Giuseppe d’Annunzio

In type 1 diabetes a subset of anti-coxsackievirus B4 antibodies recognize autoantigens and induce apoptosis of pancreatic beta cells.

Type 1 diabetes is characterized by autoimmune destruction of pancreatic beta cells. The role played by autoantibodies directed against beta cells antigens in the pathogenesis of the disease is still unclear. Coxsackievirus B infection has been linked to the onset of type 1 diabetes; however its precise role has not been elucidated yet. To clarify these issues, we screened a random peptide library with sera obtained from 58 patients with recent onset type 1 diabetes, before insulin therapy. We identified an immunodominant peptide recognized by the majority of individual patients’sera, that shares homology with Coxsackievirus B4 VP1 protein and with beta-cell specific autoantigens such as phogrin, phosphofructokinase and voltage-gated L-type calcium channels known to regulate beta cell apoptosis. Antibodies against the peptide affinity-purified from patients’ sera, recognized the viral protein and autoantigens; moreover, such antibodies induced apoptosis of the beta cells upon binding the L-type calcium channels expressed on the beta cell surface, suggesting a calcium dependent mechanism. Our results provide evidence that in autoimmune diabetes a subset of anti-Coxsackievirus antibodies are able to induce apoptosis of pancreatic beta cells which is considered the most critical and final step in the development of autoimmune diabetes without which clinical manifestations do not occur.

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.

Epilepsia partialis continua in type 1 diabetes: evolution into epileptic encephalopathy with continuous spike-waves during slow sleep.

Hyperglycemic status may be rarely complicated by Epilepsia partialis continua (EPC) that usually responds to metabolic normalization. Anti-glutamic acid decarboxylase antibodies (GAD-Ab) play a pivotal role in the autoimmune process that leads to clinical onset of type 1 diabetes mellitus (T1DM). GAD-Ab have been recently reported in association with rare forms of refractory epilepsy, with or without association to T1DM. Here we describe a young patient who developed EPC five months after T1DM onset; GAD-Ab were detected in his cerebrospinal fluid with evidence of oligoclonal bands. His epileptic disorder evolved over time into drug-resistant epilepsy with continuous spike-waves during slow sleep and severe behavioral impairment. The role of both metabolic imbalance and GAD autoimmunity is discussed.

Recommendations for self-monitoring in pediatric diabetes: a consensus statement by the ISPED

A panel of experts of the Italian Society of Pediatric Endocrinology and Diabetology comprehensively discussed and approved the Italian recommendations regarding self-monitoring of blood glucose, continuous glucose monitoring and other measures of glycemic control in children and adolescents with type 1 diabetes. After an extensive review of the literature, we took these issues into account: self-monitoring blood glucose, continuous glucose monitoring, glycemic variability, glycosuria, ketonuria, ketonemia, glycated hemoglobin, fructosamine and glycated albumin, logbook, data downloading, lancing devices, carbohydrate counting, and glycemic measurements at school. We concluded that clinical guidelines on self-management should be developed in every country with faithful adaptation to local languages and taking into account specific contexts and local peculiarities, without any substantial modifications to the international recommendations. We believe that the National Health Service should provide all necessary resources to ensure self-monitoring of blood glucose and possibly continuous glucose monitoring of all children and adolescents with type 1 diabetes, according to the standards of care provided by these recommendations and internationally.

Italian translation, cultural adaptation and validation of the PedsQL™ 3.0 Diabetes Module questionnaire in children with type 1 diabetes and their parents.

BackgroundThe PedsQL™3.0 Diabetes Module is a widely used instrument to measure the disease-specific health-related quality of life summary measures in children and adolescents with type 1 diabetes. After cultural adaptation, we confirmed reliability and validity of PedsQL™3.0 Diabetes Module in its Italian version.MethodsParticipants were 169 Italian children and adolescents with type 1 diabetes aged 5–18 years and 100 parents. Reliability was determined by internal consistency using Cronbach’s coefficient alpha, and test-retest reliability by intra-class correlation coefficient (ICC). Validity was assessed through factor validity examined by exploratory factor analysis, and discriminant validity examined through multitrait/multi-item scaling analysis. Discriminant validity with respect to dichotomous patients’ characteristics at baseline was also examined through a multivariate analysis on the summary measures using the Wilks’ Lambda test.ResultsData completeness was optimal. Item internal consistency was satisfied at 89% for the child self-report scales and at 100% for the parents’ proxy-report scales. Most diabetes module scales was acceptable for group comparisons. Discriminant validity was satisfied for 71% of children and adolescents and for 82% of parents. A ≥70% Cronbach’s α coefficient was found for the summary measures of both reports. For the test-retest reliability, the ICC coefficients ranged from 0.66 (i.e., the Worry scale) to 0.82 for the other scales of the child self-report. The ICC coefficients were ≥0.87 for all the parents’ proxy-report scales. Factor analysis showed that the PedsQL™3.0 Diabetes Module for child self-report could be summarized in 10 components, which explained the 62% of the variance. For the parent proxy-report the statistical analysis selected 9 factors, which explained about 68% of variance. The external discriminant validity of the PedsQL™3.0 Diabetes Module summary measures were compared across gender, age, time since diagnosis and HbA1c mean cut off values. Significant differences in the “Treatment adherence” scale and in the “Communication” scale were observed across age, and by time since diagnosis.ConclusionsThe results show the reliability and validity of the Italian translation of the PedsQL™3.0 Diabetes Module, supporting therefore its use as an outcome measure for diabetes cross-national clinical trials and research.

Comment on Craig et al. Prevalence of Celiac Disease in 52,721 Youth With Type 1 Diabetes: International Comparison Across Three Continents. Diabetes Care 2017;40:1034-1040

We read with interest the data by Craig et al. (1) about the prevalence of celiac disease (CD) in 52,721 youth with type 1 diabetes (T1D). The authors found a prevalence of 3.5% based on four national registries (range 1.9–7.7). We would like to share the experience of five centers of pediatric diabetes care of northern Italy (Bologna, Florence, Genoa, Trento, and Turin): we recently collected data on 2,164 children and adolescents with T1D and found 213 subjects affected by both CD and T1D (punctual prevalence 9.8% [range 6.8–12.8]). As in Italy there is no registry for pediatric diabetes, and in order to avoid a “hot spot effect” (big centers attract …

Can HbA1c combined with fasting plasma glucose help to assess priority for GCK-MODY vs HNF1A-MODY genetic testing?

Maurizio Delvecchio1 · Giuseppina Salzano2 · Clara Bonura3 · Vittoria Cauvin4 · Valentino Cherubini5 · Giuseppe d’Annunzio6 · Adriana Franzese7 · Sabrina Giglio8 · Valeria Grasso9 · Vanna Graziani10 · Dario Iafusco11 · Lorenzo Iughetti12 · Riccardo Lera13 · Claudio Maffeis14 · Giulio Maltoni15 · Vilma Mantovani16 · Claudia Menzaghi17 · Patrizia I. Patera18 · Ivana Rabbone19 · Petra Reindstadler20 · Sabrina Scelfo21 · Nadia Tinto22 · Sonia Toni23 · Stefano Tumini24 · Fortunato Lombardo2 · Antonio Nicolucci25 · Fabrizio Barbetti9,26 · The Diabetes Study Group of the Italian Society of Pediatric Endocrinology and Diabetes (ISPED)

Hyperglycaemia and β-cell antibodies: Is it always pre-type 1 diabetes?

We describe 10-year-old girl with mild incidental hyperglycaemia, impaired glucose tolerance and GADA positivity. Family history for mild hyperglycaemia and GADA fluctuation alerted us to a possible MODY diagnosis which was confirmed by detection of GCK mutation c.626C>T; p.T209M. Weak or transient β-cell autoimmunity should not preclude genetic testing for MODY when the clinical features are suggestive.

A mild impairment of K+ATP channel function caused by two different ABCC8 defects in an Italian newborn

with frequent glucose-enriched meals or continuous intravenous high-rate glucose infusion to maintain normoglycemia [1]. In pancreatic β-cells, ATP-sensitive K+channel (K+ATP) regulates glucose-stimulated insulin secretion. K+ATP is composed by 4 ion channels (Kir6.2) and 4 regulatory sulphonylurea receptors (SUR1). They are also present in brain and in other neuroendocrine tissues [1]. Inactivating mutations in ABCC8 and KCNJ11, encoding, respectively, SUR1 and Kir6.2 subunits of the β-cell (K+ATP), are the most common causes [1]. Congenital hyperinsulinism can also be associated with mutations in the HNF4A gene, a cause of maturity onset diabetes of the young (MODY). A dual phenotype is observed in HNF4A-MODY with hyperinsulinemic hypoglycemia in the neonatal period progressing to diabetes in adulthood [2]. We present an infant carrying two ABCC8 mutations with a family history of hypoglycemia in infancy and diabetes mellitus in adulthood.

Glucokinase mutations in pediatric patients with impaired fasting glucose

AbstractAimsOur aim was to detect the frequency of glucokinase (GCK) gene mutations in a cohort of patients with impaired fasting glucose and to describe the clinical manifestations of identified variants. We also aimed at predicting the effect of the novel missense mutations by computational approach. MethodsOverall 100 unrelated Italian families with impaired fasting glucose were enrolled and subdivided into two cohorts according to strict and to mild criteria for diagnosis of maturity-onset diabetes of the young (MODY). GCK gene sequencing was performed in all participants. ResultsFifty-three Italian families with 44 different mutations affecting the GCK and co-segregating with the clinical phenotype of GCK/MODY were identified. All mutations were in heterozygous state. In Sample 1, GCK defects were found in 32/36 (88.9%) subjects selected with strict MODY diagnostic criteria, while in Sample 2 GCK defects were found in 21/64 (32.8%) subjects selected with mild MODY diagnostic criteria.ConclusionsOur study enlarged the wide spectrum of GCK defects by adding 9 novel variants. The application of strict recruitment criteria resulted in 88.9% incidence of GCK/MODY, which confirmed it as the commonest form of MODY in the Italian population. In order to avoid misdiagnosis of GCK/MODY, it could be useful to perform molecular screening even if one or more clinical parameters for the diagnosis of MODY are missing. Computational analysis is useful to understand the effect of GCK defect on protein functionality, especially when the novel identified variant is a missense mutation and/or parents’ DNA is not available.