Enza Mozzillo

The Lumbar Bone Mineral Density Is Affected by Long-Term Poor Metabolic Control in Adolescents with Type 1 Diabetes mellitus

Aim: To analyze whether bone mineral density (BMD) and bone resorption status are influenced by long-term metabolic control and duration of disease in adolescents with long-standing type 1 diabetes mellitus. Methods: Twenty-seven adolescents (age 13.1 ± 1.7 years, duration of diabetes 6.9 ± 3.0 years) were studied. The BMD, expressed as z score, was measured at the lumbar spine (L1–L4) using dual-energy X-ray absorptiometry, while the urinary excretion of total deoxypiridinoline (Dpyd), a marker of bone resorption, was measured by immunoassay and was corrected by creatinine (Cr). Linear and multivariate correlations between lumbar BMD z score or Dpyd/Cr excretion and age and disease variables [short-term (Hb A1clatest) or long-term (Hb A1cwholeduration) metabolic control, duration, ‘diabetes impact index’ (mean Hb A1cwholeduration x duration of disease in months)] were sought. Results: In diabetic subjects the mean BMD z score was –0.44 ± (SD) 1.02 (95% CI: –0.03; –0.84), and the Dpyd/Cr excretion was not increased. A negative correlation was found between lumbar BMD z score and age (r –0.59; p = 0.001), duration (r –0.39; p = 0.04), and the diabetes impact index (r –0.4; p = 0.04). The Dpyd/Cr ratio correlated negatively with age (r –0.40; p = 0.04) and positively with height velocity (r 0.42; p = 0.04). By using multiple linear regression, age showed a significant inverse correlation with lumbar BMD z score (β = –0.39; p = 0.0005). A negative correlation was found between lumbar BMD z score and Hb A1cwholeduration (β = –0.40; p = 0.02) or diabetes impact index (β = –0.001; p = 0.01). Conclusions: Poor metabolic control may expose adolescents with long-standing type 1 diabetes to the risk of developing osteopenia in adult age. Optimization of metabolic control in growing diabetic children may prevent osteoporosis in later life.

Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants

Human regulatory T cells (Treg cells) that develop from conventional T cells (Tconv cells) following suboptimal stimulation via the T cell antigen receptor (TCR) (induced Treg cells (iTreg cells)) express the transcription factor Foxp3, are suppressive, and display an active proliferative and metabolic state. Here we found that the induction and suppressive function of iTreg cells tightly depended on glycolysis, which controlled Foxp3 splicing variants containing exon 2 (Foxp3-E2) through the glycolytic enzyme enolase-1. The Foxp3-E2–related suppressive activity of iTreg cells was altered in human autoimmune diseases, including multiple sclerosis and type 1 diabetes, and was associated with impaired glycolysis and signaling via interleukin 2. This link between glycolysis and Foxp3-E2 variants via enolase-1 shows a previously unknown mechanism for controlling the induction and function of Treg cells in health and in autoimmunity.

One-year glargine treatment can improve the course of lung disease in children and adolescents with cystic fibrosis and early glucose derangements

Background:  Diabetes increases morbidity and mortality in cystic fibrosis (CF) patients, but several studies indicate that also prediabetic status may have a potential impact on both nutrition and lung function.

Celiac disease in type 1 diabetes mellitus

Celiac Disease (CD) occurs in patients with Type 1 Diabetes (T1D) ranging the prevalence of 4.4-11.1% versus 0.5% of the general population. The mechanism of association of these two diseases involves a shared genetic background: HLA genotype DR3-DQ2 and DR4-DQ8 are strongly associated with T1D, DR3-DQ2 with CD. The classical severe presentation of CD rarely occurs in T1D patients, but more often patients have few/mild symptoms of CD or are completely asymptomatic (silent CD). In fact diagnosis of CD is regularly performed by means of the screening in T1D patients. The effects of gluten-free diet (GFD) on the growth and T1D metabolic control in CD/T1D patient are controversial. Regarding of the GFD composition, there is a debate on the higher glycaemic index of gluten-free foods respect to gluten-containing foods; furthermore GFD could be poorer of fibers and richer of fat. The adherence to GFD by children with CD-T1D has been reported generally below 50%, lower respect to the 73% of CD patients, a lower compliance being more frequent among asymptomatic patients. The more severe problems of GFD adherence usually occur during adolescence when in GFD non compliant subjects the lowest quality of life is reported. A psychological and educational support should be provided for these patients.

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.

A novel CISD2 intragenic deletion, optic neuropathy and platelet aggregation defect in Wolfram syndrome type 2.

BackgroundWolfram Syndrome type 2 (WFS2) is considered a phenotypic and genotypic variant of WFS, whose minimal criteria for diagnosis are diabetes mellitus and optic atrophy. The disease gene for WFS2 is CISD2. The clinical phenotype of WFS2 differs from WFS1 for the absence of diabetes insipidus and psychiatric disorders, and for the presence of bleeding upper intestinal ulcers and defective platelet aggregation. After the first report of consanguineous Jordanian patients, no further cases of WFS2 have been reported worldwide. We describe the first Caucasian patient affected by WFS2.Case presentationThe proband was a 17 year-old girl. She presented diabetes mellitus, optic neuropathy, intestinal ulcers, sensorineural hearing loss, and defective platelet aggregation to ADP. Genetic testing showed a novel homozygous intragenic deletion of CISD2 in the proband. Her brother and parents carried the heterozygous mutation and were apparently healthy, although they showed subclinical defective platelet aggregation. Long runs of homozygosity analysis from SNP-array data did not show any degree of parental relationship, but the microsatellite analysis confirmed the hypothesis of a common ancestor.ConclusionOur patient does not show optic atrophy, one of the main diagnostic criteria for WFS, but optic neuropathy. Since the “asymptomatic” optic atrophy described in Jordanian patients is not completely supported, we could suppose that the ocular pathology in Jordanian patients was probably optic neuropathy and not optic atrophy. Therefore, as optic atrophy is required as main diagnostic criteria of WFS, it might be that the so-called WFS2 could not be a subtype of WFS. In addition, we found an impaired aggregation to ADP and not to collagen as previously reported, thus it is possible that different experimental conditions or inter-patient variability can explain different results in platelet aggregation. Further clinical reports are necessary to better define the clinical spectrum of this syndrome and to re-evaluate its classification.

Thiamine responsive megaloblastic anemia: a novel SLC19A2 compound heterozygous mutation in two siblings

Thiamine responsive megaloblastic anemia (TRMA) is an autosomal recessive disease caused by loss of function mutations in the SLC19A2 gene. TRMA is characterized by anemia, deafness, and diabetes. In some cases, optic atrophy or more rarely retinitis pigmentosa is noted. We now report two sisters, the eldest of which presented to a different hospital during childhood with sensorineural deafness, which was treated with a hearing prosthesis, insulin requiring diabetes, retinitis pigmentosa, optic atrophy, and macrocytic anemia. These features initially suggested a clinical diagnosis of Wolfram syndrome (WS). Therapy with thiamine was initiated which resulted in the resolution of the anemia. The younger sister, who was affected with sensorineural deafness, was referred to our hospital for non‐autoimmune diabetes. She was found to have macrocytosis and ocular abnormalities. Because a diagnosis of TRMA was suspected, therapy with insulin and thiamine was started. Sequencing analysis of the SLC19A2 gene identified a compound heterozygous mutation p.Y81X/p.L457X (c.242insA/c.1370delT) in both sisters. Non‐autoimmune diabetes associated with deafness and macrocytosis, without anemia, suggests a diagnosis of TRMA. Patients clinically diagnosed with WS with anemia and/or macrocytosis should be reevaluated for TRMA.

Glucose derangements in very young children with cystic fibrosis and pancreatic insufficiency.

Cystic fibrosis–related diabetes (CFRD) is considered the most common comorbidity in patients affected by cystic fibrosis (CF), with a prevalence increasing with age (1). Recently, more attention has been turned to other less severe glucose metabolism derangements (GMD), since prediabetes may be related to increased morbidity (1), and early treatment may improve the clinical course in patients with CF (2). According to recent guidelines released by the Cystic Fibrosis Foundation, the American Diabetes Association, and the Pediatric Endocrine Society, the oral glucose tolerance test (OGTT) is recommended yearly in patients with CF over 10 years of age (3). Some authors recommend annual OGTT after the age of 6 years in CF patients with pancreatic insufficiency (4). In …

Meta-Immunological Profiling of Children With Type 1 Diabetes Identifies New Biomarkers to Monitor Disease Progression

Type 1 diabetes is characterized by autoimmune destruction of pancreatic β-cells in genetically susceptible individuals. Triggers of islet autoimmunity, time course, and the precise mechanisms responsible for the progressive β-cell failure are not completely understood. The recent escalation of obesity in affluent countries has been suggested to contribute to the increased incidence of type 1 diabetes. Understanding the link between metabolism and immune tolerance could lead to the identification of new markers for the monitoring of disease onset and progression. We studied several immune cell subsets and factors with high metabolic impact as markers associated with disease progression in high-risk subjects and type 1 diabetic patients at onset and at 12 and 24 months after diagnosis. A multiple correlation matrix among different parameters was evaluated statistically and assessed visually on two-dimensional graphs. Markers to predict residual β-cell function up to 1 year after diagnosis were identified in multivariate logistic regression models. The meta-immunological profile changed significantly over time in patients, and a specific signature that was associated with worsening disease was identified. A multivariate logistic regression model measuring age, BMI, fasting C-peptide, number of circulating CD3+CD16+CD56+ cells, and the percentage of CD1c+CD19−CD14−CD303− type 1 myeloid dendritic cells at disease onset had a significant predictive value. The identification of a specific meta-immunological profile associated with disease status may contribute to our understanding of the basis of diabetes progression.

Monogenic Diabetes Accounts for 6.3% of Cases Referred to 15 Italian Pediatric Diabetes Centers During 2007 to 2012

Context An etiologic diagnosis of diabetes can affect the therapeutic strategy and prognosis of chronic complications. Objective The aim of the present study was to establish the relative percentage of different diabetes subtypes in patients attending Italian pediatric diabetes centers and the influence of an etiologic diagnosis on therapy. Design, Setting, and Patients This was a retrospective study. The clinical records of 3781 consecutive patients (age, 0 to 18 years) referred to 15 pediatric diabetes clinics with a diagnosis of diabetes or impaired fasting glucose from January 1, 2007 to December 31, 2012 were examined. The clinical characteristics of the patients at their first referral to the centers, type 1 diabetes-related autoantibodies, molecular genetics records, and C-peptide measurements, if requested for the etiologic diagnosis, were acquired. Main Outcome Measures The primary outcome was to assess the percentage of each diabetes subtype in our sample. Results Type 1 diabetes represented the main cause (92.4%) of diabetes in this group of patients, followed by monogenic diabetes, which accounted for 6.3% of cases [maturity onset diabetes of the young (MODY), 5.5%; neonatal diabetes mellitus, 0.6%, genetic syndromes, 0.2%]. A genetic diagnosis prompted the transfer from insulin to sulphonylureas in 12 patients bearing mutations in the HNF1A or KCNJ11 genes. Type 2 diabetes was diagnosed in 1% of the patients. Conclusions Monogenic diabetes is highly prevalent in patients referred to Italian pediatric diabetes centers. A genetic diagnosis guided the therapeutic decisions, allowed the formulation of a prognosis regarding chronic diabetic complications for a relevant number of patients (i.e.,GCK/MODY), and helped to provide genetic counseling.