Permanent neonatal diabetes mellitus (PNDM) is a rare disorder usually presenting within 6 months of birth.Although several genes have been linked to this disorder, in almost half the cases documented in Italy, the genetic cause remains unknown. Because the Akita mouse bearing a mutation in the Ins2 gene exhibits PNDM associated with pancreatic β cell apoptosis, we sequenced the human insulin gene in PNDM subjects with unidentified mutations. We discovered 7 heterozygous mutations in 10 unrelated probands. In 8 of these patients, insulin secretion was detectable at diabetes onset, but rapidly declined over time. When these mutant proinsulins were expressed in HEK293 cells, we observed defects in insulin protein folding and secretion. In these experiments, expression of the mutant proinsulins was also associated with increased Grp78 protein expression and XBP1 mRNA splicing, 2 markers of endoplasmic reticulum stress, and with increased apoptosis. Similarly transfected INS-1E insulinoma cells had diminished viability compared with those expressing WT proinsulin. In conclusion, we find that mutations in the insulin gene that promote proinsulin misfolding may cause PNDM.

Aims/hypothesis To assess the use of paediatric continuous subcutaneous infusion (CSII) under real-life conditions by analysing data recorded for up to 90 days and relating them to outcome.Methods Pump programming data from patients aged 0-18 years treated with CSII in 30 centres from 16 European countries and Israel were recorded during routine clinical visits. HbA 1c was measured centrally.Electronic supplementary material The online version of this article

Pediatric CSII patients show a high variability in their insulin therapy. This relates both to age-dependent differences in the distribution of basal insulin as to the age-independent day-to-day variation in prandial insulin.

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.

Objective: Children and adolescents with type 1 (insulin-dependent) diabetes mellitus (T1DM) show several impairment of bone metabolism and structure, resulting in a higher risk of decreased bone mass and its related complications later in life. Alterations of the nuclear factor-kB ligand (RANK-L)/osteoprotegerin (OPG) system have been implicated in several metabolic bone diseases characterized by increased osteoclast differentiation and activation and enhanced bone resorption. Design: We aimed to assess OPG levels and to investigate the possible relation between OPG levels, bone status and glycemic control in a group of prepubertal children with T1DM without microvascular complications. Methods: Twenty-six prepubertal T1DM children (median age 9.9 years, range 4.1 -13.1 years) were studied. In all patients, serum OPG, hemoglobin (Hb)A1c, parathyroid hormone (PTH) and 25-dihydroxyvitamin D (25-D) levels were evaluated. Bone quality was determined by measuring the attenuation of ultrasound waves by bone (broadband ultrasound attenuation (BUA)) at the calcaneal site. The data were compared with those of a group of 45 age-, sex-and body-size-matched healthy children. Results: Children with T1DM showed a reduced Z-score BUA in comparison with the control group (Student's t-test, P , 0.0001). Plasma OPG levels were significantly higher in diabetic children than in controls (Student's t-test, P , 0.0001). In T1DM children, Z-score BUA values displayed a significant correlation with OPG (Student's t-test, r ¼ 2 0.62; P ¼ 0.001), and HbA1c (r ¼ 20.59; P ¼ 0.007). OPG levels were significantly correlated with HbA1c (r ¼ 0.56; P ¼ 0.008). In a multiple regression analysis including age, duration of diabetes, physical activity, calcium intake, mean HbA1c and Z-score BUA, only HbA1c significantly predicted serum OPG levels (beta 0.67; P ¼ 0.003). Conclusions: Prepubertal children with T1DM have a significant increase of OPG levels. OPG serum concentrations are correlated to calcaneal BUA and HbA1c values. OPG could be a new marker of reduced bone mass in children with T1DM.European Journal of Endocrinology 153 879-885

A b s t r a c tWe evaluated performance of the TEST 1 (SIRE Analytical Systems, Udine, Italy)

OBJECTIVETo investigate the prevalence of maturity-onset diabetes of the young (MODY) in Italian children with incidental hyperglycemia.RESEARCH DESIGN AND METHODSAmong 748 subjects age 1–18 years with incidental hyperglycemia, minimal diagnostic criteria for MODY were met by 172 families. Mutational analyses of the glucokinase (GCK) and hepatocyte nuclear factor 1α (HNF1Α) genes were performed.RESULTSWe identified 85 GCK gene mutations in 109 probands and 10 HNF1Α mutations in 12 probands. In GCK patients, the median neonatal weight and age at the first evaluation were lower than those found in patients with HNF1A mutations. Median fasting plasma glucose and impaired fasting glucose/impaired glucose tolerance frequency after oral glucose tolerance testing were higher in GCK patients, who also showed a lower frequency of diabetes than HNF1A patients.CONCLUSIONSGCK mutations are the prevailing cause of MODY (63.4%) when the index case is recruited in Italian children with incidental hyperglycemia.

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