Medication following bariatric surgery for type 2 diabetes mellitus (BY-PLUS) study: rationale and design of a randomised controlled study.

INTRODUCTION: Bariatric 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. PURPOSE: This 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 ANALYSIS: This 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 HbA1c<6.5% (48 mmol/mol) at 1 year and the proportion of patients in each arm achieving the composite endpoint of HbA1c<6.5% (48 mmol/mol), BP<130/80 mm Hg and LDL<2.6 mmol/L at 5 years. ETHICS AND DISSEMINATION: The 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 NUMBER: NCT04432025.

Heat Shock-Related Protein Responses and Inflammatory Protein Changes Are Associated with Mild Prolonged Hypoglycemia.

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.

The association between overweight/obesity and double diabetes in adults with type 1 diabetes; a cross-sectional study.

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 < 8 was used to identify individuals with DD. 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 < 0.01); with similar HbA1c. BMI correlated with total daily insulin dose (rho = 0.55; p < 0.01). Individuals with DD were older, had longer duration of diabetes, higher HbA1c, and more adverse lipid profile and microalbuminuria compared to those without DD. 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.

Amyloid-related protein changes associated with dementia differ according to severity of hypoglycemia.

INTRODUCTION: Hypoglycemia 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 METHODS: Two 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. RESULTS: In 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. CONCLUSIONS: The 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 NUMBERS: NCT02205996, NCT03102801.

Author Correction: Effect of induced hypoglycemia on inflammation and oxidative stress in type 2 diabetes and control subjects.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The relationship between obstructive sleep apnoea and quality of life in women with polycystic ovary syndrome: a cross-sectional study.

BACKGROUND: Obstructive sleep apnoea (OSA) and polycystic ovary syndrome (PCOS) are associated with significant comorbidities and commonly coexist. The primary aim of this study was to examine the relationship between OSA and quality of life (QoL) in women with PCOS. METHODS: We conducted an observational cross-sectional study. PCOS was diagnosed according to the Rotterdam criteria. Women with increased risk of OSA, based on the Berlin questionnaire or the Epworth Sleepiness Scale (ESS), had home-based polysomnography performed (ALICE PDx). Participants were divided into two groups: (a) PCOS only: women with normal ESS and low-risk Berlin questionnaire (no sleep studies performed), or women with normal sleep studies [oxygen desaturation index (ODI) < 5 events/hour]; and (b) PCOS+OSA: women with PCOS and OSA ODI ⩾ 5. QoL was assessed using the World Health Organization QoL questionnaire (WHOQOL-BREF) and the PCOS health-related quality of life questionnaire (PCOSQ). RESULTS: A total of 39 women were included; age (mean ± SD) was 32.2 ± 8.9 years, weight 92.5 ± 23.7 kg and body mass index (BMI) 34.1 ± 7.9 kg/m2; 38.5% (n = 15) had OSA. Compared with women with PCOS only, women with PCOS+OSA had higher BMI, HbA1c, C-reactive protein and low-density lipoprotein. ODI was independently associated with impaired QoL. Excessive daytime sleepiness (EDS) was independently associated with anxiety, depression and impaired QoL. CONCLUSIONS: OSA is highly prevalent and is associated with impaired QoL and worse metabolic profile in women with PCOS. Interventional studies are needed to examine the impact of OSA in women with PCOS. CLINICALTRIALSGOV IDENTIFIER: NCT03065322.

Effect of induced hypoglycemia on inflammation and oxidative stress in type 2 diabetes and control subjects.

Intensive diabetes control has been associated with increased mortality in type 2 diabetes (T2DM); this has been suggested to be due to increased hypoglycemia. We measured hypoglycemia-induced changes in endothelial parameters, oxidative stress markers and inflammation at baseline and after a 24-hour period in type 2 diabetic (T2DM) subjects versus age-matched controls. Case-control study: 10 T2DM and 8 control subjects. Blood glucose was reduced from 5 (90 mg/dl) to hypoglycemic levels of 2.8 mmol/L (50 mg/dl) for 1 hour by incremental hyperinsulinemic clamps using baseline and 24 hour samples. Measures of endothelial parameters, oxidative stress and inflammation at baseline and at 24-hours post hypoglycemia were performed: proteomic (Somalogic) analysis for inflammatory markers complemented by C-reactive protein (hsCRP) measurement, and proteomic markers and urinary isoprostanes for oxidative measures, together with endothelial function. Between baseline and 24 -hours after hypoglycemia, 15 of 140 inflammatory proteins differed in T2DM whilst only 1 of 140 differed in controls; all returned to baseline at 24-hours. However, elevated hsCRP levels were seen at 24-hours in T2DM (2.4 mg/L (1.2-5.4) vs. 3.9 mg/L (1.8-6.1), Baseline vs 24-hours, P < 0.05). In patients with T2DM, between baseline and 24-hour after hypoglycemia, only one of 15 oxidative stress proteins differed and this was not seen in controls. An increase (P = 0.016) from baseline (73.4 ng/mL) to 24 hours after hypoglycemia (91.7 ng/mL) was seen for urinary isoprostanes. Hypoglycemia resulted in inflammatory and oxidative stress markers being elevated in T2DM subjects but not controls 24-hours after the event.

The prevalence of obstructive sleep apnoea in women with polycystic ovary syndrome: a systematic review and meta-analysis.

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.

Metabolic and proteomic signatures of hypoglycaemia in type 2 diabetes.

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.

Effective Implementation of Peri-operative Local Guidelines for Metabolic Surgery in Patients with Diabetes Mellitus in a Tier 4 Setting Demonstrate Improved Work Efficiency and Resource Allocation.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

The association between obstructive sleep apnea and metabolic abnormalities in women with polycystic ovary syndrome: a systematic review and meta-analysis.

Study Objectives: In this systematic review and meta-analysis, we aimed to examine the relationship between obstructive sleep apnea (OSA) and metabolic abnormalities in women with polycystic ovary syndrome (PCOS). Methods: Electronic databases (Medline, Embase, Cinahl, PsycInfo, Scopus, Web of Science, Opengrey, and CENTRAL), conference abstracts, and reference lists of relevant articles were searched. No restriction was applied for language or publication status. Results: Six studies involving 252 participants were included. Women with PCOS and OSA had significantly higher body mass index (mean difference [MD]: 6.01 kg/m2, 95% confidence intervals [CI]: 4.69-7.33), waist circumference (MD: 10.93 cm, 95% CI: 8.03-13.83), insulin resistance, systolic and diastolic blood pressure, and worse lipids' profile and impaired glucose regulation compared with women with PCOS without OSA. Most studies did not adjust for weight in their between-groups analysis. Total and free testosterone levels were not significantly different between the two groups. The majority of studies were found to be at high risk of selection bias, did not account for important confounders, were conducted in one country (United States), and used different methodologies to assess testosterone levels (preventing a meta-analysis for this specific outcome). Conclusions: OSA is associated with obesity and worse metabolic profiles in women with PCOS. However, whether the effects of OSA are independent of obesity remain unclear. As OSA is a treatable condition, research focused on the independent effects of OSA on key clinical outcomes in women with PCOS, including fertility, psychological health, type 2 diabetes, and cardiovascular risk, is lacking and needed. PROSPERO registration number: CRD42016048587.

Obstructive sleep apnoea and polycystic ovary syndrome: A comprehensive review of clinical interactions and underlying pathophysiology.

Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder in women of reproductive age. PCOS is associated with multiple comorbidities 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 coexist 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.

Pneumomediastinum as a complication of MDMA (3,4-methylenedioxymetamfetamine, Ecstasy) ingestion.

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.

The effects of treatment with liraglutide on atherothrombotic risk in obese young women with polycystic ovary syndrome and controls.

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.

The effect of parathyroidectomy on neuropsychological symptoms and biochemical parameters in patients with asymptomatic primary hyperparathyroidism.

BACKGROUND: With increased biochemical screening, primary hyperparathyroidism (pHPT) is often discovered incidentally whilst patients are asymptomatic. OBJECTIVE: To assess the impact of parathyroidectomy on neuropsychological symptoms and biochemical parameters in people with asymptomatic pHPT, whilst controlling for the surgical procedure. PATIENTS/DESIGN/MEASUREMENTS: Twenty-four patients with asymptomatic pHPT requiring parathyroidectomy, in accordance with National Institutes for Health recommendations, were recruited prospectively. A control group of 23 subjects was recruited simultaneously from consecutive patients undergoing diagnostic hemithyroidectomy (HT) for benign thyroid nodules. Operations were performed by a single surgeon. Biochemical investigations and neuropsychological symptoms were measured preoperatively and 3 months after surgery. Neuropsychological symptoms were measured using the Hospital Anxiety (HAD-A) and Depression (HAD-D) scales and the Mood Rating Scale (MRS). RESULTS: Postoperatively, calcium and parathyroid hormone normalized in all patients in the pHPT group. Patients with pHPT showed a significant improvement in neuropsychological symptoms with a pre- and postoperative mean change of 2·45 ± 2·57 (P < 0·05) on HAD-A, 2·79 ± 3·85 (P < 0·05) on HAD-D, and 3·2 ± 4·57 (P < 0·05) on MRS, parameters that were unaltered in the HT group. The differences between the two groups remained statistically significant after adjustment for age and sex for HAD-D (mean change 2·8, 95% CI = 0·3, 5·3, P = 0·025) and MRS (mean difference 3·5, 95% CI = 0·4, 6·7, P = 0·027) but not for HAD-A (mean difference 1·5, 95% CI = -0·8, 3·8, P = 0·20). For all three mental health scores, there were no significant associations with either age or sex. CONCLUSIONS: Asymptomatic pHPT is associated with neuropsychological symptoms that improve after parathyroidectomy.

Pharmacological treatment of obesity in patients with polycystic ovary syndrome.

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.