Effect of intermittently scanned continuous glucose monitoring in people with diabetes with a psychosocial indication for initiation.

AIM: To understand the effect of intermittently scanned continuous glucose monitoring (isCGM) in people with diabetes with a 'psychosocial' indication for access. METHODS: The study utilized baseline and follow-up data from the Association of British Clinical Diabetologists nationwide audit of people with diabetes in the UK. Diabetes-related distress (DRD) was assessed using the two-item diabetes-related distress scale (DDS). Participants were categorized into two groups: high DRD (DDS score ≥ 3) and lower DRD (DDS score < 3). The t-test was used to assess the difference in the pre- and post-isCGM continuous variables. RESULTS: The study consisted of 17 036 people with diabetes, with 1314 (7%) using isCGM for 'psychosocial' reasons. Follow-up data were available for 327 participants, 322 (99%) of whom had type 1 diabetes with a median diabetes duration of 15 years; 75% (n = 241) had high levels of DRD. With the initiation of isCGM, after a mean follow-up period of 6.9 months, there was a significant reduction in DDS score; 4 at baseline versus 2.5 at follow-up (P < .001). The prevalence of high DRD reduced from 76% to 38% at follow-up (50% reduction in DRD, P < .001). There was also a significant reduction in HbA1c (78.5 mmol/mol [9.3%] at baseline vs. 66.5 mmol/mol [8.2%] at follow-up; P < .001). This group also experienced an 87% reduction in hospital admissions because of hyperglycaemia/diabetic ketoacidosis (P < .001). CONCLUSION: People with diabetes who had isCGM initiated for a psychosocial indication had high levels of DRD and HbA1c, which improved with the use of isCGM.

Intermittently scanned continuous glucose monitoring and hypoglycaemia awareness in drivers with diabetes: Insights from the Association of British Clinical Diabetologists Nationwide audit.

AIM: Frequent hypoglycaemia results in disruption to usual hypoglycaemic autonomic responses leading to impaired awareness of hypoglycaemia, which is associated with an increased risk of severe hypoglycaemia requiring third-party assistance (SH). The UK Driving and Vehicle Licensing Agency (DVLA) does not permit car driving if they have either a complete loss of hypoglycaemia awareness or more than one SH event a year. METHODS: The FreeStyle Libre (FSL) Association of British Clinical Diabetologists (ABCD) Nationwide Audit consists of data collected by clinicians during routine clinical work, submitted into a secure web-based tool held within the National Health Service (NHS) N3 network. Analysis of paired baseline and follow-up data for people with type 1 diabetes who also held a driving licence was undertaken. RESULTS: The study consisted of 6304 people who had data recorded about driving status from 102 UK specialist diabetes centres, of which 4218 held a driving licence: 4178 a group 1, standard licence, 33 a group 2, large lorries and buses, seven a taxi licence; 1819 did not drive. Paired baseline and follow-up data were available for a sub-cohort of 1606/4218. At a mean follow-up of 6.9 months [95% CI (6.8, 7.1)], the Gold score had improved (2.3 ± 1.5 vs. 2.0 ± 1.3 p < .001), and the number of people who experienced an SH episode was also significantly lower (12.1% vs. 2.7%, p < .001). CONCLUSION: This study suggests that intermittently scanned continuous glucose monitoring may improve impaired awareness of hypoglycaemia and reduce the number of people with type 1 diabetes with a driving licence experiencing a severe hypoglycaemic episode.

Clinical features of type 1 diabetes in older adults and the impact of intermittently scanned continuous glucose monitoring: An Association of British Clinical Diabetologists (ABCD) study.

AIMS: To evaluate the clinical features and impact of flash glucose monitoring in older adults with type 1 diabetes (T1D) across age groups defined as young-old, middle-old, and old-old. MATERIALS AND METHODS: Clinicians were invited to submit anonymized intermittently scanned continuous glucose monitoring (isCGM) user data to a secure web-based tool within the National Health Service secure network. We collected baseline data before isCGM initiation, such as demographics, glycated haemoglobin (HbA1c) values from the previous 12 months, Gold scores and Diabetes Distress Scale (DDS2) scores. For analysis, people with diabetes were classified as young-old (65-75 years), middle-old (>75-85 years) and old-old (>85 years). We compared baseline clinical characteristics across the age categories using a t test. All the analyses were performed in R 4.1.2. RESULTS: The study involved 1171 people with diabetes in the young-old group, 374 in the middle-old group, and 47 in the old-old group. There were no significant differences in baseline HbA1c and DDS2 scores among the young-old, middle-old, and old-old age groups. However, Gold score increased with age (3.20 [±1.91] in the young-old vs. 3.46 [±1.94] in the middle-old vs. 4.05 [±2.28] in the old-old group; p < 0.0001). This study showed reduced uptake of insulin pumps (p = 0.005) and structured education (Dose Adjustment For Normal Eating [DAFNE] course; p = 0.007) in the middle-old and old-old populations compared to the young-old population with T1D. With median isCGM use of 7 months, there was a significant improvement in HbA1c in the young-old (p < 0.001) and old-old groups, but not in the middle-old group. Diabetes-related distress score (measured by the DDS2) improved in all three age groups (p < 0.001) and Gold score improved (p < 0.001) in the young-old and old-old populations but not in the middle-old population. There was also a significant improvement in resource utilization across the three age categories following the use of is CGM. CONCLUSION: This study demonstrated significant differences in hypoglycaemia awareness and insulin pump use across the older age groups of adults with T1D. The implementation of isCGM demonstrated significant improvements in HbA1c, diabetes-related distress, hypoglycaemia unawareness, and resource utilization in older adults with T1D.

Assessing the androgenic and metabolic heterogeneity in polycystic ovary syndrome using cluster analysis.

INTRODUCTION: Some but not all women with polycystic ovary syndrome (PCOS) develop the metabolic syndrome (MS). The objective of this study was to determine if a subset of women with PCOS had higher androgen levels predisposing them to MS and whether routinely measured hormonal parameters impacted the metabolic syndrome score (siMS). METHODS: We included data from a discovery (PCOS clinic data) and a replication cohort (Hull PCOS Biobank) and utilized eight routinely measured hormonal parameters in our clinics (free androgen index [FAI], sex hormone-binding globulin, dehydroepiandrosterone sulphate (DHEAS), androstenedione, luteinizing hormone [LH], follicular stimulating hormone, anti-Müllerian hormone and 17 hydroxyprogesterone [17-OHP]) to perform a K-means clustering (an unsupervised machine learning algorithm). We used NbClust Package in R to determine the best number of clusters. We estimated the siMS in each cluster and used regression analysis to evaluate the effect of hormonal parameters on SiMS. RESULTS: The study consisted of 310 women with PCOS (discovery cohort: n = 199, replication cohort: n = 111). The cluster analysis identified two clusters in both the discovery and replication cohorts. The discovery cohort identified a larger cluster (n = 137) and a smaller cluster (n = 62), with 31% of the study participants. Similarly, the replication cohort identified a larger cluster (n = 74) and a smaller cluster (n = 37) with 33% of the study participants. The smaller cluster in the discovery cohort had significantly higher levels of LH (7.26 vs. 16.1 IU/L, p < .001), FAI (5.21 vs. 9.22, p < .001), androstenedione (3.93 vs. 7.56 nmol/L, p < .001) and 17-OHP (1.59 vs. 3.12 nmol/L, p < .001). These findings were replicated in the replication cohort. The mean (±SD) siMS score was higher in the smaller cluster, 3.1 (±1.1) versus 2.8 (±0.8); however, this was not statistically significant (p = .20). In the regression analysis, higher FAI (ß = .05, p = .003) and androstenedione (ß = .03, p = .02) were independently associated with a higher risk of SiMS score, while higher DHEAS levels were associated with a lower siMS score (ß = -.07, p = .03) CONCLUSION: We identified a subset of women in our PCOS cohort with significantly higher LH, FAI, and androstenedione levels. We show that higher levels of androstenedione and FAI are associated with a higher siMS, while higher DHEAS levels were associated with lower siMS.

The long-term impact of glucose monitoring with the FreeStyle Libre on glycaemic control and hypoglycaemia awareness in people with type 1 diabetes: Insights from the Association of British Clinical Diabetologists national audit.

AIMS: To investigate the change in glycated haemoglobin (HbA1c), hypoglycaemia awareness and diabetes-related distress in people with type 1 diabetes (T1D) using FreeStyle Libre (FSL) over a 2-year follow-up period. METHODS: FSL user data from U.K wide hospitals collected during routine clinical care were analysed. People living with T1D were categorised into four groups based on the duration of follow-up. Group I (< 1 year, n = 6940), group II (1 to 1.5 years, n = 662), group III (1.5 to 2 years, n = 385), and group IV (> 2 years, n = 642). The t-test was used to compare the baseline and follow-up HbA1c, GOLD score (a measure of hypoglycaemia awareness) and diabetes-related distress scale (DDS score) (quality of life measure). RESULTS: The study consisted of 16,834 people, with follow-up data available for 8,629 participants. The change in HbA1c, GOLD and DDS score from baseline within the follow-up sub-groups (group I vs group II vs group III vs group IV) was HbA1c (-6 vs -6 vs -4 vs -4 mmol/mol; p < 0.001) (-0.55 vs -0.55 vs -0.37 vs -0.37 %), GOLD score (-0.31 vs -0.45 vs -0.26 vs -0.42; p < 0.0001 group I, II, IV and p 0.07 group III), and DDS score(-0.59 vs -0.58 vs -0.63 vs -0.50; p < 0.001), respectively. CONCLUSIONS: In people with T1D, FSL use resulted in a sustained improvement in HbA1c, hypoglycaemia awareness and diabetes-related distress for over two years.

Impact of pharmacological interventions on biochemical hyperandrogenemia in women with polycystic ovary syndrome: a systematic review and meta-analysis of randomised controlled trials.

CONTEXT: Polycystic ovary syndrome (PCOS) is a complex endocrine disease that affects women of reproductive age and is characterised by biochemical and clinical androgen excess. AIM: To evaluate the efficacy of pharmacological interventions used to decrease androgen hormones in women with PCOS. DATA SOURCE: We searched PubMed, MEDLINE, Scopus, Embase, Cochrane library and the Web of Science from inception up to March 2021. DATA SYNTHESIS: Two reviewers selected eligible studies and extracted data, and the review is reported according to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: Of the 814 randomised clinical trials (RCTs) located in the search, 92 met the eligibility criteria. There were significant reductions in total testosterone level with metformin versus (vs) placebo (SMD: - 0.33; 95% CI  - 0.49 to  - 0.17, p < 0.0001, moderate grade evidence) and dexamethasone vs placebo (MD:-0.86 nmol/L; 95% CI  - 1.34 to  - 0.39, p = 0.0004, very low-grade evidence). Significant reductions in the free testosterone with sitagliptin vs placebo (SMD:  - 0.47; 95% CI  - 0.97 to 0.04, p = 0.07, very low-grade evidence), in dehydroepiandrosterone sulphate (DHEAS) with flutamide vs finasteride (MD:  - 0.37 µg/dL; 95% CI  - 0.05 to  - 0.58, p = 0.02, very low-grade evidence), a significant reduction in androstenedione (A4) with rosiglitazone vs placebo (SMD:  - 1.67; 95% CI  - 2.27 to  - 1.06; 59 participants, p < 0.00001, very low-grade evidence), and a significant increase in sex hormone-binding globulin (SHBG) with oral contraceptive pill (OCP) (35 µg Ethinyl Estradiol (EE)/2 mg cyproterone acetate (CPA)) vs placebo (MD: 103.30 nmol/L; 95% CI 55.54-151.05, p < 0.0001, very low-grade evidence) were observed. CONCLUSION: Metformin, OCP, dexamethasone, flutamide, and rosiglitazone use were associated with a significant reduction in biochemical hyperandrogenemia in women with PCOS, though their individual use may be limited due to their side effects. PROSPERO REGISTRATION NO: CRD42020178783.

Impact of pharmacological interventions on insulin resistance in women with polycystic ovary syndrome: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a complex endocrine condition affecting women of reproductive age. It is characterized by insulin resistance and is a major risk factor for type 2 diabetes mellitus (T2DM). The objective was to review the literature on the effect of different pharmacological interventions on insulin resistance in women with PCOS. DESIGN: We searched PubMed, MEDLINE, Scopus, Embase, Cochrane library and the Web of Science in April 2020 and updated in March 2021. The study follows the 2020 Preferred Reporting Items for Systematic reviews and Meta-ana. Reviwers extracted data and assessed the risk of bias using the Cochrane risk of bias tool. RESULTS: In 58 randomized controlled trials there were significant reductions in the fasting blood glucose (FBG) with metformin versus placebo (standardized mean difference [SMD]: -0.23; 95% confidence interval [CI]: -0.40, -0.06; I² = 0%, low-grade evidence), and acarbose versus metformin (mean difference [MD]: -10.50 mg/dl; 95% CI: -15.76, -5.24; I² = 0%, low-grade evidence). Significant reductions in fasting insulin (FI) with pioglitazone versus placebo (SMD: -0.55; 95% CI: -1.03, -0.07; I² = 37%; p = .02, very-low-grade evidence). A significant reduction in homoeostatic model assessment of insulin resistance (HOMA-IR) was seen with exenatide versus metformin (MD: -0.34; 95% CI: -0.65, -0.03; I² = 0%, low-grade evidence). No effect on homoeostatic model assessment of beta cells (HOMA-B) was observed. CONCLUSIONS: Pharmacological interventions, including metformin, acarbose, pioglitazone and exenatide have significant effects on FBG, FI, HOMA-IR but not on HOMA-B.

Effect of pharmacological interventions on lipid profiles and C-reactive protein in polycystic ovary syndrome: A systematic review and meta-analysis.

CONTEXT: Polycystic ovary syndrome (PCOS) is a heterogeneous condition affecting women of reproductive age. It is associated with dyslipidaemia and elevated plasma C-reactive protein (CRP), which increase the risks of cardiovascular disease (CVD). OBJECTIVE: To review the existing evidence on the effects of different pharmacological interventions on lipid profiles and CRP of women with PCOS. DATA SOURCES: We searched PubMed, MEDLINE, Scopus, Embase, Cochrane Library, and Web of Science in April 2020 and updated the results in March 2021. STUDY SELECTION: The study included randomized controlled trials (RCTs) and follows the 2020 Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). DATA EXTRACTION: Two independent researchers extracted data and assessed for risk of bias using the Cochrane risk of bias tool. Covidence systematic review software were used for blinded screening and study selection. DATA SYNTHESIS: In 29 RCTs, there were significant reductions in triglycerides with atorvastatin versus placebo [mean difference (MD): -0.21 mmol/L; 95% confidence interval (CI): -0.39, -0.03, I2 = 0%, moderate grade evidence]. Significant reductions were seen for low-density lipoprotein cholesterol (LDL-C) with metformin versus placebo [standardized mean difference (SMD): -0.41; 95% CI: -0.85, 0.02, I2 = 59%, low grade evidence]. Significant reductions were also seen for total cholesterol with saxagliptin versus metformin (MD: -0.15 mmol/L; 95% CI: -0.23, -0.08, I2 = 0%, very low grade evidence). Significant reductions in C-reactive protein (CRP) were seen for atorvastatin versus placebo (MD: -1.51 mmol/L; 95% CI: -3.26 to 0.24, I2 = 75%, very low-grade evidence). CONCLUSION: There were significant reductions in the lipid parameters when metformin, atorvastatin, saxagliptin, rosiglitazone and pioglitazone were compared with placebo or other agents. There was also a significant reduction of CRP with atorvastatin.

Impact of pharmacological interventions on anthropometric indices in women with polycystic ovary syndrome: A systematic review and meta-analysis of randomized controlled trials.

CONTEXT: Polycystic ovary syndrome (PCOS) is a heterogeneous condition affecting women of reproductive age and is associated with increased body weight. OBJECTIVE: To review the literature on the effect of different pharmacological interventions on the anthropometric indices in women with PCOS. DATA SOURCES: We searched PubMed, MEDLINE, Scopus, Embase, Cochrane library, and the Web of Science in April 2020 with an update in PubMed in March 2021. STUDY SELECTION: The study followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)2020. DATA EXTRACTION: Reviewers extracted data and assessed the risk of bias using the Cochrane risk of bias tool. RESULTS: 80 RCTs were included in the meta-analysis. Metformin vs placebo showed significant reduction in the mean body weight (MD: -3.13 kg; 95% confidence interval [CI]: -5.33 to -0.93, I² = 5%) and the mean body mass index (BMI) (MD: -0.75 kg/m2 ; 95% CI: -1.15 to -0.36, I² = 0%). There was a significant reduction in the mean BMI with orlistat versus placebo (MD: -1.33 kg/m²; 95% CI: -2.16 to -0.66, I² = 0.0%), acarbose versus metformin (MD: -1.26 kg/m²; 95% CI: -2.13 to -0.38, I² = 0%), and metformin versus pioglitazone (MD: -0.91 kg/m²; 95% CI: -1.62 to -0.19, I² = 0%). A significant increase in the mean BMI was also observed in pioglitazone versus placebo (MD: + 2.59 kg/m²; 95% CI: 1.78-3.38, I² = 0%) and in rosiglitazone versus metformin (MD: + 0.80 kg/m²; 95% CI: 0.32-1.27, I² = 3%). There was a significant reduction in the mean waist circumference (WC) with metformin versus placebo (MD: -1.21 cm; 95% CI: -3.71 to 1.29, I² = 0%) while a significant increase in the mean WC with pioglitazone versus placebo (MD: + 5.45 cm; 95% CI: 2.18-8.71, I² = 0%). CONCLUSION: Pharmacological interventions including metformin, sitagliptin, pioglitazone, rosiglitazone orlistat, and acarbose have significant effects on the anthropometric indices in women with PCOS.

Time in range following flash glucose monitoring: Relationship with glycaemic control, diabetes-related distress and resource utilisation in the Association of British Clinical Diabetologists national audit.

AIMS: The aim of this study was to understand the relationship between time in range (TIR) achieved using the isCGM with changes in glycaemic control, diabetes-related distress (DRD) and resource utilisation in people living with diabetes. METHODS: Clinicians from 106 National Health System (NHS) UK hospitals submitted isCGM user baseline and follow-up data in a web-based tool held within the UK NHS network. Linear regression analysis was used to identify the relationship between follow-up glucose TIR (3.9-10 mmol/L) categories (TIR% 50-70 and TIR% >70) with change in haemoglobin A1c (HbA1c), DRD and Gold score (measure of hypoglycaemia unawareness, where a score ≥4 suggests impaired awareness of hypoglycaemia). RESULTS: Of 16,427 participants, 1241 had TIR follow-up data available. In this cohort, the mean TIR was 44.8% (±22.5). With the use of isCGM, at 7.9 months mean follow-up, improvements were observed in HbA1c (-6.9 [13.5] mmol/mol, p < 0.001), Gold score (-0.35 [1.5], p < 0.001) and Diabetes Distress Screening (-0.73 [1.23], p < 0.001). In the regression analysis restricted to people living with type 1 diabetes, TIR% 50-70 was associated with a -8.9 mmol/mol (±0.6, p < 0.001) reduction in HbA1c; TIR% >70 with a -14 mmol/mol (±0.8, p < 0.001) reduction in HbA1c. Incremental improvement in TIR% was also associated with significant improvements in Gold score and DRD. TIR% >70 was associated with no hospital admissions due to hypoglycaemia, hyperglycaemia/diabetic ketoacidosis, and a 60% reduction in the paramedic callouts and 77% reduction in the incidence of severe hypoglycaemia. CONCLUSION: In a large cohort of UK isCGM users, we demonstrate a significant association of higher TIR% with improvement in HbA1c, hypoglycaemia awareness, DRD and resource utilisation.

Hyperthyroidism and bone mineral density: Dissecting the causal association with Mendelian randomization analysis.

INTRODUCTION: Untreated hyperthyroidism is associated with accelerated bone turnover, low bone mineral density (BMD) and increased susceptibility to fragility fractures. Although treatment appears to improve or even reverse some of these adverse skeletal effects, there is limited guidance on routine BMD assessment in hyperthyroid patients following treatment. By using Mendelian randomization (MR) analysis, we aimed to assess the causal association of hyperthyroid thyroid states with BMD and fractures using the UK Biobank. METHODS: This MR analysis included data from 473 818 participants (women: 54% of the total sample, the median age of 58.0 years (IQR = 50-63 years), median body mass index (BMI) of 26.70 (IQR + 24.11-29.82 kg/m2 ) as part of the UK Biobank study. The study outcomes were heel BMD assessed by quantitative ultrasound of the heel and self-reported fractures. Beta-weighted genetic risk score analysis was performed using 19 single nucleotide polymorphisms (SNPs) for Graves' disease, 9 SNPs for hyperthyroidism and 11 SNPs for autoimmune thyroiditis. Since the unadjusted risk score MR is equivalent to the inverse-variance weighted method, the genetic risk score analysis was adjusted for age, gender and BMI. Sensitivity analyses were conducted using the Mendelian randomization-Egger (MR-Egger) and the inverse-variance weighted estimate methods. Replication analysis was performed using the GEnetic Factors for Osteoporosis (GEFOS) consortium data. RESULTS: MR analysis using beta-weighted genetic risk score showed no association of genetic risk for Graves' disease (Beta = -0.01, P-value = .10), autoimmune thyroiditis (Beta = -0.006 P-value = .25) and hyperthyroidism (Beta = -0.009, P-value = .18) with heel ultrasound BMD. MR-Egger and inverse-variance MR methods in UK Biobank and GEFOS consortium confirmed these findings. The genetic risk for these hyperthyroid conditions was not associated with an increased risk of fractures. CONCLUSION: Our study shows that excess genetic risk for Graves' autoimmune thyroiditis and hyperthyroidism does not increase the risk for low BMD and is not associated fractures in the Caucasian population. Our findings do not support routine screening for osteoporosis following definitive treatment of hyperthyroid states.

Predictors of diabetes-related distress before and after FreeStyle Libre-1 use: Lessons from the Association of British Clinical Diabetologists nationwide study.

AIM: To identify the baseline demographic and clinical characteristics associated with diabetes-related distress (DRD) and factors associated with improvement in DRD after initiating use of the FreeStyle Libre (FSL) in people living with type 1 diabetes (T1D). METHODS: The study was performed using baseline and follow-up data from the Association of British Clinical Diabetologists nationwide audit of people with diabetes who initiated use of the FSL in the United Kingdom. DRD was assessed using the two-item diabetes-related distress scale (DDS; defined as the average of the two-item score ≥3). People living with T1D were categorized into two groups: those with high DRD, defined as an average DDS score ≥3 and those with lower DRD, defined as a DDS score <3. We used a gradient-boosting machine-learning (GBM) model to identify the relative influence (RI) of baseline variables on average DDS score. RESULTS: The study population consisted of 9159 patients, 96.6% of whom had T1D. The median (interquartile range [IQR]) age was 45.1 (32-56) years, 50.1% were women, the median (IQR) baseline body mass index was 26.1 (23.2-29.6) kg/m2 and the median (IQR) duration of diabetes was 20 (11-32) years. The two components of the DDS were significantly correlated (r2  = 0.73; P < 0.0001). Higher DRD was prevalent in 53% (4879/9159) of people living with T1D at baseline. In the GBM model, the top baseline variables associated with average DDS score were baseline glycated haemoglobin (HbA1c; RI = 51.1), baseline Gold score (RI = 23.3), gender (RI = 7.05) and fear of hypoglycaemia (RI = 4.96). Follow-up data were available for 3312 participants. The top factors associated with improvement in DDS score following use of the FSL were change in Gold score (RI = 28.2) and change in baseline HbA1c (RI = 19.3). CONCLUSIONS: In this large UK cohort of people living with T1D, diabetes distress was prevalent and associated with higher HbA1c, impaired awareness of hypoglycaemia and female gender. Improvement in glycaemic control and hypoglycaemia unawareness with the use of the FSL was associated with improvement in DRD in people living with T1D.

Association of endocrine active environmental compounds with body mass index and weight loss following bariatric surgery.

INTRODUCTION: The objective of this study was to study associations of a wide range of halogenated biphenyls, dibenzo-p-dioxins, dibenzofurans and diphenylethers with body mass index (BMI) and evaluate changes in their concentration following bariatric surgery. METHODS: Subcutaneous fat, visceral fat and liver tissue samples were collected from 106 patients undergoing Roux-en-Y gastric bypass surgery for weight loss or patients who were undergoing abdominal surgery for nonbariatric reasons. We measured concentrations of an extensive panel of chlorinated and brominated biphenyls, dioxins, and furans, and brominated diphenylethers in the samples. We conducted linear regression to examine associations with BMI, adjusting for age and gender. Changes in concentration for indicator chemicals were evaluated in samples collected following bariatric surgery in a small subpopulation. RESULTS: After adjustments for age and gender and correction for multiple testing, seven ortho-chlorinated biphenyls, one nonortho-chlorinated biphenyl, four PCDD/Fs and one ortho-brominated biphenyl were associated with BMI. The strongest associations between BMI and lipid-adjusted concentrations were seen with PCB-105 in subcutaneous fat (beta = 16.838 P-val = 1.45E-06) PCB-126 in visceral fat (beta = 15.067 P-val = 7.72E-06) and PCB-118 (beta = 14.101 P-val = 2.66E-05) in liver. The concentrations of sum PCBs, chlorinated toxic equivalent quantity (TEQ's) and brominated compounds increased significantly with weight loss in subcutaneous fat in a group of ten individuals resampled up to five years after bariatric surgery and substantial weight loss. CONCLUSION: We show that selected polychlorinated biphenyls PCBs and structurally related polychlorinated dibenzo-p-dioxins dibenzofurans (PCDD/Fs) were associated with BMI. Concentrations of these lipophilic compounds in subcutaneous fat increased following bariatric surgery.

Development of a novel risk prediction and risk stratification score for polycystic ovary syndrome.

OBJECTIVE: The aim of this study was to develop a simple phenotypic algorithm that can capture the underlying clinical and hormonal abnormalities to help in the diagnosis and risk stratification of polycystic ovary syndrome (PCOS). METHODS: The study consisted of 111 women with PCOS fulfilling the Rotterdam diagnostic criteria and 67 women without PCOS. A Firth's penalized logistic regression model was used for independent variable section. Model optimism, discrimination and calibration were assessed using bootstrapping, area under the curve (AUC) and Hosmer-Lemeshow statistics, respectively. The prognostic index (PI) and risk score for developing PCOS were calculated using independent variables from the regression model. RESULTS: Firth penalized logistic regression model with backward selection identified four independent predictors of PCOS namely free androgen index [ß 0.30 (0.12), P = 0.008], 17-OHP [ß = 0.20 (0.01), P = 0.026], anti-mullerian hormone [AMH; ß = 0.04 (0.01) P < 0.0001] and waist circumference [ß = 0.08 (0.02), P < 0.0001]. The model estimates indicated high internal validity (minimal optimism on 1000-fold bootstrapping), good discrimination ability (bias corrected c-statistic = 0.90) and good calibration (Hosmer-Lemeshow χ2  = 3.7865). PCOS women with a high-risk score (q1 + q2 + q3 vs q4) presented with a worse metabolic profile characterized by a higher 2-hour glucose (P = 0.01), insulin (P = 0.0003), triglycerides (P = 0.0005), C-reactive protein (P < 0.0001) and low HDL-cholesterol (P = 0.02) as compared to those with lower risk score for PCOS. CONCLUSIONS: We propose a simple four-variable model, which captures the underlying clinical and hormonal abnormalities in PCOS and can be used for diagnosis and metabolic risk stratification in women with PCOS.

Effects of empagliflozin on metabolic parameters in polycystic ovary syndrome: A randomized controlled study.

BACKGROUND: Empagliflozin is a sodium-glucose-cotransporter-2 inhibitor that improves cardiovascular risk and promotes weight loss in patients with type-2 diabetes. Polycystic ovary syndrome (PCOS) is associated with obesity and increased cardiovascular risk; therefore, empagliflozin may be of benefit for these women. The aim of this study was to compare the effects of empagliflozin vs metformin on anthropometric and body composition, hormonal and metabolic parameters in women with PCOS. MATERIALS AND METHODS: A randomized open-label study was conducted in women with PCOS who were randomized to either empagliflozin 25 mg (n = 19) or metformin 1500 mg (n = 20) daily for 12 weeks. The main outcomes assessed were changes in anthropometric and body composition, hormonal and metabolic parameters. RESULTS: Univariate analysis showed significant differences in weight (empagliflozin: -1.4 ± 3.2% vs metformin: 1.2 ± 2.3%; P = 0.006), body mass index (empagliflozin: -1.4 ± 3.2% vs metformin: 1.1 ± 2.2%; P = 0.006), waist circumference (empagliflozin: -1.6 ± 2.8% vs metformin: 0.2 ± 2.1%; P = 0.029) and hip circumference (empagliflozin: -2.0 ± 3.0% vs metformin: 1.1 ± 1.9%; P = 0.001), basal metabolic rate (empagliflozin: -1.8 ± 2.9% vs metformin: 0.1 ± 1.9%, P = 0.024) and fat mass (empagliflozin: -0.7 ± 4.9% vs metformin, 3.2 ± 5.0%; P = 0.023) between the empagliflozin and the metformin groups. These differences were confirmed in linear regression analysis after adjustment for relevant covariates. There were no significant changes in hormonal or metabolic parameters between both groups. CONCLUSION: There was a significant improvement in anthropometric parameters and body composition, in overweight and obese women with PCOS after 12 weeks of treatment with empagliflozin compared to metformin, although no changes were seen in hormonal or metabolic parameters.

Effects of acute insulin-induced hypoglycaemia on endothelial microparticles in adults with and without type 2 diabetes.

AIMS: To assess whether endothelial microparticles (EMPs), novel surrogate markers of endothelial injury and dysfunction, are differentially produced in response to acute insulin-induced hypoglycaemia in adults with and without type 2 diabetes. MATERIALS AND METHODS: A prospective, parallel study was conducted in individuals with type 2 diabetes (n = 23) and controls (n = 22). Hypoglycaemia (<2.2 mmoL/L: <40 mg/dL) was achieved by intravenous infusion of soluble insulin. Blood samples were collected at baseline and at 0, 30, 60, 120, 240 minutes and 24 hours after hypoglycaemia and analysed for CD31+ (platelet endothelial cell adhesion molecule-1), CD54+ (intercellular adhesion molecule 1), CD62-E+ (E-selectin), CD105+ (endoglin), CD106+ (vascular cell adhesion molecule 1) and CD142+ (tissue factor) EMPs by flow cytometry. The peak elevations (% rise from 0 minutes after hypoglycaemia) in EMP within 240 minutes after insulin-induced hypoglycaemia were modelled using a regression model, with adjustment for relevant covariates. All EMPs were expressed as percentage from 0 minutes hypoglycaemia for each time point and total areas under the curve (AUC0min-24h ) were calculated. RESULTS: Following insulin-induced hypoglycaemia, levels of circulating EMPs were maximal at 240 minutes (P < 0.001) and returned to baseline values within 24 hours for both groups. The peak elevations (% rise from 0 minutes following hypoglycaemia) seen in CD31+ , CD54+ , CD62-E+ , CD105+ and CD142+ EMPs within 240 minutes were associated with diabetes status after adjustments for all relevant covariates. Individuals with type 2 diabetes showed increased CD31+ EMPs AUC0min-24h (P = 0.014) and CD105+ EMPs AUC0min-24h (P = 0.006) compared with controls, but there were no differences for CD54+ (P = 0.91), CD62-E+ (P = 0.14), CD106+ (P = 0.36) or CD142+ (P = 0.77) EMPs AUC0min-24h . CONCLUSIONS: The associations between peak elevations within 240 minutes after insulin-induced hypoglycaemia for CD31+ , CD54+ , CD62-E+ , CD105+ and CD142+ and diabetes status indicate that the assessment of a panel of EMPs within this timeframe would identify a hypoglycaemic event in this population. The greater overall responses over time (AUCs) for apoptosis-induced CD31+ and CD105+ EMPs suggest that hypoglycaemia exerts greater endothelial stress in type 2 diabetes.

The Genetic Landscape of Renal Complications in Type 1 Diabetes.

Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (P=6.4×10-3). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole-exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (P=2.2×10-5) and the risk of type 2 diabetes (P=6.1×10-4) associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1×10-4). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0×10-6), and pentose and glucuronate interconversions (P=3.0×10-6) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.

Meta-analysis of genome-wide association studies of HDL cholesterol response to statins.

BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation. METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10-4 from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5×10-8) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment. CONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.