Aims This study compared the effect of insulin detemir on glycaemic control (HbA(1c), fasting plasma glucose and variability thereof) with that of Neutral Protamine Hagedorn human isophane (NPH) insulin, both combined with insulin aspart, in children with Type 1 diabetes mellitus, and compared the safety of these treatments.Methods In this 26-week, open-label, randomized (2 : 1), parallel-group study, 347 (140 prepubertal and 207 pubertal) children with Type 1 diabetes, aged 6-17 years, received insulin detemir (n = 232) or NPH insulin (n = 115) once or twice daily, according to the prestudy regimen, plus premeal insulin aspart.Results The mean HbA(1c) decreased by similar to 0.8% with both treatments. After 26 weeks, the mean difference in HbA(1c) was 0.1% (95% confidence interval -0.1, 0.3) (insulin detemir 8.0%, NPH insulin 7.9%). Within-subject variation in self-measured fasting plasma glucose was significantly lower with insulin detemir than with NPH insulin (SD 3.3 vs. 4.3, P < 0.001), as was mean fasting plasma glucose (8.4 vs. 9.6 mmol/l, P = 0.022). The risk of nocturnal hypoglycaemia (22.00-07.00 h) was 26% lower with insulin detemir (P = 0.041) and the risk of 24-h hypoglycaemia was similar with the two treatments (P = 0.351). The mean body mass index (BMI) Z-score was lower with insulin detemir (P < 0.001).Conclusions Basal-bolus treatment with insulin detemir or NPH insulin and premeal insulin aspart in children and adolescents with Type 1 diabetes mellitus improved HbA(1c) to a similar degree. The lower and more predictable fasting plasma glucose, lower risk of nocturnal hypoglycaemia and lower BMI observed with insulin detemir are clinically significant advantages compared with NPH insulin.

BACKGROUND:The month of diagnosis in childhood type 1 diabetes shows seasonal variation. OBJECTIVE:We describe the pattern and investigate if year-to-year irregularities are associated with meteorological factors using data from 50 000 children diagnosed under the age of 15 yr in 23 population-based European registries during 1989-2008. METHODS:Tests for seasonal variation in monthly counts aggregated over the 20 yr period were performed. Time series regression was used to investigate if sunshine hour and average temperature data were predictive of the 240 monthly diagnosis counts after taking account of seasonality and long term trends. RESULTS:Significant sinusoidal pattern was evident in all but two small centers with peaks in November to February and relative amplitudes ranging from ± 11 to ± 38% (median ± 17%). However, most centers showed significant departures from a sinusoidal pattern. Pooling results over centers, there was significant seasonal variation in each age-group at diagnosis, with least seasonal variation in those under 5 yr. Boys showed greater seasonal variation than girls, particularly those aged 10-14 yr. There were no differences in seasonal pattern between four 5-yr sub-periods. Departures from the sinusoidal trend in monthly diagnoses in the period were significantly associated with deviations from the norm in average temperature (0.8% reduction in diagnoses per 1 °C excess) but not with sunshine hours. CONCLUSIONS:Seasonality was consistently apparent throughout the period in all age-groups and both sexes, but girls and the under 5 s showed less marked variation. Neither sunshine hour nor average temperature data contributed in any substantial way to explaining departures from the sinusoidal pattern.

The aim of the study was to describe 20-year incidence trends for childhood type 1 diabetes in 23 EURODIAB centres and compare rates of increase in the first (1989-1998) and second (1999-2008) halves of the period.All registers operate in geographically defined regions and are based on a clinical diagnosis. Completeness of registration is assessed by capture-recapture methodology. Twenty-three centres in 19 countries registered 49,969 new cases of type 1 diabetes in individuals diagnosed before their 15th birthday during the period studied.Ascertainment exceeded 90% in most registers. During the 20-year period, all but one register showed statistically significant changes in incidence, with rates universally increasing. When estimated separately for the first and second halves of the period, the median rates of increase were similar: 3.4% per annum and 3.3% per annum, respectively. However, rates of increase differed significantly between the first half and the second half for nine of the 21 registers with adequate coverage of both periods; five registers showed significantly higher rates of increase in the first half, and four significantly higher rates in the second half.The incidence rate of childhood type 1 diabetes continues to rise across Europe by an average of approximately 3-4% per annum, but the increase is not necessarily uniform, showing periods of less rapid and more rapid increase in incidence in some registers. This pattern of change suggests that important risk exposures differ over time in different European countries. Further time trend analysis and comparison of the patterns in defined regions is warranted.

Background: Management of Diabetic Ketoacidosis (DKA) requires frequent changes of intravenous fluids in response to fluctuating needs of electrolyte, and dextrose. Abrupt changes in electrolytes and glycemia can lead to cerebral edema in DKA. The ‘‘two-bag’’ system can prevent these abrupt changes. Objective: To present experience of Diabetic Ketoacidosis (DKA) management in children using ‘‘Two Bag System’’ from a developing country. Study design: Retrospective chart review. Setting: Aga Khan University Hospital (AKUH), Pakistan. Subjects: Children 0–15 years of age, admitted with diagnosis of DKA at AKUH from June 2006 to June 2011. Methods: Files of all subjects were reviewed. The diagnosis of DKA was based on established international criteria. The time for resolution of acidosis was taken from the start of treatment to reach a venous pH of 7.30 or better. The cost of IV therapy for each bag, and the possible time delays if bags were changed were calculated with help from pharmacy services. Results: Total of 76 children were admitted with the diagnosis of DKA. Mean age of 7.3 ± 4.7 years. There were 36 (47.4%) boys and 40 (52.6%) girls. Newly diagnosed cases were 49 (64.5%). 23 (30.3%) cases had mild, 22 (28.9%) moderate and 31 (40.8%) had severe DKA. There were no episodes of hypoglycemia after initiation of therapy. The mean time for acidosis correction was 19.7 hours. There were no deaths in the study group. The time lag for changing the glucose concentration of infusion was 5 minutes after glucose check against a possible 1 hour if new bags were ordered. Cost of fluid therapy was approx. 30 ± 5 $ for two bag system against a possible 50 ± 5 $ if it was not used. Conclusions: The two-bag system enables faster fluid therapy changes, allowing a steady and gradual fall in blood glucose after start of insulin therapy in DKA. It is also cost effective and decreases the work for pharmacy and nursing staff.

1 Glostrup University Hospital, Department of Paediatrics, Glostrup, Denmark, 2 Department of Statistics, University of Southern Denmark, Denmark 3 Leicester Royal Infirmary Children’s Hospital, Leicester, United Kingdom 4 University of Ulm, Germany, 5 Trinity College , National Childrens Hospital, Dublin, Ireland 6 Ulleval University Hospital, Department of Pediatrics, Oslo, Norway 7 Clinique Pediatrique, Centre Hospitalier de Luxembourg 8 Clinica Pediatrica Universita, Chieti, Italy, 9 Kinderkrankenhaus auf der Bult, Department of Paediatrics, Hannover, Germany 10 University Children’s Hospital, Zurich, Switzerland, 11 Regionsjukhuset i Örebro, Örebro, Sweden

Aims To examine incidence and trends of Type 1 diabetes worldwide for the period 1990-1999.Methods The incidence of Type 1 diabetes (per 100 000/year) was analysed in children aged <= 14 years from 114 populations in 112 centres in 57 countries. Trends in the incidence of Type 1 diabetes were analysed by fitting Poisson regression models to the dataset.Results A total of 43 013 cases were diagnosed in the study populations of 84 million children. The age-adjusted incidence of Type 1 diabetes among 112 centres (114 populations) varied from 0.1 per 100 000/year in China and Venezuela to 40.9 per 100 000/year in Finland. The average annual increase in incidence calculated from 103 centres was 2.8% (95% CI 2.4-3.2%). During the years 1990-1994, this increase was 2.4% (95% CI 1.3-3.4%) and during the second study period of 1995-1999 it was slightly higher at 3.4% (95% CI 2.7-4.3%). The trends estimated for continents showed statistically significant increases all over the world (4.0% in Asia, 3.2% in Europe and 5.3% in North America), except in Central America and the West Indies where the trend was a decrease of 3.6%. Only among the European populations did the trend in incidence diminish with age.Conclusions The rising incidence of Type 1 diabetes globally suggests the need for continuous monitoring of incidence by using standardized methods in order to plan or assess prevention strategies.

Introduction: The islets of Langerhans are enveloped in Schwann cells which are the early target of islet auto-immunity. The islets also contain a profuse network of other neural elements. Neurotrophins are secreted by choroid plexus (CP) epithelium and we have demonstrated* that these secretions are able to prevent experimental neural damage in vitro (serum deprivation or malonate in culture) in a dose dependent fashion, and from quinolinic acid and hypoxic ischemia in vivo. In vitro we have demonstrated* the beneficial effect of CP culture supernatant on survival and function of porcine islets in long term culture. We therefore hypothesized that CP epithelial secretions might salvage islets subjected to a number of insults, including aggressive autoimmunity. Methods: Female diabetic mice at the age of 30 days were transplanted IP with alginate encapsulated neonatal porcine choroid plexus epithelial clusters derived by collagenase digestion, and subsequent culture in vitro with frequent media changes for three days in groups of 6–7 animals given 3 different escalating doses (500, 1000, 2000). Litter mates were given empty microcapsules. Diabetes incidence (blood glucose consistently >15mM) was studied in all groups up to 250 days. Results: There was a highly significant, dose independent protective effect on diabetes incidence of the CP transplants*. The control group reached the maximum diabetes incidence of 53% by day 156 of life, whereas the maximum diabetes incidence of 27% was not seen in the experimental group until day 230. CP transplants given after diabetes had occurred in the control group were ineffectual. Conclusion: It is likely that the protection afforded by CP is capable of offsetting damage caused by immune attack of islets. CP intraperitoneal transplants could provide a novel, minimally invasive means of preventing Type 1 diabetes in humans, in those deemed to be at high risk. That neuroprotection is likely to be the mechanism of action of these cells casts new light on the possible pathogenesis of Type 1 diabetes.

Background: Thyroid hormones are crucial for normal growth and central nervous system development. In recent years, germline variants of the TSHβ subunit gene have been identified as a cause of congenital TSH deficiency. Methods: We performed a genetic and clinical study in children from four European countries diagnosed with congenital isolated central hypothyroidism. Results: TSHβ gene analysis revealed compound heterozygosity for 145C→T (Q49X) and 313delT (C105Vfs114X) in 1 infant and homozygous mutation 313delT (C105Vfs114X) in 5 patients. Although all presented with typical symptoms of hypothyroidism, diagnosis and treatment was delayed until 3–5 months in 5 of 6 patients. In a longitudinal sibpair analysis, thyroxine substitution initiated immediately after birth was effective to prevent developmental delay and growth retardation. Conclusion: Clinical awareness is required to detect hypothyroidism due to TSHβ mutations, which is not identified by TSH-based newborn screening. TSHβ variants C105Vfs114X and Q49X are the most frequent cause of this severe disorder in Europe, now for the first time observed in compound heterozygous state.

OBJECTIVE:It is unclear whether the demands of good metabolic control or the consequences of poor control have a greater influence on quality of life (QOL) for adolescents with diabetes. This study aimed to assess these relations in a large international cohort of adolescents with diabetes and their families.RESEARCH DESIGN AND METHODS:The study involved 2,101 adolescents, aged 10-18 years, from 21 centers in 17 countries in Europe, Japan, and North America. Clinical and demographic data were collected from March through August 1998. HbA(1c) was analyzed centrally (normal range 4.4-6.3%; mean 5.4%). Adolescent QOL was assessed by a previously developed Diabetes Quality of Life (DQOL) questionnaire for adolescents, measuring the impact of diabetes, worries about diabetes, satisfaction with life, and health perception. Parents and health professionals assessed family burden using newly constructed questionnaires.RESULTS:Mean HbA(1c) was 8.7% (range 4.8-17.4). Lower HbA(1c) was associated with lower impact (P < 0.0001), fewer worries (P < 0.05), greater satisfaction (P < 0.0001), and better health perception (P < 0.0001) for adolescents. Girls showed increased worries (P < 0.01), less satisfaction, and poorer health perception (P < 0.01) earlier than boys. Parent and health professional perceptions of burden decreased with age of adolescent (P < 0.0001). Patients from ethnic minorities had poorer scores for impact (P < 0.0001), worries (P < 0.05), and health perception (P < 0.01). There was no correlation between adolescent and parent or between adolescent and professional scores.CONCLUSIONS:In a multiple regression model, lower HbA(1c) was significantly associated with better adolescent-rated QOL on all four subscales and with lower perceived family burden as assessed by parents and health professionals.

Uniparental disomy (UPD) is defined as the inheritance of both homologous chromosomes from only one parent. So far, maternal UPD 7 has been described in 28 cases. Here, we report 4 new cases, present clinical information of 5 cases previously reported by us, and review the clinical and molecular findings of all 32 cases. We found a phenotype characterized by pre- and postnatal growth retardation, occipitofrontal head circumference in the lower normal range, a triangular face, and retarded bone maturation. Findings of the facial gestalt included a high and broad forehead and a pointed chin. A broad mouth with down-turned corners, prominent ears, café-au-lait spots, hemihypotrophy, or clinodactyly were rarely present. Psychomotor development was delayed in 6 cases. The clinical findings strikingly resemble the phenotype of the heterogeneous Silver-Russell syndrome (SRS). Other anomalies were less frequently found than in SRS. Molecular investigations revealed 11 cases with isodisomy and 17 cases with heterodisomy. In 4 cases this information was not available. From the allelic distribution of the microsatellites investigated, 9 cases might be the consequence of an error at maternal meiosis I, and 6 cases might be due to non-disjunction at maternal meiosis II. Three of the 17 heterodisomic cases had trisomy 7 in chorionic villi, in the remaining cases no prenatal diagnosis through chorionic villus sampling was reported.

Familial syndrome of infantile polycythemia with markedly elevated erythropoietin, severe pulmonary hypertension, and intrapulmonary hematopoiesis - an “inappropriate” hypoxic response?

We report a patient with a clinical picture consisting of small birth weight, connatal hypoplastic anaemia, vacuolised bone marrow precursors, failure to thrive, and, subsequently, by insulin-dependent diabetes, renal Fanconi syndrome, lactic acidosis, complex organic aciduria, and elevation of haemoglobin F and of adenosine deaminase activity. The clinical course was progressive and death occurred at age 19 months. A high proportion of mitochondrial (mt) DNA molecules with a deletion of nucleotides 9238 to 15575 were identified in several tissues; about half of the shortened mtDNA molecules were concatenated to form circular dimers. The clinical and laboratory findings support recent conclusions that Pearson syndrome is not confined to bone marrow and pancreas, as originally described, but is a multi-organ disorder associated with deletions in part of the mtDNA molecules. The tissue distribution and the relative proportions of the abnormal mtDNA molecules apparently determine the phenotype and clinical course.

Results of IGF-I and IGF-II measured in 70 GH deficient children (51m, 19f) treated with r-hGH for up to 18 months and grouped according to sex and BA at start of therapy, are shown in the table During treatment we observed a significant transient decrease of IGF-I in 25/51m and 14/19f and of IGF-II in 4l/51m and 14/19f. After 18 months of therapy, IGF's vere normalized in all groups.

It has been suggested that bromocriptine treatment of tall girls and boys reduces growth prediction by inhibiton of growth hormone secretion (J Clin Endocr Metab 58.1022-1026.1984). We have treated 15 girls and 5 boys (chron age 10.1-14.6 years. bone age 11.0-14.0 years) with bromocriptine (2×2.5 mg/day) over a period of 1.14 ± 0.31 years (0.6-1.75). Results (paired Wilcoxon rank test): The differences between the mean adult height prediction before and after bromocriptine were -0.8 ± 3.5 cm according to Bailey-Pinneau (p = 0.433) and +0.2 ± 2.5 cm according to Tanner Mark I (p = 0.586). The mean peak GH values after TRH i.v. were 53.0 ± 50.2 mU/l before, and 59.0 ± 50.2 mU/l during bromocriptine treatment (p = 0.314). The wide range of the GH results most probably reflects physiological variations in this age group. Our results are essentially negative. Moreover, the concept, that bromocriptine reduces GH secretion, seems doubtful: in 6 of our patients we have measured plasma GH after 2.5 mg of bromocriptine and found a significant increase within the first three hours. Our results do not support the data from the literature. We conclude, that bromocriptine is ineffective in reducing adult height of tall girls and boys. Supported by Swiss National Science Foundation grant 3.906.083.

Pure human IGF I (43 and 103 micrograms/day) and IGF II (131 micrograms/day) were infused into hypophysectomized rats during 6 days by means of sc implanted minipumps. Their effects on several growth indices were compared with those of various doses of sc infused human growth hormone. Growth hormone infusion produced a dose-dependent rise of endogenous rat IGF from 39 (without growth hormone) to 86 microU equivalents/ml (with 400 mU hGH/day) as determined by a competitive protein binding assay with a human IGF standard. In rats receiving the two doses of IGF I, total serum IGF levels rose to 83 and 99 microU equivalents/ml, respectively, in those receiving the IGF II dose the total serum IGF level rose to 146 microU equivalents/ml. These increases corresponded to steady state levels of 168 and 286 ng/ml of immunoreactive insulin-like growth factor (IR-IGF) I and 320 ng/ml of IR-IGF II. IGF I, but not IGF II led to an increase in body weight similar to that induced by the low doses of hGH (12.5 and 25 mU, respectively). The rise of endogenous rat IGF as well as the infused human IGF I and II caused a widening of the tibial epiphysis and an increase of the [3H]thymidine incorporation into costal cartilage. With respect to these two indices IGF II was clearly less potent that IGF I. When expressed in microU equivalents of the protein binding assay, endogenous rat IGF induced by hGH appeared to be relatively more effective than infused human IGF I or II.(ABSTRACT TRUNCATED AT 250 WORDS)

We undertook a comparison of human growth hormone (hGH) binding and metabolic responses in rat adipocytes of epididymal, subcutaneous, and retroperitoneal origin to determine whether the site of fat depot biopsy might affect the response to hGH stimulation. The results showed highest specific binding in epididymal (3.6%), followed by subcutaneous (2.3%) and retroperitoneal adipocytes (1.5%); half-maximal binding was achieved at 14-18 ng/ml hGH for the three sites. Scatchard analysis of the binding data from each site was linear; there was no significant difference in binding affinities (2.1 to 3.3 X 10(9), M-1), but the number of binding sites was statistically higher in epididymal (9.8 X 10(3) as compared to subcutaneous (7.5 X 10(3), P less than 0.05) and retroperitoneal cells (3.3 X 10(3), P less than 0.01). Stimulation with 5 to 2500 ng pituitary hGH produced a dose-related increase in glucose incorporation, with the largest increase in epididymal fat cells (31%, P less than 0.05) followed by subcutaneous cells (18%, P less than 0.05); no significant increase was seen with retroperitoneal cells. Biosynthetic hGH produced a similar pattern of glucose incorporation in the three sites. Addition of hGH antibodies blocked the glucose incorporation in epididymal adipocytes using both pituitary-derived and biosynthetic hGH. It seems clear that this insulin-like effect is caused by hGH, not an insulin-like impurity. We conclude that the number of binding sites, perhaps related to adipose cell size, differs in adipose tissue from different locations and this influences the metabolic response to hGH stimulation.

Insulin-like growth factors (IGF) I and II produce acute insulin-like effects or promote growth indices in hypophysectomized rats, depending on their mode of administration. Intravenous bolus injections of IGF I and II, like insulin, lower the blood sugar level and lead to a pronounced stimulation of glycogen synthesis in skeletal muscle. The two factors are equipotent in this respect. Continuous subcutaneous infusions of IGF I or II over six days have no hypoglycaemic effect. They mimic the effects of growth hormone, increasing the width of the tibial epiphysis and stimulating the thymidine-incorporating activity of costal cartilage in the absence of growth hormone. IGF I (identical to somatomedin C) is more potent than IGF II and causes a dose-dependent increase in body weight at concentrations where IGF II is still ineffective. The absence of acute insulin-like effects in long-term experiments is explained by the presence in serum of highly specific carrier proteins that interfere with the insulin-like properties of IGF I and II and restrict their capillary permeability. Growth hormone induces the formation of both IGF and the major IGF carrier protein in the liver. Thus, while IGFs mediate the actions of growth hormone on growth, growth hormone appears to modulate these actions via IGF carrier proteins.