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Neonatal diabetes is a genetically heterogeneous disorder with nine different genetic aetiologies reported to date. Heterozygous activating mutations in the KCNJ11 gene encoding Kir6.2, the pore-forming subunit of the ATP-sensitive potassium (K(ATP)) channel, are the most common cause of permanent neonatal diabetes. The sulphonylurea receptor (SUR) SUR1 serves as the regulatory subunit of the K(ATP) channel in pancreatic beta cells. We therefore hypothesized that activating mutations in the ABCC8 gene, which encodes SUR1, might cause neonatal diabetes. We identified a novel heterozygous mutation, F132L, in the ABCC8 gene of a patient with severe developmental delay, epilepsy and neonatal diabetes (DEND syndrome). This mutation had arisen de novo and was not present in 150 control chromosomes. Residue F132 shows evolutionary conservation across species and is located in the first set of transmembrane helices (TMD0) of SUR1, which is proposed to interact with Kir6.2. Functional studies of recombinant K(ATP) channels demonstrated that F132L markedly reduces the sensitivity of the K(ATP) channel to inhibition by MgATP and this increases the whole-cell K(ATP) current. The functional consequence of this ABCC8 mutation mirrors that of KCNJ11 mutations causing neonatal diabetes and provides new insights into the interaction of Kir6.2 and SUR1. As SUR1 is expressed in neurones as well as in beta cells, this mutation can account for both neonatal diabetes and the neurological phenotype. Our results demonstrate that SUR1 mutations constitute a new genetic aetiology for neonatal diabetes and that they act by reducing the K(ATP) channel's ATP sensitivity.

Objective:  Effects of pump treatment vs. four times daily injections were explored in children with diabetes with regard to quality of life and impact of disease as well as adverse effects and parameters of metabolic control. Methods:  An open, parallel, randomized controlled prospective comparative study lasting 14 months was completed by 38 type 1 children with diabetes (age 4–16 yr) following a 3.5‐months run‐in phase. Standardized quality‐of‐life Pediatric Quality of life Inventory (PedsQL) and impact of disease scores were obtained every 3.5 months as well as regular medical parameters. Parallel treatment group data and longitudinal within‐patient data were analysed for each treatment modality. Results:  Within‐patient comparisons of the two treatment modalities showed significant improvement in PedsQL and impact scores after pump treatment. Treatment group comparisons did not show significant improvement. Pump treatment resulted in decreased symptomatic hypoglycaemia and lowered haemoglobin A1c by 0.22% after run in. Conclusions:  Within‐patient comparison suggests that metabolic control, frequency of severe hypoglycaemia (a threefold decrease), quality of life and impact of disease scores are improved by pump treatment in comparison to regular treatment with four daily insulin injections.

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Immunoprecipitating IgG autoantibodies to glutamic acid decarboxylase, GAD 65 , and/or a tyrosine phosphatase, IA2, are present in the majority of individuals experiencing pancreatic ␤ cell destruction and development of type 1 diabetes. Here we identify a third islet cell autoantigen, a novel 38-kD protein, which is specifically immunoprecipitated with sera from a subset of prediabetic individuals and newly diagnosed type 1 diabetic patients. The 38-kD autoantigen, named glima 38, is an amphiphilic membrane glycoprotein, specifically expressed in islet and neuronal cell lines, and thus shares the neuroendocrine expression patterns of GAD 65 and IA2. Removal of N-linked carbohydrates results in a protein of 22,000 M r . Glima 38 autoantibodies were detected in 16/86 (19%) of newly diagnosed patients, including three very young children, who had a rapid onset of disease, and in 6/44 (14%) of prediabetic individuals up to several years before clinical onset. The cumulative incidence of GAD 65 and glima 38 antibodies in these two groups was 83 and 80%, respectively, and the cumulative incidence of GAD 65