Changes in Prandial Glucagon Levels After a 2-Year Treatment With Vildagliptin or Glimepiride in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Monotherapy

OBJECTIVE - To determine if the dipeptidyl peptidase-4 inhibitor vildagliptin more effectively inhibits glucagon levels than the sulfonylurea glimepiride during a meal. RESEARCH DESIGN AND METHODS - Glucagon responses to a standard meal were measured at baseline and study end point (mean 1.8 years) in a trial evaluating add-on therapy to metformin with 50 mg vildagliptin bid. compared with glimepiride up to 6 mg q.d. in type 2 diabetes (baseline MC 7.3 +/- 0.6%). RESULTS - A1C and prandial glucose area under the curve (AUC)(0-2 h) were reduced similarly in both groups, whereas prandial insulin AUC(0-2 h) increased to a greater extent by glimepiride. Prandial glucagon AUC(0-2 h) (baseline 66.6 +/- 2.3 pmol . h(-1) . l(-1)) decreased by 3.4 +/- 1.6 pmol . h(-1) . l(-1) by vildagliptin (n = 137) and increased by 3.8 +/- 1.7 pmol . h(-1) . l(-1) by glimepiride (n = 121). The between-group difference was 7.3 +/- 2.1 pmol . h(-1) . l(-1) (P < 0.001). CONCLUSIONS - Vildagliptin therapy but not glimepiride improves postprandial a-cell function, which persists for at least 2 years

Baseline Characteristics of the Vitamin D and Type 2 Diabetes (D2d) Study: A Contemporary Prediabetes Cohort That Will Inform Diabetes Prevention Efforts

© 2018 by the American Diabetes Association. OBJECTIVE: To describe baseline characteristics of the Vitamin D and Type 2 Diabetes (D2d) study, the first large U.S. diabetes prevention clinical trial to apply current American Diabetes Association (ADA) criteria for prediabetes.RESEARCH DESIGN AND METHODS: This is a multicenter (n = 22 sites), randomized, double-blind, placebo-controlled, primary prevention clinical trial testing effects of oral daily 4,000 IU cholecalciferol (D3) compared with placebo on incident diabetes in U.S. adults at risk for diabetes. Eligible participants were at risk for diabetes, defined as not meeting criteria for diabetes but meeting at least two 2010 ADA glycemic criteria for prediabetes: fasting plasma glucose (FPG) 100-125 mg/dL, 2-h postload glucose (2hPG) after a 75-g oral glucose load 140-199 mg/dL, and/or a hemoglobin A1c (HbA1c) 5.7-6.4% (39-46 mmol/mol).RESULTS: A total of 2,423 participants (45% of whom were women and 33% nonwhite) were randomized to cholecalciferol or placebo. Mean (SD) age was 59 (9.9) years and BMI 32 (4.5) kg/m2. Thirty-five percent met all three prediabetes criteria, 49% met the FPG/HbA1c criteria only, 9.5% met the 2hPG/FPG criteria only, and 6.3% met the 2hPG/HbA1c criteria only. Black participants had the highest mean HbA1c and lowest FPG concentration compared with white, Asian, and other races (P \u3c 0.01); 2hPG concentration did not differ among racial groups. When compared with previous prediabetes cohorts, the D2d cohort had lower mean 2hPG concentration but similar HbA1c and FPG concentrations.CONCLUSIONS: D2d will establish whether vitamin D supplementation lowers risk of diabetes and will inform about the natural history of prediabetes per contemporary ADA criteria

Effect of liraglutide on cardiovascular outcomes in elderly patients: A post hoc analysis of a randomized controlled trial

Background: Comorbidities and complications associ-ated with type 2 diabetes mellitus (T2DM) increase with age, making treatment of elderly persons with this condition chal-lenging. Clinical data on the effect of antihyperglycemic treat-ment on cardiovascular (CV) events in elderly persons are limited (1). The U.S. Food and Drug Administration and Euro-pean Medicines Agency recommend collecting comprehen-sive data on elderly patients with diabetes, particularly those aged 75 years or older, to inform appropriate treatment of this growing populatio

Day-to-day fasting glycaemic variability in DEVOTE: associations with severe hypoglycaemia and cardiovascular outcomes (DEVOTE 2)

AIMS/HYPOTHESIS: The Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) was a double-blind, randomised, event-driven, treat-to-target prospective trial comparing the cardiovascular safety of insulin degludec with that of insulin glargine U100 (100 units/ml) in patients with type 2 diabetes at high risk of cardiovascular events. This paper reports a secondary analysis investigating associations of day-to-day fasting glycaemic variability (pre-breakfast self-measured blood glucose [SMBG]) with severe hypoglycaemia and cardiovascular outcomes. METHODS: In DEVOTE, patients with type 2 diabetes were randomised to receive insulin degludec or insulin glargine U100 once daily. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In this article, day-to-day fasting glycaemic variability was based on the standard deviation of the pre-breakfast SMBG measurements. The variability measure was calculated as follows. Each month, only the three pre-breakfast SMBG measurements recorded before contact with the site were used to determine a day-to-day fasting glycaemic variability measure for each patient. For each patient, the variance of the three log-transformed pre-breakfast SMBG measurements each month was determined. The standard deviation was determined as the square root of the mean of these monthly variances and was defined as day-to-day fasting glycaemic variability. The associations between day-to-day fasting glycaemic variability and severe hypoglycaemia, MACE and all-cause mortality were analysed for the pooled trial population with Cox proportional hazards models. Several sensitivity analyses were conducted, including adjustments for baseline characteristics and most recent HbA1c. RESULTS: Day-to-day fasting glycaemic variability was significantly associated with severe hypoglycaemia (HR 4.11, 95% CI 3.15, 5.35), MACE (HR 1.36, 95% CI 1.12, 1.65) and all-cause mortality (HR 1.58, 95% CI 1.23, 2.03) before adjustments. The increased risks of severe hypoglycaemia, MACE and all-cause mortality translate into 2.7-, 1.2- and 1.4-fold risk, respectively, when a patient's day-to-day fasting glycaemic variability measure is doubled. The significant relationships of day-to-day fasting glycaemic variability with severe hypoglycaemia and all-cause mortality were maintained after adjustments. However, the significant association with MACE was not maintained following adjustment for baseline characteristics with either baseline HbA1c (HR 1.19, 95% CI 0.96, 1.47) or the most recent HbA1c measurement throughout the trial (HR 1.21, 95% CI 0.98, 1.49). CONCLUSIONS/INTERPRETATION: Higher day-to-day fasting glycaemic variability is associated with increased risks of severe hypoglycaemia and all-cause mortality. TRIAL REGISTRATION: ClinicalTrials.gov NCT01959529

LOFAR MSSS: The Scaling Relation between AGN Cavity Power and Radio Luminosity at Low Radio Frequencies

This article has been accepted for publication in a forthcoming issue of Astronomy & Astrophysics. Reproduced with permission from Astronomy & Astrophysics. © 2018 ESO.We present a new analysis of the widely used relation between cavity power and radio luminosity in clusters of galaxies with evidence for strong AGN feedback. We study the correlation at low radio frequencies using two new surveys - the First Alternative Data Release of the TIFR GMRT Sky Survey (TGSS ADR1) at 148 MHz and LOFAR's first all-sky survey, the Multifrequency Snapshot Sky Survey (MSSS) at 140 MHz. We find a scaling relation $P_{\rm cav} \propto L_{148}^{\beta}$, with a logarithmic slope of $\beta = 0.51 \pm 0.14$, which is in good agreement with previous results based on data at 327 MHz. The large scatter present in this correlation confirms the conclusion reached at higher frequencies that the total radio luminosity at a single frequency is a poor predictor of the total jet power. We show that including measurements at 148 MHz alone is insufficient to reliably compute the bolometric radio luminosity and reduce the scatter in the correlation. For a subset of four well-resolved sources, we examine the detected extended structures at low frequencies and compare with the morphology known from higher frequency images and Chandra X-ray maps. In Perseus we discuss details in the structures of the radio mini-halo, while in the 2A 0335+096 cluster we observe new diffuse emission associated with multiple X-ray cavities and likely originating from past activity. For A2199 and MS 0735.6+7421, we confirm that the observed low-frequency radio lobes are confined to the extents known from higher frequencies. This new low-frequency analysis highlights the fact that existing cavity power to radio luminosity relations are based on a relatively narrow range of AGN outburst ages. We discuss how the correlation could be extended using low frequency data from the LOFAR Two-metre Sky Survey (LoTSS) in combination with future, complementary deeper X-ray observations.Peer reviewe

Refined multiscale entropy using fuzzy metrics : validation and application to nociception assessment

The refined multiscale entropy (RMSE) approach is commonly applied to assess complexity as a function of the time scale. RMSE is normally based on the computation of sample entropy (SampEn) estimating complexity as conditional entropy. However, SampEn is dependent on the length and standard deviation of the data. Recently, fuzzy entropy (FuzEn) has been proposed, including several refinements, as an alternative to counteract these limitations. In this work, FuzEn, translated FuzEn (TFuzEn), translated-reflected FuzEn (TRFuzEn), inherent FuzEn (IFuzEn), and inherent translated FuzEn (ITFuzEn) were exploited as entropy-based measures in the computation of RMSE and their performance was compared to that of SampEn. FuzEn metrics were applied to synthetic time series of different lengths to evaluate the consistency of the different approaches. In addition, electroencephalograms of patients under sedation-analgesia procedure were analyzed based on the patient's response after the application of painful stimulation, such as nail bed compression or endoscopy tube insertion. Significant differences in FuzEn metrics were observed over simulations and real data as a function of the data length and the pain responses. Findings indicated that FuzEn, when exploited in RMSE applications, showed similar behavior to SampEn in long series, but its consistency was better than that of SampEn in short series both over simulations and real data. Conversely, its variants should be utilized with more caution, especially whether processes exhibit an important deterministic component and/or in nociception prediction at long scales

DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality

AIMS/HYPOTHESIS: The double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality. METHODS: In DEVOTE, patients with type 2 diabetes were randomised to receive either insulin degludec or insulin glargine U100 (100 units/ml) once daily (between dinner and bedtime) in an event-driven, double-blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In the present analysis, the associations of severe hypoglycaemia with both MACE and all-cause mortality was evaluated in the pooled trial population using time-to-event analyses, with severe hypoglycaemia as a time-dependent variable and randomised treatment as a fixed factor. An investigation with interaction terms indicated that the effect of severe hypoglycaemia on the risk of MACE and all-cause mortality were the same for both treatment arms, and so the temporal association for severe hypoglycaemia with subsequent MACE and all-cause mortality is reported for the pooled population. RESULTS: There was a non-significant difference in the risk of MACE for individuals who had vs those who had not experienced severe hypoglycaemia during the trial (HR 1.38, 95% CI 0.96, 1.96; p = 0.080) and therefore there was no temporal relationship between severe hypoglycaemia and MACE. There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycaemia during the trial (HR 2.51, 95% CI 1.79, 3.50; p < 0.001). There was a higher risk of all-cause mortality 15, 30, 60, 90, 180 and 365 days after experiencing severe hypoglycaemia compared with not experiencing severe hypoglycaemia in the same time interval. The association between severe hypoglycaemia and all-cause mortality was maintained after adjustment for the following baseline characteristics: age, sex, HbA1c, BMI, diabetes duration, insulin regimen, hepatic impairment, renal status and cardiovascular risk group. CONCLUSIONS/INTERPRETATION: The results from these analyses demonstrate an association between severe hypoglycaemia and all-cause mortality. Furthermore, they indicate that patients who experienced severe hypoglycaemia were particularly at greater risk of death in the short term after the hypoglycaemic episode. These findings indicate that severe hypoglycaemia is associated with higher subsequent mortality; however, they cannot answer the question as to whether severe hypoglycaemia serves as a risk marker for adverse outcomes or whether there is a direct causal effect. TRIAL REGISTRATION: ClinicalTrials.gov NCT01959529

Resonant tunnelling between the chiral Landau states of twisted graphene lattices

A class of multilayered functional materials has recently emerged in which the component atomic layers are held together by weak van der Waals forces that preserve the structural integrity and physical properties of each layer. An exemplar of such a structure is a transistor device in which relativistic Dirac Fermions can resonantly tunnel through a boron nitride barrier, a few atomic layers thick, sandwiched between two graphene electrodes. An applied magnetic field quantises graphene's gapless conduction and valence band states into discrete Landau levels, allowing us to resolve individual inter-Landau level transitions and thereby demonstrate that the energy, momentum and chiral properties of the electrons are conserved in the tunnelling process. We also demonstrate that the change in the semiclassical cyclotron trajectories, following an inter-layer tunnelling event, is analogous to the case of intra-layer Klein tunnelling