Aims/hypothesis 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)(1990)(1991)(1992)(1993)(1994)(1995)(1996)(1997)(1998) and second (1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008) halves of the period. Methods 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. Results 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 -012-2571-8 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. Conclusions/interpretation 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.Diabetologia (2012) 55:2142-2147 DOI 10.1007/s00125

The mechanism by which the β-cell transcription factor Pax4 influences cell function/mass was studied in rat and human islets of Langerhans. Pax4 transcripts were detected in adult rat islets, and levels were induced by the mitogens activin A and betacellulin. Wortmannin suppressed betacellulin-induced Pax4 expression, implicating the phosphatidylinositol 3-kinase signaling pathway. Adenoviral overexpression of Pax4 caused a 3.5-fold increase in β-cell proliferation with a concomitant 1.9-, 4-, and 5-fold increase in Bcl-xL (antiapoptotic), c-myc, and Id2 mRNA levels, respectively. Accordingly, Pax4 transactivated the Bcl-xL and c-myc promoters, whereas its diabetes-linked mutant was less efficient. Bcl-xL activity resulted in altered mitochondrial calcium levels and ATP production, explaining impaired glucose-induced insulin secretion in transduced islets. Infection of human islets with an inducible adenoviral Pax4 construct caused proliferation and protection against cytokine-evoked apoptosis, whereas the mutant was less effective. We propose that Pax4 is implicated in β-cell plasticity through the activation of c-myc and potentially protected from apoptosis through Bcl-xL gene expression.

We suggest that in adolescent girls with primary amenorrhea, müllerian duct abnormalities, and hyperandrogenism, a WNT4 mutation should be sought. Moreover, our data confirm that WNT4 is involved in the regulation of müllerian duct development and ovarian androgen biosynthesis. WNT4 may also contribute to human follicle development and/or maintenance.

word count: 250 excluding headingsMain text word count: 2,564 including Table and Figure legends Tables and Figures: Tables (2) Methods Twenty-three population-based registers recorded date of diagnosis for new cases of type 1 diabetes among children under 15 years. Tests for seasonal variation in monthly counts aggregated over the 20 year period were conducted. 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 centres with peaks in December to February and relative amplitudes ranging from 11% to 39% (median 18%). However, most centres showed significant departures from a sinusoidal pattern. Pooling results over centres, there was significant seasonal variation in each age-group at diagnosis, with least seasonal variation in those under 5 years. Boys showed greater seasonal variation than girls, particularly those aged 10-14 years. There were no differences in seasonal pattern between four five-year 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/interpretation Seasonality was consistently apparent throughout the period in all age-groups and both sexes, but girls and the under 5s showed less marked variation. Neither sunshine hour nor average temperature data contributed in any substantial way to explaining departures from the sinusoidal pattern.

Friedreich's ataxia is known to be associated with diabetes mellitus in up to 20% of the patients. However, type, development and course of diabetes mellitus are not well characterised. We report on 3 patients (2 female and 1 male, age 13-20 years) with the combination of Friedreich's ataxia and diabetes mellitus. Diabetes mellitus was characterised as follows: (1) it was strictly insulin-dependent and ketosis-prone, (2) the average insulin requirement was 1 U/kg body weight, (3) the HLA haplotype was not typical of Type 1 (insulin-dependent) diabetes mellitus, (4) there were no positive immune parameters typical of Type 1 diabetes at the clinical onset of diabetes mellitus and (5) there was no remission. To evaluate a preclinical phase as in common autoimmune Type 1 diabetes, i.v. glucose tolerance tests (0.5 g glucose/kg body weight) were performed in 8 patients with Friedreich's ataxia without diabetes mellitus. Seven patients had normal early phase insulin response. In contrast, the glucose disappearance rate was slow in 4 and normal in 3 patients. One of the 8 patients showed a prediabetic metabolic state: the early-phase insulin response was abolished and the glucose disappearance rate was abnormal. The results suggest that diabetes in Friedreich's ataxia is caused by a loss of islet cells similar to common Type 1 diabetes but without HLA-association and without serologic evidence for autoimmune destruction of the islet cells.