Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes : the randomised, head-to-head CONCLUDE trial

Aims/hypothesis A head-to-head randomised trial was conducted to evaluate hypoglycaemia safety with insulin degludec 200 U/ml (degludec U200) and insulin glargine 300 U/ml (glargine U300) in individuals with type 2 diabetes treated with basal insulin. Methods This randomised (1:1), open-label, treat-to-target, multinational trial included individuals with type 2 diabetes, aged ≥18 years with HbA1c ≤80 mmol/mol (9.5%) and BMI ≤45 kg/m2. Participants were previously treated with basal insulin with or without oral glucose-lowering drugs (excluding insulin secretagogues) and had to fulfil at least one predefined criterion for hypoglycaemia risk. Both degludec U200 and glargine U300 were similarly titrated to a fasting blood glucose target of 4.0–5.0 mmol/l. Endpoints were assessed during a 36 week maintenance period and a total treatment period up to 88 weeks. There were three hypoglycaemia endpoints: (1) overall symptomatic hypoglycaemia (either severe, an event requiring third-party assistance, or confirmed by blood glucose [<3.1 mmol/l] with symptoms); (2) nocturnal symptomatic hypoglycaemia (severe or confirmed by blood glucose with symptoms, between 00:01 and 05:59 h); and (3) severe hypoglycaemia. The primary endpoint was the number of overall symptomatic hypoglycaemic events in the maintenance period. Secondary hypoglycaemia endpoints included the number of nocturnal symptomatic events and number of severe hypoglycaemic events during the maintenance period. Results Of the 1609 randomised participants, 733 of 805 (91.1%) in the degludec U200 arm and 734 of 804 (91.3%) in the glargine U300 arm completed the trial (87.3% and 87.8% completed on treatment, respectively). Baseline characteristics were comparable between the two treatment arms. For the primary endpoint, the rate of overall symptomatic hypoglycaemia was not significantly lower with degludec U200 vs glargine U300 (rate ratio [RR] 0.88 [95% CI 0.73, 1.06]). As there was no significant difference between treatments for the primary endpoint, the confirmatory testing procedure for superiority was stopped. The pre-specified confirmatory secondary hypoglycaemia endpoints were analysed using pre-specified statistical models but were now considered exploratory. These endpoints showed a lower rate of nocturnal symptomatic hypoglycaemia (RR 0.63 [95% CI 0.48, 0.84]) and severe hypoglycaemia (RR 0.20 [95% CI 0.07, 0.57]) with degludec U200 vs glargine U300. Conclusions/interpretation There was no significant difference in the rate of overall symptomatic hypoglycaemia with degludec U200 vs glargine U300 in the maintenance period. The rates of nocturnal symptomatic and severe hypoglycaemia were nominally significantly lower with degludec U200 during the maintenance period compared with glargine U300

Mapping of HNF4α target genes in intestinal epithelial cells

© 2009 Boyd et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Retinal glycoprotein enrichment by concanavalin a enabled identification of novel membrane autoantigen synaptotagmin-1 in equine recurrent uveitis.

Complete knowledge of autoantigen spectra is crucial for understanding pathomechanisms of autoimmune diseases like equine recurrent uveitis (ERU), a spontaneous model for human autoimmune uveitis. While several ERU autoantigens were identified previously, no membrane protein was found so far. As there is a great overlap between glycoproteins and membrane proteins, the aim of this study was to test whether pre-enrichment of retinal glycoproteins by ConA affinity is an effective tool to detect autoantigen candidates among membrane proteins. In 1D Western blots, the glycoprotein preparation allowed detection of IgG reactions to low abundant proteins in sera of ERU patients. Synaptotagmin-1, a Ca2+-sensing protein in synaptic vesicles, was identified as autoantigen candidate from the pre-enriched glycoprotein fraction by mass spectrometry and was validated as a highly prevalent autoantigen by enzyme-linked immunosorbent assay. Analysis of Syt1 expression in retinas of ERU cases showed a downregulation in the majority of ERU affected retinas to 24%. Results pointed to a dysregulation of retinal neurotransmitter release in ERU. Identification of synaptotagmin-1, the first cell membrane associated autoantigen in this spontaneous autoimmune disease, demonstrated that examination of tissue fractions can lead to the discovery of previously undetected novel autoantigens. Further experiments will address its role in ERU pathology

Genetic and other factors determining mannose-binding lectin levels in American Indians: the Strong Heart Study

<p>Abstract</p> <p>Background</p> <p>Mannose-binding lectin (MBL) forms an integral part of the innate immune system. Persistent, subclinical infections and chronic inflammatory states are hypothesized to contribute to the pathogenesis of atherosclerosis. MBL gene (<it>MBL2</it>) variants with between 12 to 25% allele frequency in Caucasian and other populations, result in markedly reduced expression of functional protein. Prospective epidemiologic studies, including a nested, case-control study from the present population, have demonstrated the ability of <it>MBL2 </it>genotypes to predict complications of atherosclerosis,. The genetic control of <it>MBL2 </it>expression is complex and genetic background effects in specific populations are largely unknown.</p> <p>Methods</p> <p>The Strong Heart Study is a longitudinal, cohort study of cardiovascular disease among American Indians. A subset of individuals genotyped for the above mentioned case-control study were selected for analysis of circulating MBL levels by double sandwich ELISA method. Mean MBL levels were compared between genotypic groups and multivariate regression was used to determine other independent factors influencing <it>MBL2 </it>expression.</p> <p>Results</p> <p>Our results confirm the effects of variant structural (B, C, and D) and promoter (H and Y) alleles that have been seen in other populations. In addition, MBL levels were found to be positively associated with male gender and hemoglobin A1c levels, but inversely related to triglyceride levels. Correlation was not found between MBL and other markers of inflammation.</p> <p>Conclusion</p> <p>New data is presented concerning the effects of known genetic variants on MBL levels in an American Indian population, as well as the relationship of <it>MBL2 </it>expression to clinical and environmental factors, including inflammatory markers.</p

SPACE for physical activity - a multicomponent intervention study: study design and baseline findings from a cluster randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>The aim of the School site, Play Spot, Active transport, Club fitness and Environment (SPACE) Study was to develop, document, and assess a comprehensive intervention in local school districts that promote everyday physical activity (PA) among 11-15-year-old adolescents. The study is based on a social ecological framework, and is designed to implement organizational and structural changes in the physical environment.</p> <p>Methods/design</p> <p>The SPACE Study used a cluster randomized controlled study design. Twenty-one eligible schools in the Region of Southern Denmark were matched and randomized in seven pairs according to eight matching variables summarized in an audit tool (crow-fly distance from residence to school for 5-6^thgraders; area household income; area education level; area ethnicity distribution; school district urbanity; condition and characteristics of school outdoor areas; school health policy; and active transport in the local area). Baseline measurements with accelerometers, questionnaires, diaries, and physical fitness tests were obtained in Spring 2010 in 5-6^thgrade in 7 intervention and 7 control schools, with follow-up measurements to be taken in Spring 2012 in 7-8^thgrade. The primary outcome measure is objective average daily physical activity and will be supported by analyses of time spent in moderate to vigorous activity and time spent sedentary. Other secondary outcome measures will be obtained, such as, overweight, physical fitness, active commuting to/from school and physical activity in recess periods.</p> <p>Discussion</p> <p>A total of 1348 adolescents in 5-6^thgrade in the Region of Southern Denmark participated at baseline (n = 14 schools). The response rate was high in all type of measurements (72.6-97.4%). There were no significant differences between intervention and control groups at baseline according to selected background variables and outcome measures: gender (p = .54), age (p = .17), BMI (p = .59), waist circumference (p = .17), physical fitness (p = .93), and physical activity (accelerometer) (p = .09).</p> <p>The randomization and matched pair design produced equivalent groups according to central outcome measures and background variables. The SPACE for physical activity Study will provide new insights on the effectiveness of multicomponent interventions to improve adolescents' physical activity level.</p> <p>Trial registration</p> <p>Current Controlled Trials <a href="http://www.controlled-trials.com/ISRCTN79122411">ISRCTN79122411</a></p

Repeated evolution of drag reduction at the air-water interface in diving kingfishers

Piscivorous birds have a unique suite of adaptations to forage under the water. One method aerial birds use to catch fish is the plunge dive, wherein birds dive from a height to overcome drag and buoyancy in the water. The kingfishers are a well-known clade that contains both terrestrially foraging and plunge-diving species, allowing us to test for morphological and performance differences between foraging guilds in an evolutionary context. Diving species have narrower bills in the dorsoventral and sagittal plane and longer bills (size-corrected data, n = 71 species, p < 0.01 for all). Although these differences are confounded by phylogeny (phylogenetically corrected ANOVA for dorsoventral p = 0.26 and length p = 0.14), beak width in the sagittal plane remains statistically different (p < 0.001). We examined the effects of beak morphology on plunge performance by physically simulating dives with three-dimensional printed models of beaks coupled with an accelerometer, and through computational fluid dynamics (CFD). From physically simulated dives of bill models, diving species have lower peak decelerations, and thus enter the water more quickly, than terrestrial and mixed-foraging species (ANOVA p = 0.002), and this result remains unaffected by phylogeny (phylogenetically corrected ANOVA p = 0.05). CFD analyses confirm these trends in three representative species and indicate that the morphology between the beak and head is a key site for reducing drag in aquatic species