Clinical and molecular characterization of a novel INS mutation identified in patients with MODY phenotype.

Correct diagnosis of Maturity-Onset Diabetes of the Young (MODY) is based on genetic tests requiring an appropriate subject selection by clinicians. Mutations in the insulin (INS) gene rarely occur in patients with MODY. This study is aimed at determining the genetic background and clinical phenotype in patients with suspected MODY. 34 patients with suspected MODY, negative for mutations in the GCK, HNF1α, HNF4α, HNF1ß and PDX1 genes, were screened by next generation sequencing (NGS). A heterozygous INS mutation was identified in 4 members of the same family. First genetic tests performed identified two heterozygous silent nucleotide substitutions in MODY3/HNF1α gene. An ineffective attempt to suspend insulin therapy, administering repaglinide and sulphonylureas, was made. DNA was re-sequenced by NGS investigating a set of 102 genes. Genes implicated in the pathway of pancreatic ß-cells, candidate genes for type 2 diabetes mellitus and genes causative of diabetes in mice were selected. A novel heterozygous variant in human preproinsulin INS gene (c.125T > C) was found in the affected family members. The new INS mutation broadens the spectrum of possible INS phenotypes. Screening for INS mutations is warranted not only in neonatal diabetes but also in MODYx patients and in selected patients with type 1 diabetes mellitus negative for autoantibodies. Subjects with complex diseases without a specific phenotype should be studied by NGS because Sanger sequencing is ineffective and time consuming in detecting rare variants.

Continuous subcutaneous infusion of protein C concentrate using an insulin pump in a newborn with congenital protein C deficiency.

We describe the case of a newborn presenting with multicystic encephalomalacy, hydrocephalus and bilateral hemovitreous. An underlying coagulation disorder was suspected and laboratory tests revealed severe protein C deficiency. At 25 days of life, after the appearance of purpura fulminans, replacement therapy with intravenous protein C concentrate (Ceprotin; Baxter, Vienna, Austria) was started.Due to difficulties in getting peripheral venous access and to repeated loss of the venous access, continuous subcutaneous infusion of protein C was started with an insulin pump (VEO 754; Medtronic, Minneapolis, Minnesota, USA), normally adopted in patients with type 1 diabetes mellitus. Protein C values increased into the normal range and the resolution of the purpuric skin lesion was achieved. Chronic prophylaxis with low-molecular-weight heparin failed and, due to cutaneous and cerebral recrudescence, replacement therapy with the pump was started again. The insulin pump allowed us to reduce the number of injections per day and to deal with the difficulties in getting peripheral venous access, permitting medical and paramedical staff an easier management of the therapy. The dosing schedule could be easily adapted with the insulin pump and the continuous subcutaneous administration of small amounts of protein C concentrate prevented fluctuation in trough levels of protein C. This is the first reported case of a novel, successful use of an insulin pump in an extremely rare disease, to administer a drug different from insulin, which needs to be further analyzed, underlining the importance of a multidisciplinary team approach in order to provide effective and efficient care in high-complexity diseases.

Specific use of CSII during enteral nocturnal nutrition in a child with type 1 diabetes, Hashimoto's thyroiditis, and Down syndrome.

The management of insulin therapy in diabetic patients who have comorbidities that involve nutritional aspects, is a major challenge for diabetes care teams. In diabetic patients with compromised nutritional status, artificial nutrition, both enteral or parenteral, may help in the treatment of chronic and acute diseases, leading to better and faster recover of the health status but, if not adequately associated with insulin therapy, it may negatively affect blood glucose levels and lead to poorer metabolic control. In particular, evidence-based recommendations for the treatment of diabetic patients during enteral nutrition therapy are not currently available and, therefore, medical practices are often based on case reports, rather than outcomes of research. We report our experience with a diabetic patient receiving nocturnal enteral feeding due to comorbidities and malnutrition, who was followed up at our centre and precociously treated with continuous subcutaneous insulin infusion after the onset of type 1 diabetes. There is great need for adequately powered randomized controlled trials to provide scientific evidence for the insulin treatment of diabetic patients undergoing enteral feeding.

Specific use of CSII during enteral nocturnal nutrition in a child with type 1 diabetes, Hashimoto's thyroiditis, and Down syndrome / Uso específico de ISCI durante a nutrição enteral noturna em criança com diabetes tipo 1, tireoidite de Hashimoto e síndrome de Down

The management of insulin therapy in diabetic patients who have comorbidities that involve nutritional aspects, is a major challenge for diabetes care teams. In diabetic patients with compromised nutritional status, artificial nutrition, both enteral or parenteral, may help in the treatment of chronic and acute diseases, leading to better and faster recover of the health status but, if not adequately associated with insulin therapy, it may negatively affect blood glucose levels and lead to poorer metabolic control. In particular, evidence-based recommendations for the treatment of diabetic patients during enteral nutrition therapy are not currently available and, therefore, medical practices are often based on case reports, rather than outcomes of research. We report our experience with a diabetic patient receiving nocturnal enteral feeding due to comorbidities and malnutrition, who was followed up at our centre and precociously treated with continuous subcutaneous insulin infusion after the onset of type 1 diabetes. There is great need for adequately powered randomized controlled trials to provide scientific evidence for the insulin treatment of diabetic patients undergoing enteral feeding.

O manejo da terapia com insulina em pacientes diabéticos que têm comorbidades que envolvam aspectos nutricionais é um grande desafio para os especialistas em diabetes. Em pacientes diabéticos com estado nutricional comprometido, a nutrição artificial, tanto enteral quanto parenteral, pode ajudar no tratamento de doenças crônicas e agudas, levando à recuperação melhor e mais rápida do estado de saúde. Entretanto, se não adequadamente associada à terapia com insulina, a nutrição artificial pode afetar negativamente os níveis de glucose e levar a um pior controle glicêmico. Particularmente, não há recomendações baseadas em evidências para o tratamento de pacientes diabéticos durante a terapia nutricional enteral e, portanto, as práticas médicas são geralmente baseadas em relatos de caso, em vez de desfechos de estudos. Relatamos nossa experiência com uma paciente diabética que recebeu nutrição enteral noturna em função de comorbidades e desnutrição, acompanhada no nosso centro e tratada precocemente com infusão subcutânea contínua de insulina depois do estabelecimento do diabetes tipo 1. Existe grande necessidade de estudos randomizados controlados para se obter evidências científicas sobre o tratamento insulínico de pacientes diabéticos que sejam submetidos à nutrição enteral.

Thyroid autoimmunity and type 1 diabetes in children and adolescents: screening data from Juvenile Diabetes Tuscany Regional Centre.

BACKGROUND AND AIMS: The incidence of autoimmune thyroiditis in patients with type 1 diabetes mellitus (T1DM) is higher than in healthy population. The aim of this study is to investigate epidemiology and natural history of thyroid autoimmunity (AIT), thyroiditis diagnosis and need for therapy in paediatric patients with T1DM and to find the most suitable timing of AIT screening. METHODS: T1DM patients (493 pts., 268 males and 225 females) treated in the Juvenile Diabetes Tuscany Regional Centre at Meyer's Children Hospital were enrolled to determine TSH, fT4, thyroid autoantibodies levels and to undergo thyroid ultrasound. Anamnestic data about T1DM onset, AIT onset, time frame between T1DM and AIT onsets and the relationship between AIT and celiac disease (CD) were studied. RESULTS: In the screened population 11.7% of patients presented with increased thyroid autoantibodies, and 63.6% of them showed positive thyroid ultrasound. AIT was significantly more frequent in females compared to males (p < 0.01). The mean age at AIT onset was 11.17 +/- 3.29 years (range 4.99-20, 30) and AIT onset before 12 yrs. of age was found in 54.5% of cases; 18.4% patients (all females) presented CD. The mean time between T1DM and AIT onset was 2.46 +/- 3.41 years (range 0-13, 41). The subgroup with increased thyroid autoantibodies was not statistically different from the whole population with regard to TDM1 duration and mean age at onset. CONCLUSIONS: AIT is frequently associated with T1DM (11.7%) regardless of age and duration of diabetes. We suggest a yearly screening for AIT after TDM1 onset, at every age.