Circulating PCSK9 levels in acute coronary syndrome: Results from the PC-SCA-9 prospective study

BackgroundSerum proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations have been shown to be positively associated with LDL cholesterol (LDL-C), but the relationship between PCSK9 and coronary atherosclerosis lesions remains unclear.ObjectiveThis study aims to investigate the correlation between serum PCSK9 levels and coronary damage severity in patients hospitalized for acute coronary syndrome (ACS).MethodsIn this prospective proof-of-concept study, coronary lesions were assessed using SYNTAX scores. Serum PCSK9 concentrations were measured on admission (Day 0) for ACS by Elisa, and on every day of hospitalization. Spearman's correlations were used to determine the association between PCSK9 levels, SYNTAX score and metabolic parameters.ResultsA total of 174 patients (mean age: 59 ± 14 years, 79% male) with ACS (on Day 0, 119 patients were not taking statins, but 55 were) were included. After initiation of high-intensity statin therapy, serum PCSK9 concentrations increased significantly, reaching maximum levels on Day 2 (+31% vs. Day 0), and remained stable up to Day 4 (P < 0.001, by mixed model). Serum PCSK9 on Day 0 was associated with LDL-C (rho = 0.226, P = 0.017) and apolipoprotein B (rho = 0.282, P = 0.005) in the statin-naïve group only, and with triglycerides and non-HDL-C in all groups. More important, PCSK9 levels on Day 0 were positively associated with SYNTAX scores in the statin-naïve group (rho = 0.239, P = 0.009), but not in the statin-treated group (P = NS). This association was maintained after adjusting for LDL-C (P = 0.014) and major CV risk factors (P = 0.008).ConclusionSerum PCSK9 levels are positively associated with severity of coronary artery lesions independently of LDL-C concentrations in patients hospitalized for ACS. This reinforces the potential importance of PCSK9 inhibition in the management of ACS.     

Effects of adipose tissue distribution on maximum lipid oxidation rate during exercise in normal-weight women

AimFat mass localization affects lipid metabolism differently at rest and during exercise in overweight and normal-weight subjects. The aim of this study was to investigate the impact of a low vs high ratio of abdominal to lower-body fat mass (index of adipose tissue distribution) on the exercise intensity (Lipox_max) that elicits the maximum lipid oxidation rate in normal-weight women.MethodsTwenty-one normal-weight women (22.0 ± 0.6 years, 22.3 ± 0.1 kg.m⁻²) were separated into two groups of either a low or high abdominal to lower-body fat mass ratio [L-A/LB (n = 11) or H-A/LB (n = 10), respectively]. Lipox_max and maximum lipid oxidation rate (MLOR) were determined during a submaximum incremental exercise test. Abdominal and lower-body fat mass were determined from DXA scans.ResultsThe two groups did not differ in aerobic fitness, total fat mass, or total and localized fat-free mass. Lipox_max and MLOR were significantly lower in H-A/LB vs L-A/LB women (43 ± 3% VO_2max vs 54 ± 4% VO_2max, and 4.8 ± 0.6 mg min⁻¹ kg FFM⁻¹ vs 8.4 ± 0.9 mg min⁻¹ kg FFM⁻¹, respectively; P < 0.001). Total and abdominal fat mass measurements were negatively associated with Lipox_max (r = –0.57 and r = –0.64, respectively; P < 0.01) and MLOR [r = –0.63 (P < 0.01) and r = –0.76 (P < 0.001), respectively].ConclusionThese findings indicate that, in normal-weight women, a predominantly abdominal fat mass distribution compared with a predominantly peripheral fat mass distribution is associated with a lower capacity to maximize lipid oxidation during exercise, as evidenced by their lower Lipoxmax and MLOR.     

Usefulness of the plasma glucose concentration-to-HbA1c ratio in predicting clinical outcomes during acute illness with extreme hyperglycaemia

AimsTo evaluate the correlation between the plasma glucose-to-glycated haemoglobin ratio (GAR) and clinical outcome during acute illness.MethodsThis retrospective observational cohort study enrolled 661 patients who visited the emergency department of our hospital between 1 July 2008 and 30 September 2010 with plasma glucose concentrations > 500 mg/dL. Systolic blood pressure, heart rate, white blood cells, neutrophils, haematocrit, blood urea nitrogen, serum creatinine, liver function and plasma glucose concentration were recorded at the initial presentation to the emergency department. Data on glycated haemoglobin over the preceding 6 months were reviewed from our hospital database. The glucose-to-HbA_1c ratio (GAR) was calculated as the plasma glucose concentration divided by glycated haemoglobin.ResultsThe GAR of those who died was significantly higher than that of the survivors (81.0 ± 25.9 vs 67.6 ± 25.0; P < 0.001). There was a trend towards a higher 90-day mortality rate in patients with higher GARs (log-rank test P < 0.0001 for trend). On multivariate Cox regression analysis, the GAR was significantly related to 90-day mortality (hazard ratio [HR] for 1 standard deviation [SD] change: 1.41, 95% confidence interval [CI]: 1.22–1.63; P < 0.001), but not to plasma glucose (HR: 0.89, 95% CI: 0.70–1.13; P = 0.328). Rates of intensive care unit (ICU) admission and mechanical ventilator use were also higher in those with higher GARs.ConclusionGAR independently predicted 90-day mortality, ICU admission and use of mechanical ventilation. It was also a better predictor of patient outcomes than plasma glucose alone in patients with extremely high glucose levels.     

Epicardial adipose tissue volume as a marker of coronary artery disease severity in patients with diabetes independent of coronary artery calcium: Findings from the CTRAD study

AimsThe association between epicardial adipose tissue (EAT) volume and coronary artery disease (CAD) severity was evaluated, independent of traditional risk factors and coronary artery calcium (CAC) scores, in patients with diabetes type 2 (DM-2) using cardiac computed tomography angiography (CTA).MethodsA multivariate analysis was utilized to assess for an independent association after calculating EAT volume, CAD severity, and calcium scores in 92 patients with DM-II from the CTRAD study. We graded CAD severity as none (normal coronaries), mild-moderate (<70% stenosis), and severe (70% or greater stenosis).ResultsA total of 39 (42.3%) asymptomatic patients with diabetes did not have CAD; 30.4% had mild/moderate CAD; and 27.1% had severe CAD. Mean EAT volume was highest in patients with severe CAD (143.14 cm³) as compared to mild/moderate CAD (112.7 cm³), and no CAD (107.5 cm³) (p = 0.003). After adjustment of clinical risk factors, notably, CAC score, multivariate regression analysis showed EAT volume was an independent predictor of CAD severity in this sample (odds ratio 11.2, 95% confidence interval 1.7–73.8, p = 0.01).ConclusionsIncreasing EAT volume in asymptomatic patients with DM-II is associated with presence of severe CAD, independent of BMI and CAC, as well as traditional risk factors.     

Microalbuminuria,but not reduced eGFR,is associated with cardiovascular subclinical organ damage in type 2 diabetes

AimThis study explored the association between reduced estimated glomerular filtration rate (eGFR) and microalbuminuria vs. subclinical organ damage in patients with type 2 diabetes.MethodsData from middle-aged patients with type 2 diabetes (n = 706) treated in primary care were analyzed for microalbuminura, defined as a urinary albumin/creatinine ratio (uACR) ≥ 3.0 mmol/mol, and reduced eGFR, defined as < 60 mL/min/1.73 m², in relation to blood pressure, pulse wave velocity (PWV), left ventricular mass index (LVMI), and carotid intima–media thickness (IMT) and lumen diameter (LD).ResultsPatients with microalbuminuria had significantly higher 24-h ambulatory systolic blood pressure (ASBP) compared with subjects with uACR < 3 mg/mmol: 137 vs. 128 mmHg (P < 0.001). There were no differences in ASBP in patients with eGFR < 60 mL/min/1.73 m². However, patients with vs. without microalbuminuria had increased PWV (11.4 vs. 10.1 m/s; P < 0.001), LVMI (134.4 vs. 118.6 g/m²; P < 0.001), LD (7.01 ± 0.93 vs. 6.46 ± 0.74 mm; P < 0.001) and IMT (0.78 vs. 0.74 mm; P = 0.047), respectively. The associations between uACR vs. PWV and LVMI were more robust after adjusting for age, diabetes duration, ASBP, HbA_1c, LDL-cholesterol, and antihypertensive and lipid-lowering therapy compared with uACR vs. IMT. There were no statistically significant differences in PWV, LVMI or IMT between patients with reduced (< 60 mL/min/1.73 m²) vs. normal eGFR.ConclusionLevels of urinary albumin excretion, but not reduced eGFR, were associated with increased arterial stiffness, left ventricular mass and atherosclerosis in patients with type 2 diabetes.     

Efficacy and safety of alirocumab in insulin-treated patients with type 1 or type 2 diabetes and high cardiovascular risk: Rationale and design of the ODYSSEY DM–INSULIN trial

AimsThe coadministration of alirocumab, a PCSK9 inhibitor for treatment of hypercholesterolaemia, and insulin in diabetes mellitus (DM) requires further study. Described here is the rationale behind a phase-IIIb study designed to characterize the efficacy and safety of alirocumab in insulin-treated patients with type 1 (T1) or type 2 (T2) DM with hypercholesterolaemia and high cardiovascular (CV) risk.MethodsODYSSEY DM–INSULIN (NCT02585778) is a randomized, double-blind, placebo-controlled, multicentre study that planned to enrol around 400 T2 and up to 100 T1 insulin-treated DM patients. Participants had low-density lipoprotein cholesterol (LDL-C) levels at screening ≥ 70 mg/dL (1.81 mmol/L) with stable maximum tolerated statin therapy or were statin-intolerant, and taking (or not) other lipid-lowering therapy; they also had established CV disease or at least one additional CV risk factor. Eligible patients were randomized 2:1 to 24 weeks of alirocumab 75 mg every 2 weeks (Q2W) or a placebo. Alirocumab-treated patients with LDL-C ≥ 70 mg/dL at week 8 underwent a blinded dose increase to 150 mg Q2W at week 12. Primary endpoints were the difference between treatment arms in percentage change of calculated LDL-C from baseline to week 24, and alirocumab safety.ResultsThis is an ongoing clinical trial, with 76 T1 and 441 T2 DM patients enrolled; results are expected in mid-2017.ConclusionThe ODYSSEY DM–INSULIN study will provide information on the efficacy and safety of alirocumab in insulin-treated individuals with T1 or T2 DM who are at high CV risk and have hypercholesterolaemia not adequately controlled by the maximum tolerated statin therapy.     

Association between serum uric acid (SUA) levels and metabolic syndrome (MetS) components in personnel of Shahroud University of Medical Sciences

AimsSerum uric acid level has been suggested to be associated with metabolic syndrome risk factors. However, the association between metabolic syndrome and serum uric acid is still controversial and challenging. This study was aimed to investigate the association between serum uric acid levels and metabolic syndrome components in personnel of the Shahroud University of Medical Sciences.Material and methodsThis case–control study was conducted on 499 personnel aged 30–60 years old who were working in Shahroud University of Medical Sciences, in 2015. MetS was defined according to the National Cholesterol Education Program (NCEP) criteria. The relationship between serum UA level and the number of metabolic components was determined by linear regression analysis.ResultIn this study, the mean concentration of serum uric acid in men with the syndrome was higher than that in women. Mean serum UA level increased as the number of metabolic factors increased. The mean serum uric acid levels was 4.98 ± 1.64 in patients with metabolic syndrome and 4.5 ± 1.28 in non-patients (p = 0.005). Subject with abnormal uric acid were almost 2.62 times more likely than other subject to develop the syndrome.ConclusionsThe results of this study showed that only hypertriglyceridemia is a component which increases the risk of hyperuricemia. In addition, hyperuricemia increases the risk of metabolic syndrome by more than two fold. It seems that high uric acid can be considered as a predisposing factor for metabolic syndrome; thus, it is recommended to measure serum uric acid in routine tests.     

Evolution of subcutaneous adipose tissue fibrosis after bariatric surgery

AimObesity is associated with the development of metabolic complications such as insulin resistance (IR). The mechanisms leading to IR remain unclear. This study aimed to investigate the relationship between adipose tissue fibrosis and IR in obese patients before and after bariatric surgery.MethodsThirty-five obese patients awaiting bariatric surgery (12 with type 2 diabetes) were included in the study. Non-diabetic patients were classified as either insulin-sensitive (n = 11) or insulin-resistant (n = 12), based on the Matsuda insulin sensitivity index (ISI_Matsuda). Homoeostasis model assessment (HOMA-IR) was used for longitudinal evaluation of insulin resistance. Fibrosis was quantified by Masson's trichrome staining on microscopy, and mRNA levels of fibrosis-related genes were examined in subcutaneous (SAT) and visceral adipose tissue (VAT) biopsies collected during and 6 months after bariatric surgery (SAT only).ResultsDespite their similar age, body mass index and fat mass, SAT fibrosis was significantly higher in diabetic vs insulin-sensitive patients (P < 0.05), and associated with IR as assessed by both ISI_Matsuda (r = −0.417, P = 0.038) and HOMA-IR (r = 0.464, P = 0.007) at baseline, whereas VAT fibrosis was not. Six months after surgery and significant weight loss, fibrosis levels remained unchanged in SAT, although IR was significantly reduced in all groups (P < 0.0001). No correlation was found between SAT fibrosis and IR after surgery.ConclusionOverall, these results show a significant but, most likely, transient association between SAT fibrosis and IR in obese humans.     

Heart failure and chronic kidney disease in a registry of internal medicine wards

BackgroundThe aim of the present study was to evaluate the association between heart failure (HF) and chronic kidney disease (CKD) in tertiary care centers using the clinical records of patients enrolled in internal medicine departments.Patients and methodsWe used the clinical records of 1380 elderly patients to identify patients with a history of HF and CKD using admission ICD codes and glomerular filtration rate (GFR) formulas. Magnitude and strength of such associations were investigated by univariable and multivariable analysis.ResultsOf the 1380 patients enrolled, 27.9% had HF (age 80 ± 7, BMI 27 ± 6 kg/m²) and 17.4% CKD (age 81 ± 7, BMI 26.8 ± 6 kg/m²). Both groups were significantly older (P < 0.0001) with BMI higher than the patients without those diagnosis (P < 0.02). Patients with a history of CKD showed higher non-fasting glycaemia (140 ± 86 vs. 125 ± 63 mg/dL, P < 0.001). CKD was significantly associated with HF (P < 0.0001). Patients with HF had an estimated GFR lower than patients without HF (P < 0.0001). Comorbidity and severity indices were significantly higher in subjects with HF (P < 0.0001) and CKD (P < 0.0001) than in those without. Multivariable analysis showed a significant association between HF and age (for five years increase OR 1.13, P < 0.009), BMI (for each 3 kg/m² increase OR 1.15, P < 0.001), GFR (for each decrease of 10 mL/min increase OR 0.92, P < 0.002) and severity index (IS) (for each 0.25 units increase OR 1.43, P < 0.001).ConclusionHF on admission is strongly associated with CKD, older age, BMI, and SI. These data focus the value of epidemiological studies such REPOSI in identifying and monitoring multimorbidity in elderly.     

T-cadherin gene variants are associated with type 2 diabetes and the Fatty Liver Index in the French population

AimAdiponectin is an adipocyte-secreted protein associated with insulin sensitivity. T-cadherin is a receptor for high and medium molecular weight adiponectin. In GWAS, T-cadherin gene (CDH13) polymorphisms are associated with circulating adiponectin levels. This study investigated the associations between genetic variants of CDH13 and type 2 diabetes (T2D), and its related parameters, in a Caucasian population.MethodsTwo polymorphisms of CDH13 (rs11646213 and rs3865188) were genotyped in two French cohorts, a general population from the D.E.S.I.R. study (n = 5212) and people with T2D in the DIABHYCAR study (n = 3123). Baseline adiponectin levels were measured in D.E.S.I.R. participants who were normoglycaemic at baseline, but hyperglycaemic after 3 years (n = 230), and in controls who remained normoglycaemic (n = 226) throughout.ResultsIn a cross-sectional analysis, CDH13 genotype distributions differed between those with and without T2D, with T2D odds ratios (OR) of 1.11 (95% CI: 1.04–1.18; P = 0.001) and 0.92 (95% CI: 0.87–0.98; P = 0.01) for rs11646213 and rs3865188, respectively. The rs11646213 variant, associated with a higher OR for T2D, was also associated with higher BMI (P = 0.03) and HbA_1c (P = 0.006), and lower plasma adiponectin levels (P = 0.03) in the D.E.S.I.R. participants. Conversely, the rs3865188 variant, associated with a lower OR for T2D, was also associated with lower BMI (P = 0.03), HbA_1c (P = 0.02) and Fatty Liver Index (FLI; P ≤ 0.01), and higher plasma adiponectin levels (P = 0.002). Associations with HbA_1c, FLI and adiponectin levels persisted after adjusting for BMI.ConclusionCDH13 polymorphisms are associated with prevalent T2D in this French population study. The association may be mediated through effects on BMI and/or plasma adiponectin.     

Measures of trainee performance in advanced endoscopy: A systematic review

IntroductionThe diversity, technical skills required, and risk inherent to advanced endoscopy techniques all contribute to complex training curricula and steep learning curves. Since trainees develop endoscopy skills at different rates, there has been a shift towards competency-based training and certification. Validated endoscopy performance measures for trainees are, therefore, necessary. The aim of this systematic review was to describe and critically assess the existing evidence regarding measures of performance for trainees in advanced endoscopy.MethodsA systematic review of the literature from January 1980 to January 2016 was carried out using the MEDLINE, EMBASE, CENTRAL, and ISI Web of knowledge databases. MeSH terms related to 'advanced endoscopy' and 'performance' were applied to a highly sensitive search strategy. The main outcomes were face, content, and construct validity, as well as reliability.ResultsThe literature search yielded 1,662 studies and 77 met the inclusion criteria after abstract and full-text review (endoscopic retrograde cholangiopancreatography (ERCP) = 23, endoscopic ultrasound (EUS) = 30, colonoscopic polypectomy (CP) = 11, balloon-assisted enteroscopy (BAE) = 7, luminal stenting = 3, radiofrequency ablation (RFA) = 2, and endoscopic muscosal resection (EMR) = 1). Good validity and reliability were found for measurement tools of overall performance in ERCP, EUS and CP, with applications for both patient-based and simulator training models. A number of specific technical skills were also shown to be valid measures of performance. These include: selective biliary cannulation, sphincterotomy, biliary stent placement, stone extraction and procedure time for ERCP; pancreatic solid mass T-staging, EUS-guided fine needle aspiration (EUS-FNA) procedure time, number of EUS-FNA passes and puncture precision for EUS; procedure time and en bloc resection rate for CP; retrograde fluoroscopy time for BAE; and mean number of endoscopy sessions required to achieve complete eradication of intestinal metaplasia (CIEM) for RFA. The evidence for EMR and luminal stenting is of insufficient quality to make recommendations.ConclusionsWe have identified multiple valid and readily available performance measures for advanced endoscopy trainees for ERCP, EUS, CP, BAE and RFA procedures. These tools should be considered in advanced endoscopy training programs wishing to move away from apprenticeship-based training and towards competency-based learning with the help of patient-based and simulator tools.     

Late successful weight reduction and maintenance among overweight and obese adults—A two-year retrospective study

AimsOur purpose was to identify those factors associated with successful late weight reduction and maintenance among overweight and obese adults who failed to achieve initial weight reduction success.MethodsMedical computerized files of 5254 participants, who failed to achieve ≥5% weight reduction after an initial 6-month period, were retrospectively analyzed to identify predictors associated with late successful weight reduction and maintenance (≥5% during the first and second years, respectively). Over 40 independent variables were analyzed. The main outcome was the percentage of weight change.ResultsSignificant predictors of late success in weight reduction were as follows: more visits to a dietitian, higher baseline BMI, and any initial weight reduction (0–5%) (OR = 3.69, compared with participants who initially gained weight). The use of insulin (OR = 0.499) and the presence of hypertension (OR = 0.75) were significantly correlated with failure to reduce weight. Predictors of late maintenance were as follows: more visits to a dietitian, higher baseline BMI, any initial weight reduction, a younger age, not being treated with insulin (OR = 0.316), and more weighings (OR = 1.68).ConclusionsA substantial sub-group of obese and overweight patients was able to reduce their weight at a slower rate than the defined successful time of 6 months. Significant specific predictors were identified. Diabetic and hypertensive patients are at a significantly higher risk of failure to reduce and maintain weight. Using regression models, we calculated the probability of successful late weight reduction. This calculation could serve as a clinical tool for a professional team.     

Dipeptidyl peptidase-4 inhibitors and risk of arthralgia: A systematic review and meta-analysis

BackgroundThe US Food and Drug Administration has warned that treatment with dipeptidyl peptidase (DPP)-4 inhibitors may promote serious arthralgia. However, the clinical evidence for this is relatively lacking.ObjectiveFor this reason, a systematic review and meta-analysis of randomized controlled trials (RCTs) were carried out to determine the relationship between DPP-4 inhibitors and risk of arthralgia, and also to investigate any potential risk factors.MethodsAn extensive electronic search for RCTs comparing DPP-4 inhibitors with any comparators was performed up to July 2016. Outcomes of interest were overall and serious arthralgia. Summary risk ratios (RRs) with 95% confidence intervals (CIs) were calculated.ResultsA total of 67 RCTs (involving 79,110 patients) was ultimately included. Pooled results showed that DPP-4 inhibitors were associated with a slightly but significantly increased risk of overall arthralgia (RR: 1.13, 95% CI: 1.04–1.22; P = 0.003) and a non-significant increased risk of serious arthralgia (RR: 1.44, 95% CI: 0.83–2.51; P = 0.20). Also, subgroup analyses showed that add-on/combination therapy and longer diabetes duration (> 5 years) were possible factors associated with the increased risk of overall arthralgia.ConclusionThese findings suggest that DPP-4 inhibitors can increase the risk of arthralgia. Thus, the benefits of glycaemic control must be weighed against the risk of arthralgia when prescribing DPP-4 inhibitors. Further studies are now needed to identify and confirm these risk factors.     

Telemedicine and type 1 diabetes: Is technology per se sufficient to improve glycaemic control?

AimIn the TELEDIAB-1 study, the Diabeo system (a smartphone coupled to a website) improved HbA_1c by 0.9% vs controls in patients with chronic, poorly controlled type 1 diabetes. The system provided two main functions: automated advice on the insulin doses required; and remote monitoring by teleconsultation. The question is: how much did each function contribute to the improvement in HbA_1c?MethodsEach patient received a smartphone with an insulin dose advisor (IDA) and with (G3 group) or without (G2 group) the telemonitoring/teleconsultation function. Patients were classified as “high users” if the proportion of “informed” meals using the IDA exceeded 67% (median) and as “low users” if not. Also analyzed was the respective impact of the IDA function and teleconsultations on the final HbA_1c levels.ResultsAmong the high users, the proportion of informed meals remained stable from baseline to the end of the study 6 months later (from 78.1 ± 21.5% to 73.8 ± 25.1%; P = 0.107), but decreased in the low users (from 36.6 ± 29.4% to 26.7 ± 28.4%; P = 0.005). As expected, HbA_1c improved in high users from 8.7% [range: 8.3–9.2%] to 8.2% [range: 7.8–8.7%] in patients with (n = 26) vs without (n = 30) the benefit of telemonitoring/teleconsultation (−0.49 ± 0.60% vs −0.52 ± 0.73%, respectively; P = 0.879). However, although HbA_1c also improved in low users from 9.0% [8.5–10.1] to 8.5% [7.9–9.6], those receiving support via teleconsultation tended to show greater improvement than the others (−0.93 ± 0.97 vs −0.46 ± 1.05, respectively; P = 0.084).ConclusionThe Diabeo system improved glycaemic control in both high and low users who avidly used the IDA function, while the greatest improvement was seen in the low users who had the motivational support of teleconsultations.     

Sex hormone levels are not associated with progression of renal disease in male patients with T2DM

BackgroundGreater renal function decline (RFD) in type 2 diabetes (T2DM) has been suggested in men compared with women, and imbalances in estrogen/androgen levels have been associated with cardiovascular disease mortality in elderly men, but it remains unclear whether sex hormone disequilibrium is related to diabetic nephropathy (DN) in men with T2DM.ObjectiveThis study examined the relationship between sex steroid concentrations and renal outcomes in male T2DM patients.Population and methodsTotal testosterone (T), total estradiol (E2), sex hormone-binding globulin (SHBG), and total and calculated free (cf) E2/T ratios were compared in 735 male T2DM patients with (n = 513) and without (n = 222) DN, using a cross-sectional approach. Also, in a pilot complementary prospective nested case-control cohort, total E2/total T and cfE2/cfT were evaluated according to a hard renal outcome (HRO): end-stage renal disease/doubling of baseline serum creatinine (36 HRO cases, 72 HRO controls) and rate of eGFR decline (68 rapid vs 68 slow RFD).ResultWith the cross-sectional approach, E2 and cfE2 were higher in DN cases vs DN controls (95.5 vs 86.8 pmol/L [P = 0.0246] and 2.59 vs 2.36 pmol/L [P = 0.005], respectively). The difference in E2 persisted on multivariate analysis. In the prospective approach, E2 and T concentrations, and total E2/total T and cfE2/cfT2 ratios did not differ in HRO cases vs controls or in patients with rapid vs slow RFD.ConclusionAlthough positively related to DN in the cross-sectional analysis, progression of renal disease in male patients with T2DM was not related to either sex hormone levels or aromatase index as reflected by E2/T ratio.     

Associations between a fetal imprinted gene allele score and late pregnancy maternal glucose concentrations

AimWe hypothesised that some of the genetic risk for gestational diabetes (GDM) is due to the fetal genome affecting maternal glucose concentrations. Previously, we found associations between fetal IGF2 gene variants and maternal glucose concentrations in late pregnancy.MethodsIn the present study, we tested associations between SNP alleles from 15 fetal imprinted genes and maternal glucose concentrations in late pregnancy in the Cambridge Baby Growth and Wellbeing cohorts (1160 DNA trios).ResultsFour fetal SNP alleles with the strongest univariate associations: paternally-transmitted IGF2 rs10770125 (P-value = 2 × 10^–4) and INS rs2585 (P-value = 7 × 10^–4), and maternally-transmitted KCNQ1(OT1) rs231841 (P-value = 1 × 10^–3) and KCNQ1(OT1) rs7929804 (P-value = 4 × 10^–3), were used to construct a composite fetal imprinted gene allele score which was associated with maternal glucose concentrations (P-value = 4.3 × 10^–6, n = 981, r² = 2.0%) and GDM prevalence (odds ratio per allele 1.44 (1.15, 1.80), P-value = 1 × 10^–3, n = 89 cases and 899 controls). Meta-analysis of the associations including data from 1367 Hyperglycaemia and Adverse Pregnancy Outcome Study participants confirmed the paternally-transmitted fetal IGF2/INS SNP associations (rs10770125, P-value = 3.2 × 10^–8, rs2585, P-value = 3.6 × 10^–5) and the composite fetal imprinted gene allele score association (P-value = 1.3 × 10^–8), but not the maternally-transmitted fetal KCNQ1(OT1) associations (rs231841, P-value = 0.4; rs7929804, P-value = 0.2).ConclusionThis study suggests that polymorphic variation in fetal imprinted genes, particularly in the IGF2/INS region, contribute a small but significant part to the risk of raised late pregnancy maternal glucose concentrations.     

Adipose tissue is influenced by hypoxia of obstructive sleep apnea syndrome independent of obesity

AimsObstructive sleep apnea syndrome (OSAS) is associated with increased cardiovascular risk and diabetes independent of obesity. We investigated whether adipose tissue dysfunction is exacerbated due to increased tissue hypoxia.MethodsAdipose tissue (AT) oxygenation was measured with a Clarke-type electrode (p_ATO₂) in 16 men with OSAS before and after 4 months of continuous positive airway pressure therapy (CPAP) and in BMI-matched controls. Oxygenation was simultaneously monitored in arterial blood by pulse oximetry (SaO₂); mixed blood in AT microcirculation by reflectance spectroscopy (S_ATO₂) along with blood flow. Markers of hypoxia, adipo- and angiogenesis, inflammation and fibrosis were analysed in AT and serum.ResultsOSAS subjects were more insulin resistant. Despite lower arterial SaO₂ (95.4 ± 1.3% vs. 97.1 ± 1.6%, P = 0.013) in subjects with OSAS, there was no difference in the oxygen content of AT microcirculation (61.6 ± 18.4 vs. 72.2 ± 7.0%, P = 0.07) or p_ATO₂ (49.2 ± 7.5 vs. 50.4 ± 14.7 mmHg, P = 0.83) between groups. Resting AT blood flow was higher in OSAS compared to controls (108.5 ± 22.7 vs. 78.9 ± 24.9 au, P < 0.005) and strongly associated with inflammation markers IL-6 and MCP-1. AT of OSAS subjects showed increased inflammation (TNFA P = 0.049) and fibrosis (COL3A1 P = 0.02), a trend of higher HIF1A expression (P = 0.06) and reduced adipogenesis (PPARG P = 0.006). After CPAP, only expression of the lipid deposition marker LPL increased (30%, P = 0.047).ConclusionsAdipose tissue of awake OSAS subjects appears no more hypoxic than adipose tissue of BMI-matched controls despite daytime hypoxaemia. Increased adipose tissue blood flow may be explained by an increased inflammatory response. We observe features of adipose dysfunction in subjects with OSAS, which attribute to increased cardiometabolic risk associated with this condition.     

Glycaemic control and hypoglycaemia with insulin glargine 300 U/mL compared with glargine 100 U/mL in Japanese adults with type 2 diabetes using basal insulin plus oral anti-hyperglycaemic drugs (EDITION JP 2 randomised 12-month trial including 6-month extension)

AimsTo compare insulin glargine 300 U/mL (Gla-300) with glargine 100 U/mL (Gla-100) in Japanese adults with uncontrolled type 2 diabetes on basal insulin and oral anti-hyperglycaemic drugs over 12 months.MethodsEDITION JP 2 was a randomised, open-label, phase 3 study. Following a 6-month treatment period, participants continued receiving previously assigned once daily Gla-300 or Gla-100, plus oral anti-hyperglycaemic drugs, in a 6-month extension period. Glycaemic control, hypoglycaemia and adverse events were assessed.ResultsThe 12-month completion rate was 88% for Gla-300 and 96% for Gla-100, with comparable reasons for discontinuation. Mean HbA_1c decrease from baseline to month 12 was 0.3% in both groups. Annualised rates of confirmed (≤ 3.9 mmol/L [≤ 70 mg/dL]) or severe hypoglycaemia were lower with Gla-300 than Gla-100 (nocturnal [00:00–05:59 h]: rate ratio 0.41; 95% confidence interval: 0.18 to 0.92; anytime [24 h]: rate ratio 0.64; 95% confidence interval: 0.44 to 0.94). Cumulative number of hypoglycaemic events was lower with Gla-300 than Gla-100. Adverse event profiles were comparable between treatments.ConclusionOver 12 months, Gla-300-treated participants achieved sustained glycaemic control and experienced less hypoglycaemia, particularly at night, versus Gla-100, supporting 6-month results.     

Differences in vitamin D concentration between metabolically healthy and unhealthy obese adults: Associations with inflammatory and cardiometabolic markers in 4391 subjects

AimThis study aimed to compare concentrations of serum 25-hydroxy vitamin D and inflammatory markers in metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO), and to determine whether the relationship between vitamin D levels and both cardiometabolic and inflammatory markers differs between MHO and MUO.MethodsThis cross-sectional study comprised 4391 obese subjects aged > 18 years. A panel of cardiometabolic and inflammatory markers, including anthropometric variables, glycaemic indices, lipid profiles, liver enzymes, homocysteine, C-reactive protein (CRP), fibrinogen and serum 25-hydroxy vitamin D levels, was investigated. All cardiometabolic and inflammatory markers in MHO and MUO as well as in vitamin D deficiency were compared.ResultsPrevalence of MHO was 41.9% in our obese subjects using International Diabetes Federation criteria. Considering insulin resistance and inflammation, the prevalence of MHO was 38.4%. Individuals with MHO had significantly higher vitamin D concentrations compared with MUO, and this difference in vitamin D status persisted after accounting for BMI and waist circumference. Subjects with MHO had significantly better metabolic status, lower liver enzymes, lower inflammatory markers and higher serum 25-hydroxy vitamin D than those with MUO. Associations between vitamin D levels and inflammatory and cardiometabolic markers differed according to MHO/MUO status. Among MUO subjects, vitamin D deficiency was associated with higher liver marker and homocysteine levels. Serum vitamin D was negatively associated with fasting plasma glucose and HbA_1c in MHO only.ConclusionSerum 25-hydroxy vitamin D levels were lower in MUO vs MHO, and reduced vitamin D concentrations were more strongly associated with cardiometabolic and inflammatory markers in MUO than in MHO subjects. These findings suggest that a deficiency in vitamin D could be a key component of MUO.     

Serum sex steroids and steroidogenesis-related enzyme expression in skeletal muscle during experimental weight gain in men

ObjectivesLow-circulating testosterone is associated with development of type 2 diabetes in obese men. In this study, we examined the effects of experimental overfeeding and weight gain on serum levels of sex hormones and skeletal muscle expression of steroidogenic enzymes in healthy men with (FH+) and without (FH–) a family history of type 2 diabetes.MethodsFollowing a 3-day lead in energy balanced diet, FH+ (n = 9) and FH– men (n = 11) were overfed by 5200 kJ/day (45% fat) for 28 days. Body weight, fasting glucose, insulin, sex steroid, sex hormone binding globulin (SHBG) levels, insulin sensitivity (hyperinsulinaemic-euglycaemic clamp) and body fat (DXA) were assessed in all individuals at baseline and day 28, and sex steroidogenesis-related enzyme expression in vastus lateralis biopsies was examined in a subset (n = 11).ResultsBody weight, fat mass and fasting insulin levels were increased by overfeeding (P < 0.01) and insulin was increased significantly more in FH+ men (P < 0.01). Serum sex hormone binding globulin (SHBG) and 5α-dihydrotestosterone (DHT) were reduced with overfeeding (P < 0.05), and serum testosterone and DHT were reduced to a greater extent in FH+ men (P < 0.05). Overfeeding reduced mRNA expression of 3β-hydroxysteroid dehydrogenase (HSD) and 17βHSD (P ≤ 0.007), independently of group. 5α-Reductase (SRD5A1) mRNA expression was not changed overall, but a time by group interaction was observed (P = 0.04).ConclusionOverfeeding reduced SHBG and muscle expression of enzymes involved in the formation of testosterone in skeletal muscle. Men with a family history of T2DM were more susceptible to deleterious outcomes of overfeeding with greater reductions in serum testosterone and DHT and greater increases in markers of insulin resistance, which may contribute to increased risk of developing type 2 diabetes.