Objective: To evaluate insulin-secretion kinetics and insulin sensitivity in cystic fibrosis (CF) patients with normal glucose tolerance (CF-NGT), impaired glucose tolerance (CF-IGT) or CF-related diabetes (CFRD), and the potential effects of moderate hyperglycemia on clinical and nutritional status. Design and methods: Cross-sectional study including 50 outpatients with CF. Patients underwent both oral (OGGT) and intravenous (IVGTT) glucose tolerance tests in order to assess insulin secretion and peripheral insulin sensitivity. Homeostasis assessment model and OGGT were used to investigate insulin sensitivity. Forced expiratory volume in the first second (FEV 1 ) and forced vital capacity (FVC) were measured to evaluate pulmonary function. Body mass index (BMI) was determined to assess nutritional status. Results: Insulin secretion was significantly decreased (and delayed at OGTT) in the CFRD group (n ¼ 9) versus the CF-IGT group (n ¼ 10) and the CF-IGT versus the CF-NGT group (n ¼ 31). Insulin sensitivity was significantly different in the CF-IGT and CFRD groups versus the CF-NGT group. FEV 1 , FVC and BMI presented a significant linear correlation with plasma glucose value at 120 min at OGTT and were significantly lower in both CF-IGT and CFRD versus the CF-NGT group, whereas no differences were found between the CF-IGT and CFRD groups. Conclusions: CF patients with IGT present diminished insulin secretion and increased peripheral insulin resistance, correlating with a worse clinical status, undernutrition and impaired pulmonary function. These findings open the question of whether early treatment of mild alterations of glucose metabolism with insulin secretagogues or short-action insulin may lead to improvement of clinical status in CF patients.European Journal of Endocrinology 152 241-247

Objective: Obesity is associated with insulin-resistance (IR), type 2 diabetes (T2D) and a constellation of cardiovascular risk factors at the early years of life. These features define the so-called metabolic syndrome (MS). Aims: To assess the frequency of the MS among obese pediatric Spanish population and analyse the individual contribution and the predictive potential of individual components to the development of the syndrome. Patients and methods: A total of 429 patients, 220 boys and 209 girls, aged 4-18 years, with a body mass index of O2 standard deviation scores for Spanish normative charts, were included in the study. Forty-seven percent were prepubertal and ten percent had Hispanic ethnicity. HbA1c, lipids, liver enzymes and uric acid levels were determined from blood and a standard 2-h oral glucose tolerance test was performed. MS was defined by the National Cholesterol Education Program's Adult Treatment Panel III criteria modified by Cook as having at least three features among: obesity, low high-density lipoprotein (HDL), hypertriglyceridemia, hypertension (HTA) or impaired glucose metabolism (IGM). We defined IR as homeostatic model assessment of IR index and/or fasting insulin levelsO95th centile of the control population. Results: Almost 18% of the patients had MS, with significantly higher frequency in Hispanic (32%) than in Caucasian (16%) population. There were no differences by sex or pubertal status. Prevalence of low HDL, HTA, hypertriglyceridemia and IGM were 27, 23, 16 and 7% respectively. No silent T2D was identified. According to International Obesity Task Force charts, 22% of the patients were overweight and not obese, but no differences in the frequency of individual features of MS between these two groups were observed. Among IR patients (35% of our population), the frequency of MS reached 28%. IR predicted the presence of MS independently from age and race. Conclusion: MS is present in 18% of our obese pediatric population. IR is closely associated with the components of MS and strongly predicts its development.European Journal of Endocrinology 155 313-319

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Neonatal diabetes mellitus (NDM) is a rare form of diabetes diagnosed within the first 6 months of life. Genetic studies have allowed the identification of several genes linked to the development of NDM; however, genetic causes for ∼20% of the cases remain to be clarified. Most cases of NDM involve isolated diabetes, but sometimes NDM appears in association with other pathological conditions, including autoimmune diseases. Recent reports have linked activating mutations in with early-onset autoimmune disorders that include diabetes of autoimmune origin, but the functional impact of-activating mutations have not been characterized at the pancreatic β-cell level. By using whole-exome sequencing, we identified a novel missense mutation in the binding domain of the STAT3 protein in a patient with NDM. The functional analyses showed that the mutation results in an aberrant activation of STAT3, leading to deleterious downstream effects in pancreatic β-cells. The identified mutation leads to hyperinhibition of the transcription factor Isl-1 and, consequently, to a decrease in insulin expression. These findings represent the first functional indication of a direct link between an NDM-linked activating mutation in and pancreatic β-cell dysfunction.