'insulin and glucagon question' are key factors that may improve the full integration of the child with diabetes.

Serum transforming growth factor ß1 during diabetes development in non-obese diabetic mice and humans.

Recent data show that regulatory cells with transforming growth factor (TGF)-ß1-dependent activity are able to restore self-tolerance in overtly diabetic non-obese diabetic (NOD) mice. Thus, TGF-ß1 seems to have a relevant role in protection from autoimmune diabetes. Our aim was to investigate the possible significance of serum TGF-ß1 measurement in the natural history of diabetes in NOD mice, as well as in children positive for at least one islet-related antibody. Serum TGF-ß1 (both total and active) was measured by enzyme-linked immunosorbent assay at monthly intervals in 26 NOD mice during the spontaneous development of diabetes and, on a yearly basis, in nine siblings of patients with type 1 diabetes (T1D) with a follow-up of 4 years. Diabetes appeared between the 12th week of age and the end of the study period (36 weeks) in 17 mice. TGF-ß1 serum level variations occurred in the prediabetic period in both NOD mice and humans and diabetes diagnosis followed a continuing reduction of active TGF-ß1 (aTGF-ß1) serum levels. In mice, aTGF-ß1 serum levels measured at 4 weeks of age correlated positively with severity of insulitis, and negatively with percentage of insulin-positive cells. Our findings suggest that in NOD mice serum TGF-ß1 levels during the natural history of the diabetes reflect the course of islet inflammation. The measurement of aTGF-ß1 in islet-related antibody-positive subjects may provide insights into the natural history of prediabetic phase of T1D.

Genetic investigation in an Italian child with an unusual association of atrial septal defect, attributable to a new familial GATA4 gene mutation, and neonatal diabetes due to pancreatic agenesis.

AIMS: Permanent neonatal diabetes is a rare condition affecting 1 in 300,000-400,000 live births; only in 60% of cases it is possible to identify the genetic defect. The condition of pancreatic agenesis is rarer still. Only two genes are known to determine this phenotype: PDX-1 and PTF1A. Congenital heart defects are among the most common developmental anomalies, affecting 1% of newborns, and the GATA4 gene is less frequently involved in these disorders. An Italian child with pancreatic agenesis and an atrial septal defect was genetically investigated to elucidate whether the association of the two pathologies was casual, or represented a new pancreatic/cardiac syndrome. METHODS: A panel of pancreas development genes, including GCK, Kir6.2, PTF1A, PDX-1, HNF-1A, NgN3, SOX17, SOX7, SOX9, INS, HNF1-B and SUR1 plus the GATA4 gene, were screened for characterization of pancreatic agenesis and cardiac defect. RESULTS: Screening for genes causing permanent neonatal diabetes was negative. A novel mutation in GATA4 (c1512C>T) was detected and functional characterization confirmed a reduced activity of the protein. In the family members, the GATA4 mutation co-segregates with a cardiac phenotype, but not with pancreatic agenesis. CONCLUSIONS: We describe the first report of pancretic agenesis with an associated cardiac defect and a mutation in the GATA4 gene. We could not establish that the GATA4 mutation was causative for pancreatic agenesis and further genetic investigation to detect the genetic cause of the pancreas agenesis was unsuccessful. We conclude that, the two pathologies are attributable to two independent events.

The osteopontin gene +1239A/C single nucleotide polymorphism is associated with type 1 diabetes mellitus in the Italian population.

Secreted phosphoprotein 1, also known as Osteopontin (Opn), is a proinflammatory cytokine involved in the TH1 response and is highly expressed in the islets and pancreatic lymph nodes of non-obese diabetic mice before the onset of diabetes. In humans, typing of the +1239A/C single nucleotide polymorphism (SNP) in the 3UTR of the Opn gene (SPP1) showed that +1239C carriers displayed higher Opn serum levels than +1239A homozygotes and a higher risk of developing autoimmune/lymphoproliferative syndrome, multiple sclerosis, and systemic lupus erythematosus. The aim of this work is to evaluate whether +1239A/C is also associated with type 1 diabetes mellitus (T1DM). We typed +1239A/C in an initial cohort of 184 T1DM patients and 361 controls, and confirmed our data in a second cohort of 513 patients and 857 controls. In both cohorts, +1239C carriers displayed a significantly higher risk of T1DM than +1239A homozygotes (combined cohorts: OR=1.63, 95 percent CI: 1.34-1.97). Clinical analysis did not detect any differences between patients carrying or not +1239C in terms of gender distribution and age at T1DM diagnosis. These data suggest that SPP1 variants marked by +1239C are associated with T1DM development in the Italian population. The predisposing effect may depend on its effect on Opn levels.

Late onset of pANCA renal and pulmonary vasculitis in a girl affected by undifferentiated connective tissue disease.

Vasculitides are clinicopathologic entities characterized by inflammation and damage of blood vessels. They are heterogeneous diseases related to immunopathogenetic mechanisms. For example, anti-neutrophil cytoplasmic autoantibodies directed against perinuclear or cytoplasmic proteins of neutrophils are present in a high percentage of patients with systemic vasculitis, and they can be suggestive of Wegener's Granulomatosis and Microscopic Polyangiitis. This case report underlines the necessity of more specific laboratory and instrumental testing if clinical signs and/or other parameters (p-ANCA and/or c-ANCA staining and/or urinalysis) are suggestive of systemic vasculitis.

Estimation of genetic risk for Type 1 diabetes mellitus in newborns on dried blood spot.

BACKGROUND: The main contribution to genetic susceptibility for Type 1 Diabetes Mellitus (T1DM) is conferred by the Human Leukocyte Antigens (HLA). AIM: We evaluated the feasibility of large scale screening on Dried Blood Spot (DBS) to estimate the genetic risk for T1DM in newborns. SUBJECTS AND METHODS: Peripheral blood DBS samples from 256 newborns, were genotyped for HLA DRB1 and DQB1 alleles identification by a commercially available assay based on a dissociation enhancer lanthanide fluorescence system available in many newborn screening laboratories. Results were compared with those obtained in two wide multicentric studies on cord blood (DIABFIN and PREVEFIN). RESULTS: Genotyping on DBS revealed 6 subjects at high risk for T1DM, 99 at moderate risk for T1DM and the remaining at low risk for T1DM. We found 100% concordance between both techniques for HLA-DQB1 and DRB1 determination, confirming the feasibility of large scale screening on DBS. CONCLUSIONS: DBSs represent a resource for future studies about new genetics markers. This assay for estimate the genetic risk of T1DM on DBS showed an excellent sensitivity, specificity and accuracy compared with conventional techniques. Moreover, this assay resulted less expensive, and it could be easily performed on material already collected for newborn screening programs.

Folic acid, vitamin B12, and homocysteine levels during fasting and after methionine load in patients with Type 1 diabetes mellitus.

AIMS: To assess plasma concentrations of folic acid, vitamin B12, and total plasma homocysteine (tHCY) during fasting and after methionine load in young patients with Type 1 diabetes mellitus (T1DM). METHODS: We enrolled 41 young patients with T1DM without any sign of microvascular complications and 123 healthy controls in a 1:3 case-control study. Fasting and post-methionine load (PML) tHCY, folic acid, and vitamin B12 levels were measured in both groups. Data regarding chronological age, metabolic control (assessed by mean values of glycated hemoglobin in the last 12 months) and disease duration were also recorded. RESULTS: Fasting and PML tHCY levels were significantly lower in patients than in controls: 7.3+/-2.7 micromol/l vs 8.3+/-2.5 micromol/l (p=0.01), and 16.7+/-5.8 micromol/l vs 17.3+/-4.3 micromol/l (p=0.01), respectively. No correlation was found between fasting and PML tHCY levels and chronological age, disease duration, metabolic control, and insulin requirement. Patients had significantly higher vitamin B12 levels compared to controls: 767+/-318 pg/ml vs 628+/-236 pg/ml (p=0.003), while folic acid turned out to be lower in patients than in controls: 5.3+/-1.9 nmol/l vs 7.5+/-2.6 nmol/l (p<0.0001). CONCLUSIONS: Adolescents and young adults with T1DM without microvascular complications showed lower tHCY both during fasting and after methionine load. Lower folate concentrations in these patients might benefit from food fortification.

The role of lymphoscintigraphy in the diagnosis of lymphedema in Turner syndrome.

Lymphedema can be present in patients affected by Turner syndrome (TS) with the dorsum of the hands and feet most commonly affected. This lymphedema results from underdevelopment of the lymphatic system before birth, and it usually decreases during childhood. The aim of our study was to evaluate the role of lymphoscintigraphy as a diagnostic tool in patients with TS to assess possible impairments in the lymphatic system. Eighteen patients with TS were karyotyped to confirm diagnosis and were evaluated by lymphoscintigraphy. Lymphatic dysfunction was demonstrated in 15/18 patients. Lymphoscintigraphic studies showed: 1) lymphatic channels, 2) collateral lymphatic channels, 3) interrupted lymphatic structures, and 4) lymph nodes of the deep lymphatic system. Our data demonstrate that lymphoscintigraphy should be mandatory not only in patients affected by Turner syndrome with signs of lymphatic dysplasia but also in those with minimal or absent signs of lymphatic impairment in order to obtain a very early diagnosis and to provide substantial information for possible medical or surgical treatment.

Serum Th1 (CXCL10) and Th2 (CCL2) chemokine levels in children with newly diagnosed Type 1 diabetes: a longitudinal study.

AIMS: Cell-mediated immunity and pro-inflammatory cytokines are implicated in the pathogenesis of Type 1 diabetes. The aim of this study was to investigate whether circulating chemokines involved in T-helper 1 (CXCL10) and T-helper 2 (CCL2) autoimmunity are increased in children with Type 1 diabetes at onset and follow-up. METHODS: Serum CXCL10 and CCL2 were measured in 96 children with newly diagnosed Type 1 diabetes, 59 age-matched first-degree relatives of diabetic children and 40 age-matched non-diabetic children with no family history of diabetes. In the diabetic children, an additional serum sample was obtained a median of 16 months after diagnosis. RESULTS: Serum CXCL10 levels were significantly higher in Type 1 children than in relatives or control children (P < 0.001); 44.7% of patients had a serum CXCL10 level >or= 2 standard deviation above the mean value of the control group vs. 3.4% of relatives (P < 0.0001). In contrast, serum CCL2 levels were similar in patients, relatives and control subjects. In the Type 1 diabetic patients at follow-up, CXCL10 was significantly reduced vs. baseline (P = 0.01), while CCL2 did not change. CONCLUSIONS: In children with newly diagnosed Type 1 diabetes, raised serum CXCL10 and normal CCL2 concentrations signal a predominant T-helper 1-driven autoimmune process, which shifts toward T-helper 2 immunity over the first 1-2 years from diagnosis.