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IntroductionBariatric surgery is an effective method of controlling glycaemia in patients with type 2 diabetes mellitus (T2DM) and obesity. Long-term studies suggest that although glycaemic control remains good, only 20%–40% of patients will maintain remission according to the American Diabetes Association criteria.PurposeThis trial aims to examine the safety and efficacy of combining Roux-en-Y gastric bypass or sleeve gastrectomy with goal-directed medical therapy to improve long-term glycaemic control of T2DM.Methods and analysisThis prospective, open-label multicentre randomised controlled trial (RCT) will recruit 150 patients with obesity and T2DM from tertiary care obesity centres. Patients will be randomised 1:1 to receive either bariatric surgery and standard medical care or bariatric surgery and intensive goal-directed medical therapy, titrated to specific targets for glycated haemoglobin (HbA1c), blood pressure (BP) and low-density lipoproteins (LDL) cholesterol. The primary endpoints are the proportion of patients in each arm with an HbA1cEthics and disseminationThe local institutional review board approved this study. This study represents the first RCT to examine the safety and efficacy of combining bariatric surgery with intensive medical therapy compared with bariatric surgery and usual care for long-term diabetes control.Trial registration numberNCT04432025.

Introduction: Severe hypoglycemia is associated with an increased risk of cardiovascular (CV) death, and platelet responses to hypoglycemia (hypo) have been described. The impact of a transient severe hypo versus prolonged less severe hypo is unclear. Methods: 2 hypo studies were compared; firstly, in 18 subjects (type 2 diabetes (T2D) : 8 controls) blood glucose lowered to 3.5mmoL/L (90mg/dL) for 1-hour; secondly, in 46 subjects (23 T2D: 23 controls) blood glucose lowered to Results: In T2D, from baseline to hypo, differences were seen for 4 PRPs, three showing increased percent change in study-2 (plasminogen activator inhibitor-1 (PAI-1) , platelet glycoprotein VI (PGVI) and Tissue factor) , one showing increased percent change in study-1 (CD40 ligand (CD40LG)) ; at 24-hours in T2D, percent change for CD40LG remained increased, together with von Willebrand factor (vWF) , in study-2. In controls, from baseline to hypo, differences were seen for four PRPs, three showing increased percent change in study-2 (PAI-1, CD40LG and Protein S) , one showing increased percent change in study-1 (vWF) ; at 24-hours in controls, percent change for Protein S remained increased in study-2, whilst percent change for vWF and plasminogen were increased in study-1. Conclusion: Thrombogenic potential was enhanced in T2D versus controls, as evidenced by an increased thrombogenic protein expression profile in both mild and severe hypoglycemia, that showed persistent changes at 24-hours in severe hypo. Disclosure A. Moin: None. H. Kahal: None.

Saxenda, Liraglutide 3.0 mg, is a glucagon-like peptide-1 (GLP-1) analogue that is licensed for the treatment of adults with overweight and obesity. In this commentary we review the NICE technology appraisal (TA664) on the use of Saxenda in the National Health Service (NHS) and its implication in clinical practice.

Mild hypoglycemia is common in clinical practice. Severe hypoglycemia results in heat shock protein and associate co-chaperone changes. Whether mild prolonged hypoglycemia elicits a similar response with inflammatory and oxidative-stress responses compared with a severe hypoglycemic event is unclear; therefore, this pilot exploratory study was undertaken. We performed a case–control induced hypoglycemia clamp study, maintaining blood glucose at 2.8 mmol/L (50 mg/dL) for 1 h in 17 subjects (T2D (n = 10); controls (n = 7)). Blood sampling was performed at baseline, hypoglycemia, and 24 h; slow off-rate modified aptamer (SOMA)-scan plasma protein analysis of HSP-related proteins, inflammatory stress markers, and oxidative stress markers was performed. In total, 16 HSPs were analyzed. At baseline, TLR4:MD-2 complex was elevated (p = 0.01), whilst HSPA8 was lower (p < 0.05) in T2D. At hypoglycemia, UBE2N, STIP1, and UBE2L3 increased (all p < 0.05), whilst TLR4:MD-2 and HSPA8 decreased (p < 0.05) in T2D versus baseline. In follow-up after hypoglycemia, HSPs normalized to baseline by 24 h, except UBE2L3 (p < 0.05), which was decreased in controls versus baseline. Correlation of altered inflammatory markers with HSPs revealed the following: at baseline, TLR4:MD-2 correlated with CXCL10 (p < 0.01) and SIGLEC1 (p < 0.05) in controls; HSPA8 negatively correlated with IL5 (p < 0.05) in T2D. A negative correlation between urinary isoprostane 8-iso PGF2α, a marker of oxidative stress, and HSPA1A was seen at 24 h in T2D only (p < 0.05). In conclusion, the HSP changes seen for mild prolonged hypoglycemia were similar to those previously reported for a severe event. However, mild prolonged hypoglycemia appeared to elicit an increased inflammatory response that was associated with heat shock and related proteins.

IntroductionHypoglycemia in type 2 diabetes (T2D) may increase risk for Alzheimer’s disease (AD), but no data on changes in AD-related proteins with differing degrees of hypoglycemia exist. We hypothesized that milder prolonged hypoglycemia would cause greater AD-related protein changes versus severe transient hypoglycemia.Research design and methodsTwo prospective case-control induced hypoglycemia studies were compared: study 1, hypoglycemic clamp to 2.8 mmol/L (50 mg/dL) for 1 hour in 17 subjects (T2D (n=10), controls (n=7)); study 2, hypoglycemic clamp to 2.0 mmol/L (36 mg/dL) undertaken transiently and reversed in 46 subjects (T2D (n=23), controls (n=23)). Blood sampling at baseline, hypoglycemia and 24-hour post-hypoglycemia, with proteomic analysis of amyloid-related proteins performed.ResultsIn control subjects, the percentage change from baseline to hypoglycemia differed between study 1 and study 2 for 5 of 11 proteins in the AD-related panel: serum amyloid A1 (SAA1) (p=0.009), pappalysin (PAPPA) (p=0.002), apolipoprotein E2 (p=0.02), apolipoprotein E3 (p=0.03) and apolipoprotein E4 (p=0.02). In controls, the percentage change from baseline to 24 hours differed between studies for two proteins: SAA1 (p=0.003) and PAPPA (p=0.004); however, after Bonferroni correction only SAA1 and PAPPA remain significant. In T2D, there were no differential protein changes between the studies.ConclusionsThe differential changes in AD-related proteins were seen only in control subjects in response to iatrogenic induction of hypoglycemic insults of differing length and severity and may reflect a protective response that was absent in subjects with T2D. Milder prolonged hypoglycemia caused greater AD-related protein changes than severe acute hypoglycemia in control subjects.Trial registration numbersNCT02205996, NCT03102801.

Aims To determine the biochemical changes that underlie hypoglycaemia in a healthy control group and in people with type 2 diabetes (T2D). Materials and methods We report a hypoglycaemic clamp study in seven healthy controls and 10 people with T2D. Blood was withdrawn at four time points: at baseline after an overnight fast; after clamping to euglycaemia at 5 mmol/L; after clamping to hypoglycaemia at 2.8 mmol/L; and 24 hours later, after overnight fast. Deep molecular phenotyping using non-targeted metabolomics and the SomaLogic aptamer-based proteomics platform was performed on collected samples. Results A total of 955 metabolites and 1125 proteins were identified, with significant alterations in >90 molecules. A number of metabolites significantly increased during hypoglycaemia, but only cortisol, adenosine-3',5'-cyclic monophosphate (cyclic AMP), and pregnenolone sulphate, were independent of insulin. By contrast, identified protein changes were triggered by hypoglycaemia rather than insulin. The T2D group had significantly higher levels of fatty acids including 10-nonadecenoate, linolenate and dihomo-linoleate during hypoglycaemia compared with the control group. Molecules contributing to cardiovascular complications such as fatty-acid-binding protein-3 and pregnenolone sulphate were altered in the participants with T2D during hypoglycaemia. Almost all molecules returned to baseline at 24 hours. Conclusions The present study provides a comprehensive description of molecular events that are triggered by insulin-induced hypoglycaemia. We identified deregulated pathways in T2D that may play a role in the pathophysiology of hypoglycaemia-induced cardiovascular complications.

Polycystic ovary syndrome (PCOS) is associated with reduced quality of life (QoL), though the role of associated obesity is unclear. In this study we examined the effects of six months treatment with liraglutide, 1.8 mg od, on obesity, depression and QoL in young women with PCOS and obesity compared to age- and weight-matched controls. In a cross-sectional study, 36 women were recruited (19 PCOS, 17 controls), age 33.9 ± 6.7 vs. 33.5 ± 7.1 yr, and weight 102.1 ± 17.1 vs. 100.4 ± 15.1 kg, respectively. PCOS was diagnosed according to the Rotterdam criteria. Depression was measured using the Centre for Epidemiologic Studies Depression Scale (CES-D). QoL was measured using the World Health Organization QoL questionnaire (WHOQOL-BREF). At baseline there was no difference in QoL or CES-D scores between the two groups. At six months, weight was reduced by 3.0 ± 4.2 kg, p = .01, in the PCOS group and 3.8 ± 3.4 kg, p = .001, in controls. Psychological health improved in the PCOS group (percentage change 11.3%, p .02). Combining the two groups revealed significant improvement (p .05) in physical (82.6 ± 11.2 vs. 78.9 ± 13.6), psychological (62.4 ± 16.5 vs. 57.5 ± 16.4) and social health (76.6 ± 15.3 vs. 71 ± 16.8) components of the WHOQOL-BREF at six months. Weight loss is associated with an improvement in QoL; and when matched for age and obesity, PCOS was not independently associated with reduced QoL or depression.

Introduction: Heat shock proteins (HSPs) protect against protein misfolding, contribute to diabetes-induced complications and are affected by hypoglycemia. Misfolded proteins are degraded by ubiquination through UBE2L3/UBE2N proteins. Methods: Two prospective case-control induced hypoglycemia studies were compared: Study1, hypoglycemic clamp to 2.8mmol/l(50mg/dl) for 1-hour, 17 subjects (T2D(n=10); controls(n=7));Study2, hypoglycemic clamp to 2.0mmol/l(36mg/dl) transiently, 46 subjects (T2D(n=23); controls(n=23)).Blood sampling: baseline, hypoglycemia and 24-hours; Somalogic proteomic analysis of HSPs was undertaken. Results: HSP changes were seen in both studies separately; however, percentage-change baseline to hypoglycemia differed between studies for seven of 19 HSP panel proteins, with notable changes in Study 1: elevated levels in controls at hypoglycemia for TLR4:MD-2(p=0.01) and CD274(p=0.04), and at 24-hours for MAPKAPK5(p=0.047); elevated levels in T2D at hypoglycemia for DNAJB1(p=0.01), STIP1(p=0.01), UBE2L3(p=0.01) and UBE2N(p=0.001) (Figure1). Conclusion: Milder-prolonged hypoglycaemia caused greater HSP changes than severe-acute hypoglycaemia for HSPs protective against protein misfolding and for increasing UBE2L3/UBE2N degradation proteins in T2D, suggesting hypoglycemic duration may cause greater cell damage than severity. Disclosure A. Moin: None. A. S. Atkin: None. H. Kahal: None. A. Al-qaissi: None. T. Sathyapalan: Research Support; Self; Abbott, Eli Lilly and Company, Novo Nordisk. S. Atkin: None. A. E. Butler: None.

Background Double Diabetes (DD), type 1 diabetes (T1DM) + insulin resistance (IR), is associated with increased risk of micro/macro-vascular complications and mortality. Obesity can contribute to the development of DD. This study explored the prevalence of overweight/obesity and their association with DD in adults with T1DM. Methods Cross-sectional study of consecutive adults with T1DM attending diabetes clinics in a secondary care hospital (January-November 2019). Estimated glucose disposal rate (eGDR) was used as a marker of IR, and an eGDR Results One hundred seven adults with T1DM were included; female/male: 51/56; age [median (inter-quartile range): 30.0 (23–51) years]; BMI 25.4 (22.8–30.0) kg/m2. Overweight/obesity prevalence was 57/107 (53.3 %) [overweight: 30/107 (28 %); obesity: 27/107 (25.2 %)]. Compared to those with normal BMI, individuals with T1DM and overweight/obesity had longer diabetes duration; higher total daily insulin dose; and higher DD prevalence: 48/57 (84.2 %) vs. 14/50 (28 %) (p Conclusions Overweight/obesity is very common in adults with T1DM, and is associated with double diabetes. BMI is positively associated with total insulin dose. Double diabetes is associated with adverse cardiovascular risk profile and is also common in lean individuals with T1DM. Further research is needed to examine the impact of overweight/obesity in people with T1DM and whether weight loss in this population can improve diabetes-related outcomes.

Background Obesity is a common risk factor for polycystic ovary syndrome (PCOS) and obstructive sleep apnoea (OSA). Both PCOS and OSA are associated with increased risk of type 2 diabetes and cardiovascular disease. Hence, it is important to determine the burden of OSA in women with PCOS. Methods We searched electronic databases (MEDLINE, Embase, CINAHL, PsycINFO, Scopus, Web of Science, OpenGrey, CENTRAL), conference abstracts, and reference lists of relevant articles, up to January 2019. No restriction for language or publication status. Studies that examined the presence of OSA in women with PCOS using polysomnography and/or level III devices were eligible for inclusion. Results Seventeen studies involving 648 participants were included. Our meta-analysis showed that 35.0% (95% CI 22.2–48.9%) of women with PCOS had OSA. This prevalence was not affected by variation in PCOS definition between studies. Approximately one-tenth of the variation in OSA prevalence was related to differences in study population (higher in adults than adolescents and mixed populations), and around one-tenth was related to sample size (higher in smaller studies). OSA prevalence was markedly higher in obese versus lean women with PCOS, and in women with PCOS compared to controls (odds ratio = 3.83, 95% CI 1.43–10.24, eight studies, 957 participants (349 PCOS and 608 controls)). However, most of the studies were at high risk of selection bias, did not account for important confounders, included predominantly women with class II obesity, and were conducted in one country (USA). Conclusions Future studies need to examine the true prevalence of OSA in a more representative sample of women with PCOS. Nevertheless, our results suggest that the prevalence of OSA in women with PCOS and obesity is high and clinicians should have a high index of suspicion of OSA in these women. Electronic supplementary material The online version of this article (10.1007/s11325-019-01835-1) contains supplementary material, which is available to authorized users.

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m2 and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.

MDMA (3,4-methylenedioxymethamfetamine, Ecstasy) is a widely used recreational drug. We present a case of pneumomediastinum as a complication of MDMA use in a 21-year-old man with no previous history of lung or gastrointestinal pathology. We have performed a literature review, and summarised the symptoms, signs, and prognosis for this under-recognised complication of a commonly used recreational drug. We recommend enquiring about illicit drug use in any patient presenting with spontaneous pneumomediastinum.

Aim: Strict glycaemic control has been associated with an increased mortality rate in subjects with type 2 diabetes (T2DM). Here we examined platelet function immediately and 24 hours following induced hypoglycaemia in people with type 2 diabetes compared to healthy age-matched controls. Methods: Hyperinsulinaemic clamps reduced blood glucose to 2.8 mmol/L (50 mg/dl) for 1 hour. Sampling at baseline; euglycaemia 5 mmol/L (90 mg/dl); hypoglycaemia; and at 24 post clamp were undertaken. Platelet function was measured by whole blood flow cytometry. Results: 10 subjects with T2DM and 8 controls were recruited. Platelets from people with T2DM showed reduced sensitivity to prostacyclin (PGI2, 1 nM) following hypoglycaemia. The ability of PGI2 to inhibit platelet activation was significantly impaired at 24 hours compared to baseline in the T2DM group. Here, inhibition of fibrinogen binding was 29.5% (10.3–43.8) compared to 50.8% (36.8–61.1), (P < 0.05), while inhibition of P-selectin expression was 32% (16.1–47.6) vs. 54.4% (42.5–67.5) (P < 0.05). No significant changes in platelet function were noted in controls. Conclusion: Induced hypoglycaemia in T2DM enhances platelet hyperactivity through impaired sensitivity to prostacyclin at 24 hours.

Background\ud \ud Dynamic changes in glycaemia predominate peri-operatively in patients with type 2 diabetes mellitus (T2DM) undergoing metabolic surgery. There is a lack of consensus and clear guidance on effective glycaemic management of such patients. The aim of this study was to design, pilot, and implement a proforma to improve consistency of glycaemic management and clarity of communication with healthcare professionals following metabolic surgery in patients with T2DM, thereby reducing unnecessary diabetes specialist nurse (DSN) referrals.\ud \ud Methods\ud \ud A proforma was designed and piloted for 12 months to guide healthcare professionals on managing glycaemic therapies for T2DM patients undergoing metabolic surgery. Glycaemic control (HbA1c) and glycaemic therapies were reviewed 3 weeks pre-operatively and a proforma was completed accordingly.\ud \ud Results\ud \ud Of the patients with T2DM (n = 34) who underwent metabolic surgery prior to the new proforma being implemented, 71% (n = 24) had a DSN referral. Half of these referrals were deemed unnecessary by the DSNs. Of the patients with T2DM (n = 33) who underwent metabolic surgery following implementation of the proforma, 21% (n = 7) had a DSN referral. Only 10% of these were deemed unnecessary. Despite the reduced DSN input, no diabetes-related complications were reported.\ud \ud Conclusion\ud \ud Implementation of our proforma effectively halved the proportion of patients with T2DM requiring a DSN referral. Additionally, there was a 40% absolute reduction in the proportion of unnecessary DSN referrals. The proforma improved clarity of communication and guidance for healthcare professionals in the glycaemic management of patients. This also facilitated improved work efficiency and resource allocation.

Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder in women of reproductive age. PCOS is associated with multiple co-morbidities including, obesity, insulin resistance and type 2 diabetes, as well as mood disorders and impaired quality of life (QoL). Obstructive sleep apnoea (OSA) is also a common medical condition that is often undiagnosed, particularly in women. OSA is associated with a similar spectrum of comorbidities to that observed in PCOS, including manifestations of the metabolic syndrome and impaired QoL, whilst obesity frequently constitutes a common denominator in the pathophysiology of both OSA and PCOS. Hence, it is not surprising that OSA and PCOS may co-exist in women of reproductive age, and the current clinical guidelines on the management of PCOS recommend screening for OSA symptoms in overweight/obese women with PCOS. In this review, we examine the relationship between OSA and PCOS and explore the potential underlying mechanisms that link these two conditions. This article is protected by copyright. All rights reserved. [Abstract copyright: This article is protected by copyright. All rights reserved.]

Background Polycystic ovary syndrome (PCOS) is associated with obesity and increased cardiovascular (CV) risk markers. In this study our aim was to assess the effects of six months treatment with liraglutide 1.8 mg od on obesity, and CV risk markers, particularly platelet function, in young obese women with PCOS compared to controls of similar age and weight. Methods Carotid intima-media wall thickness (cIMT) was measured by B-mode ultrasonography, platelet function by flow cytometry, clot structure/lysis by turbidimetric assays and endothelial function by ELISA and post-ischaemic reactive hyperemia (RHI). Data presented as mean change (6-month – baseline) ± standard deviation. Results Nineteen obese women with PCOS and 17 controls, of similar age and weight, were recruited; baseline atherothrombotic risk markers did not differ between the two groups. Twenty five (69.4%) participants completed the study (13 PCOS, 12 controls). At six months, weight was significantly reduced by 3.0 ± 4.2 and 3.8 ± 3.4 kg in the PCOS and control groups, respectively; with no significant difference between the two groups, P = 0.56. Similarly, HOMA-IR, triglyceride, hsCRP, urinary isoprostanes, serum endothelial adhesion markers (sP-selectin, sICAM and sVCAM), and clot lysis area were equally significantly reduced in both groups compared to baseline. Basal platelet P-selectin expression was significantly reduced at six months in controls −0.17 ± 0.26 but not PCOS −0.12 ± 0.28; between groups difference, 95% confidence interval = −0.14 – 0.26, P = 0.41. No significant changes were noted in cIMT or RHI. Conclusions Six months treatment with liraglutide (1.8 mg od) equally affected young obese women with PCOS and controls. In both groups, liraglutide treatment was associated with 3–4% weight loss and significant reduction in atherothrombosis markers including inflammation, endothelial function and clotting. Our data support the use of liraglutide as weight loss medication in simple obesity and suggest a potential beneficial effect on platelet function and atherothrombotic risk at 6 months of treatment. Trial registration Clinical trial reg. no. ISRCTN48560305. Date of registration 22/05/2012.

Polycystic ovary syndrome (PCOS) is a common disorder affecting women of reproductive age and it is associated with increased cardiovascular risk. Obesity plays an important role in the pathogenesis of PCOS, and the majority of patients with PCOS are obese. Over the last 20 years, the prevalence of obesity has dramatically increased, with probable associated increase in PCOS. Weight reduction plays an integral part in the management of women with PCOS. In this paper, current available weight reduction therapies in the management of PCOS are discussed.