Type 1 diabetes (T1D) is one of the most common chronic disorders of childhood and adolescence and its incidence is rising worldwide, with an annual increase over the last years of about 3-4% [1]. Based on recent estimates, between 2005 and 2010, there will be a 70% increase in the prevalence of T1D, with a doubling of new cases in children younger than 5 years [1] . These data are worrisome given that a diagnosis of T1D during childhood determines a longer exposure to the metabolic

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... of the disease when compared to adult-onset T1D, therefore increasing the burden of the disease [2]. In addition, an early onset of T1D is often associated with more acute presentations, such as diabetic ketoacidosis and admission to hospital, which increase T1D morbidity [3] . Many efforts are continuously made to better understand the pathogenesis of the disease, to identify subjects at increased risk of developing it, to improve daily management of T1D and to identify factors which could predict subjects particularly predisposed to the long-term vascular complications, and towards whom more aggressive and intensive interventions should be directed. The emergence of new and promising treatment options always creates optimism among clinicians and researchers, in particular when dealing with a chronic disease such as T1D and when the aim is to improve the future of our children. All the above-mentioned aspects are the focus of the articles chosen for the 2010 Yearbook chapter on T1D. Background: A recent hypothesis based on in vivo data from hypoglycemic rats proposes that glucagon secretion during hypoglycemia is triggered by a decrease in zinc co-secreted with insulin from ␤-cells, rather than the decrease in insulin itself. The aim of this study was to determine whether closure of the ␣-cell ATP-sensitive K + channel (K ATP channel) is the mechanism through which the zinc switch-off signal triggers glucagon secretion during glucose deprivation. Methods: Studies were performed using perifused isolated islets. Results: The expected glucagon response to an endogenous insulin switch-off signal during glucose deprivation was observed in wild-type mouse islets. In experiments with streptozotocin-treated wild-type islets, a glucagon response to an exogenous zinc switch-off signal was observed during glucose deprivation. However, this glucagon response to the zinc switch-off signal during glucose deprivation was not seen in the presence of nifedipine, diazoxide, or tolbutamide or if K ATP channel knockout mouse islets were used. All islets had intact glucagon responses to epinephrine. Conclusions: This study shows that zinc co-release with insulin during glucose deprivation is a switch-off signal triggering glucagon secretion and that this zinc action is mediated through closure of K ATP channels and consequent opening of calcium channels. Glucagon release from pancreatic ␣-cells represents one of the main compensatory mechanisms stimulated by hypoglycemia. This response is often impaired, to a variable degree, in people with diabetes. Background: In this study the mode of onset of hyperglycemia and how insulin sensitivity and ␤-cell function contribute to the progression to T1D in relatives of patients with diabetes were assessed. Methods: 328 islet cell autoantibody-positive, non-diabetic relatives from the observational arms of the Diabetes Prevention Trial-1 Study (median age 11 years [interquartile range (IQR): 8] underwent sequential OGTT at baseline, every 6 months, and 2.7 years later, when 115 subjects developed T1D. ␤-Cell glucose sensitivity (slope of the insulin-secretion/plasma glucose dose-response function) and insulin sensitivity were obtained by mathematical modeling of the OGTT glucose/C-peptide responses. Results: At baseline, insulin sensitivity, fasting insulin secretion, and total post-glucose insulin output did not differ between progressors and non-progressors. In contrast, ␤-cell glucose sensitivity was significantly reduced in progressors (median 48 pmol/min/m 2 /mmol/l [IQR: 36] vs. 87 pmol/min/m 2 /mmol/l [IQR: 67]; p < 0.0001) and predicted incident diabetes (p < 0.0001) independently of gender, age, BMI, and clinical risk. Glucose sensitivity progressively declined over time with a significant fall 1.45 years before diagnosis. In contrast, 2-hour glucose levels did not significantly change until 0.78 years before diagnosis, when they started to rise rapidly (approx. 13 mmol · l -1 · year-1). During this anticipation phase, both insulin secretion and insulin sensitivity were essentially stable. Conclusions: ␤-Cell glucose sensitivity is the earliest parameter to be impaired in relatives of patients with T1D and represents a strong predictor of diabetes progression. The time trajectories of plasma glucose New paradigms 2 Growing faster increases T1D risk Background: The aim of the study was to assess a potential association of childhood size and growth rate with the development of islet autoimmunity (IA) and T1D. Methods: The study population was represented by participants to the Diabetes Autoimmunity Study in the Young (DAISY), which, since 1993, has followed children at increased T1D risk, based on HLA-DR, -DQ genotype or family history, for the development of IA (defined as the presence of autoantibodies to insulin, GAD or protein tyrosine phosphatase islet antigen 2 twice in succession) and T1D. Height and weight were collected starting at age 2 years, and these parameters together with BMI and velocities of growth in height, weight and BMI were assessed in relation to the development of IA and T1D, which developed in 143 and 21, respectively, of the 1,714 DAISY children aged less than 11.5 years. Results: Greater height growth velocity was associated with IA development (HR 1.63 [95% CI 1.31-2.05]) and even more strongly with the development of T1D (HR 3.34 [95% CI 1.73-6.42]) for a 1 SD difference in velocity. Conclusions: In prepubertal children at increased genetic risk of T1D, greater height growth velocity may be involved in the progression from genetic susceptibility to autoimmunity and then to T1D.