The Impact of Low-dose Gliclazide on the Incretin Effect and Indices of Beta-cell Function

AIMS/HYPOTHESIS: Studies in permanent neonatal diabetes suggest that sulphonylureas lower blood glucose without causing hypoglycemia, in part by augmenting the incretin effect. This mechanism has not previously been attributed to sulphonylureas in patients with type 2 diabetes (T2DM). We therefore aimed to evaluate the impact of low-dose gliclazide on beta-cell function and incretin action in patients with T2DM. METHODS: Paired oral glucose tolerance tests and isoglycemic infusions were performed to evaluate the difference in the classical incretin effect in the presence and absence of low-dose gliclazide in 16 subjects with T2DM (hemoglobin A1c < 64 mmol/mol, 8.0%) treated with diet or metformin monotherapy. Beta-cell function modeling was undertaken to describe the relationship between insulin secretion and glucose concentration. RESULTS: A single dose of 20 mg gliclazide reduced mean glucose during the oral glucose tolerance test from 12.01 ± 0.56 to 10.82 ± 0.5mmol/l [P = 0.0006; mean ± standard error of the mean (SEM)]. The classical incretin effect was augmented by 20 mg gliclazide, from 35.5% (lower quartile 27.3, upper quartile 61.2) to 54.99% (34.8, 72.8; P = 0.049). Gliclazide increased beta-cell glucose sensitivity by 46% [control 22.61 ± 3.94, gliclazide 33.11 ± 7.83 (P = 0.01)] as well as late-phase incretin potentiation [control 0.92 ± 0.05, gliclazide 1.285 ± 0.14 (P = 0.038)]. CONCLUSIONS/INTERPRETATION: Low-dose gliclazide reduces plasma glucose in response to oral glucose load, with concomitant augmentation of the classical incretin effect. Beta-cell modeling shows that low plasma concentrations of gliclazide potentiate late-phase insulin secretion and increase glucose sensitivity by 50%. Further studies are merited to explore whether low-dose gliclazide, by enhancing incretin action, could effectively lower blood glucose without risk of hypoglycemia

Risk of anemia with metformin use in type 2 diabetes:A MASTERMIND study

Objective: To evaluate the association between metformin use and anemia risk in type 2 diabetes, and the time-course for this, in a randomized controlled trial (RCT) and real-world population data. Research Design and Methods: Anemia was defined as a hemoglobin measure of &lt;11 g/dL. In the RCTs A Diabetes Outcome Progression Trial (ADOPT; n = 3,967) and UK Prospective Diabetes Study (UKPDS; n = 1,473), logistic regression was used to model anemia risk and nonlinear mixed models for change in hematological parameters. In the observational Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) population (n = 3,485), discrete-time failure analysis was used to model the effect of cumulative metformin exposure on anemia risk. Results: In ADOPT, compared with sulfonylureas, the odds ratio (OR) (95% CI) for anemia was 1.93 (1.10, 3.38) for metformin and 4.18 (2.50, 7.00) for thiazolidinediones. In UKPDS, compared with diet, the OR (95% CI) was 3.40 (1.98, 5.83) for metformin, 0.96 (0.57, 1.62) for sulfonylureas, and 1.08 (0.62, 1.87) for insulin. In ADOPT, hemoglobin and hematocrit dropped after metformin initiation by 6 months, with no further decrease after 3 years. In UKPDS, hemoglobin fell by 3 years in the metformin group compared with other treatments. At years 6 and 9, hemoglobin was reduced in all treatment groups, with no greater difference seen in the metformin group. In GoDARTS, each 1 g/day of metformin use was associated with a 2% higher annual risk of anemia. Conclusions: Metformin use is associated with early risk of anemia in individuals with type 2 diabetes, a finding consistent across two RCTs and replicated in one real-world study. The mechanism for this early fall in hemoglobin is uncertain, but given the time course, is unlikely to be due to vitamin B12 deficiency alone

Predicting post one-year durability of glucose-lowering monotherapies in patients with newly-diagnosed type 2 diabetes mellitus – A MASTERMIND precision medicine approach (UKPDS 87)

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record Aims: Predicting likely durability of glucose-lowering therapies for people with type 2 diabetes (T2D) could help inform individualised therapeutic choices. Methods: We used data from UKPDS patients with newly-diagnosed T2D randomised to first-line glucose-lowering monotherapy with chlorpropamide–glibenclamide–basal insulin or metformin. In 2339 participants who achieved one-year HbA1c values <7.5% (<59 mmol/mol)–we assessed relationships between one-year characteristics and time to monotherapy-failure (HbA1c ≥ 7.5% or requiring second-line therapy). Model validation was performed using bootstrap sampling. Results: Follow-up was median (IQR) 11.0 (8.0–14.0) years. Monotherapy-failure occurred in 72%–82%–75% and 79% for those randomised to chlorpropamide–glibenclamide–basal insulin or metformin respectively–after median 4.5 (3.0–6.6)–3.7 (2.6–5.6)–4.2 (2.7–6.5) and 3.8 (2.6– 5.2) years. Time-to-monotherapy-failure was predicted primarily by HbA1c and BMI values–with other risk factors varying by type of monotherapy–with predictions to within ±2.5 years for 55%–60%–56% and 57% of the chlorpropamide–glibenclamide–basal insulin and metformin monotherapy cohorts respectively. Conclusions: Post one-year glycaemic durability can be predicted robustly in individuals with newly-diagnosed T2D who achieve HbA1c values < 7.5% one year after commencing traditional monotherapies. Such information could be used to help guide glycaemic management for individual patients.Medical Research Council (MRC

Cerebrospinal fluid cortisol levels are higher in patients with delirium versus controls

<p>Abstract</p> <p>Background</p> <p>High plasma cortisol levels can cause acute cognitive and neuropsychiatric dysfunction, and have been linked with delirium. CSF cortisol levels more closely reflect brain exposure to cortisol, but there are no studies of CSF cortisol levels in delirium. In this pilot study we acquired CSF specimens at the onset of spinal anaesthesia in patients undergoing hip fracture surgery, and compared CSF and plasma cortisol levels in delirium cases versus controls.</p> <p>Findings</p> <p>Delirium assessments were performed the evening before or on the morning of operation with a standard battery comprising cognitive tests, mental status assessments and the Confusion Assessment Method. CSF and plasma samples were obtained at the onset of the operation and cortisol levels measured. Twenty patients (15 female, 5 male) aged 62 - 93 years were studied. Seven patients were diagnosed with delirium. The mean ages of cases (81.4 (SD 7.2)) and controls (80.5 (SD 8.7)) were not significantly different (p = 0.88). The median (interquartile range) CSF cortisol levels were significantly higher in cases (63.9 (40.4-102.1) nmol/L) than controls (31.4 (21.7-43.3) nmol/L; Mann-Whitney U, p = 0.029). The median (interquartile range) of plasma cortisol was also significantly higher in cases (968.8 (886.2-1394.4) nmol/L, than controls (809.4 (544.0-986.4) nmol/L; Mann Whitney U, p = 0.036).</p> <p>Conclusions</p> <p>These findings support an association between higher CSF cortisol levels and delirium. This extends previous findings linking higher plasma cortisol and delirium, and suggests that more definitive studies of the relationship between cortisol levels and delirium are now required.</p

Be outraged: there are alternatives

Pushed to extremes, austerity is bad economics, bad arithmetic, and ignores the lessons of history. We, an international group of economists and social scientists, are outraged at the narrow range of austerity policies which are bringing so many people around the world to their knees, especially in Europe. Austerity and cutbacks are reducing growth and worsening poverty. In our professional opinions, there are alternatives – for Britain, Europe and all countries that currently imagine that government cutbacks are the only way out of debt. The low-growth, no-growth trap means that the share of debt in GNP falls ever more slowly, if at all. It may even rise – as it has in some countries

Mental health of people with multiple sclerosis during the COVID-19 outbreak: A prospective cohort and cross-sectional case–control study of the UK MS Register

Background: People with MS (pwMS) have had higher rates of anxiety and depression than the general population before the COVID-19 pandemic, placing them at higher risk of experiencing poor psychological wellbeing during the pandemic.Objective: To assess mental health and its social/lifestyle determinants in pwMS during the first wave of the outbreak in the UK.Methods: This is a community-based, prospective longitudinal cohort and cross-sectional case-control online questionnaire study. It includes 2,010 pwMS from the UK MS Register and 380 people without MS.Results: The Hospital Anxiety and Depression Scale scores of pwMS for anxiety and depression during the outbreak did not change from the previous year. PwMS were more likely to have anxiety (using General Anxiety Disorder-7) and/or depression (using Patient Health Questionnaire-9) than controls during the outbreak (OR:2.14[95%CI:1.58-2.91]). PwMS felt lonelier (OR:1.37[95%CI:1.04-1.80]), reported worse social support (OR:1.90[95%CI:1.18-3.07]) and reported worsened exercise habits (OR:1.65[95%CI:1.18-2.32]) during the outbreak than controls.Conclusion: Early in the pandemic, pwMS remained at higher risk of experiencing anxiety and depression than the general population. It is important that multidisciplinary teams improve their support for the wellbeing of pwMS, who are vulnerable to the negative effects of the pandemic on their lifestyle and social support

Quantifying the extent to which index event biases influence large genetic association studies

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.As genetic association studies increase in size to 100,000s of individuals, subtle biases may influence conclusions. One possible bias is "index event bias" (IEB) that appears due to the stratification by, or enrichment for, disease status when testing associations between genetic variants and a disease-associated trait. We aimed to test the extent to which IEB influences some known trait associations in a range of study designs and provide a statistical framework for assessing future associations. Analysing data from 113,203 non-diabetic UK Biobank participants, we observed three (near TCF7L2, CDKN2AB and CDKAL1) overestimated (BMI-decreasing) and one (near MTNR1B) underestimated (BMI-increasing) associations among 11 type 2 diabetes risk alleles (at P  500,000 if the prevalence of those diseases differs by > 10% from the background population. In conclusion, IEB may result in false positive or negative genetic associations in very large studies stratified or strongly enriched for/against disease cases.H.Y., A.R.W. and T.M.F. are supported by the European Research Council grant: 323195; SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC. S.E.J. is funded by the Medical Research Council (grant: MR/M005070/1). M.A.T., M.N.W. and A.M. are supported by the Wellcome Trust Institutional Strategic Support Award (WT097835MF). R.M.F. is a Sir Henry Dale Fellow (Wellcome Trust and Royal Society grant: 104150/Z/14/Z). R.B. is funded by the Wellcome Trust and Royal Society grant: 104150/Z/14/Z. J.T. is funded by a Diabetes Research and Wellness Foundation Fellowship. Z.K. received financial support from the Leenaards Foundation, the Swiss Institute of Bioinformatics and the Swiss National Science Foundation (31003A-143914) and SystemsX.ch (39). The work of M.P.B was supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award no. T32HL007779. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. E.R.P. holds a WT New investigator award 102820/Z/13/Z

The Next Linear Collider Test Accelerator

During the past several years, there has been tremendous progress on the development of the RF system and accelerating structures for a Next Linear Collider (NLC). Developments include high-power klystrons, RF pulse compression systems and damped/detuned accelerator structures to reduce wakefields. In order to integrate these separate development efforts into an actual X-band accelerator capable of accelerating the electron beams necessary for an NLC, we are building an NLC Test Accelerator (NLCTA). The goal of the NLCTA is to bring together all elements of the entire accelerating system by constructing and reliably operating an engineered model of a high-gradient linac suitable for the NLC. The NLCTA will serve as a testbed as the design of the NLC evolves. In addition to testing the RF acceleration system, the NLCTA is designed to address many questions related to the dynamics of the beam during acceleration. In this paper, we will report on the status of the design, component development, and construction of the NLC Test Accelerator