The Effect of PCSK1 Variants on Waist, Waist-Hip Ratio and Glucose Metabolism Is Modified by Sex and Glucose Tolerance Status

on measures of body fat and glucose homeostasis in Danish individuals and to assess interactions of genotypes with age, sex and glucose tolerance status. Data were included in meta-analyses of additional Europeans. = 0.02) elevated level of acute insulin response for this variant. Finally, we found that the rs6232 G-allele associated with higher levels of GLP-1, GLP-2 and glucagon and that the rs6235 C-allele associated with higher levels of GIP and glucagon during a meal-test. rs6232 G-allele and rs6235 C-allele have an effect on body composition which may be modified by sex, whereas the effect of rs6235 C-allele on fasting and stimulated circulating plasma glucose and hormone levels may be influenced by glucose tolerance status

Effectiveness of Liraglutide and Lixisenatide in the Treatment of Type 2 Diabetes: Real-World Evidence from The Health Improvement Network (THIN) Database in the United Kingdom.

INTRODUCTION: The glucagon-like peptide-1 receptor agonists liraglutide and lixisenatide are effective at reducing glycated hemoglobin (HbA1c) levels in patients with type 2 diabetes mellitus (T2DM). Although liraglutide has demonstrated superior efficacy in head-to-head clinical trials, real-world evidence of comparative effectiveness is lacking. This observational study aimed to assess the effectiveness of liraglutide versus lixisenatide in UK clinical practice. METHODS: Electronic medical records from The Health Improvement Network (THIN) UK primary care database were analyzed. Patients aged ≥18 years, diagnosed with T2DM, and prescribed liraglutide or lixisenatide between 01 May 2013 and 31 December 2015 were included in the study. Adjusted linear regression models compared the difference in mean change in HbA1c, body mass index (BMI), and systolic blood pressure (SBP) after 12-month follow-up. The proportion of patients achieving glycemic control (HbA1c 1%; and weight reduction ≥3% within 12 months were determined. Cox proportional hazards modeling was used to evaluate the effect of treatment on time to achieving HbA1c and weight reduction targets. Healthcare resource use (HCRU) (GP, secondary care, hospitalizations) was compared using analysis of covariance. RESULTS: The primary outcome was assessed in 579 liraglutide and 213 lixisenatide new users. Fully adjusted linear regression indicated that liraglutide reduced HbA1c significantly more than lixisenatide (mean treatment difference -0.30; 95% CI -0.56, -0.04; p = 0.025). Compared to lixisenatide, liraglutide recipients were 2.5 times more likely to achieve HbA1c 1% HbA1c reduction (HR 1.29; p = 0.0002). BMI and SBP reductions were greater for the liraglutide group but results were not significant. HCRU was comparable between treatment groups. CONCLUSION: These results from the THIN database indicate that liraglutide treatment provided better outcomes related to glycemic control. FUNDING: Novo Nordisk

Protocol for ADDITION-PRO: a longitudinal cohort study of the cardiovascular experience of individuals at high risk for diabetes recruited from Danish primary care.

BACKGROUND: Screening programmes for type 2 diabetes inevitably find more individuals at high risk for diabetes than people with undiagnosed prevalent disease. While well established guidelines for the treatment of diabetes exist, less is known about treatment or prevention strategies for individuals found at high risk following screening. In order to make better use of the opportunities for primary prevention of diabetes and its complications among this high risk group, it is important to quantify diabetes progression rates and to examine the development of early markers of cardiovascular disease and microvascular diabetic complications. We also require a better understanding of the mechanisms that underlie and drive early changes in cardiometabolic physiology. The ADDITION-PRO study was designed to address these issues among individuals at different levels of diabetes risk recruited from Danish primary care. METHODS/DESIGN: ADDITION-PRO is a population-based, longitudinal cohort study of individuals at high risk for diabetes. 16,136 eligible individuals were identified at high risk following participation in a stepwise screening programme in Danish general practice between 2001 and 2006. All individuals with impaired glucose regulation at screening, those who developed diabetes following screening, and a random sub-sample of those at lower levels of diabetes risk were invited to attend a follow-up health assessment in 2009-2011 (n=4,188), of whom 2,082 (50%) attended. The health assessment included detailed measurement of anthropometry, body composition, biochemistry, physical activity and cardiovascular risk factors including aortic stiffness and central blood pressure. All ADDITION-PRO participants are being followed for incident cardiovascular disease and death. DISCUSSION: The ADDITION-PRO study is designed to increase understanding of cardiovascular risk and its underlying mechanisms among individuals at high risk of diabetes. Key features of this study include (i) a carefully characterised cohort at different levels of diabetes risk; (ii) detailed measurement of cardiovascular and metabolic risk factors; (iii) objective measurement of physical activity behaviour; and (iv) long-term follow-up of hard clinical outcomes including mortality and cardiovascular disease. Results will inform policy recommendations concerning cardiovascular risk reduction and treatment among individuals at high risk for diabetes. The detailed phenotyping of this cohort will also allow a number of research questions concerning early changes in cardiometabolic physiology to be addressed.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

TH17 cells require ongoing classic IL-6 receptor signaling to retain transcriptional and functional identity

Acting in concert with TGF-b, IL-6 signaling induces Th17 cell development by programming Th17-related genes via STAT3. A role for IL-6 signaling beyond the inductive phase of Th17 cell development has not been defined, as IL-23 signaling downstream of Th17 cell induction also activates STAT3 and is thought responsible for Th17 cell maintenance. Here, we find that IL-6 signaling is required for both induction and maintenance of Th17 cells; IL-6Ra–deficient Th17 cells rapidly lost their Th17 phenotype and did not cause disease in two models of colitis. Cotransfer of WT Th17 cells with IL-6Ra–deficient Th17 cells induced colitis but was unable to rescue phenotype loss of the latter. High IL-6 in the colon promoted classic, or cis, rather than trans receptor signaling that was required for maintenance of Th17 cells. Thus, ongoing classic IL6 signaling underpins the Th17 program and is required for Th17 cell maintenance and function

Serum neurofilament light chain – A potential biomarker for polyneuropathy in type 2 diabetes?

AimsTo investigate the relationship between neurofilament light chain (NfL) and the presence and severity of diabetic polyneuropathy (DPN).MethodsWe performed cross-sectional analysis of data from 178 participants of the ADDITION-Denmark cohort of people with screen-detected type 2 diabetes and 32 healthy controls. Biobank serum samples were analyzed for NfL using single-molecule array. DPN was defined by Toronto criteria for confirmed DPN. Original and axonal nerve conduction study (NCS) sum z-scores were used as indicators of the severity of DPN and peripheral nerve damage.Results39 (21.9%) participants had DPN. Serum NfL (s-NfL) was significantly higher in participants with DPN (18.8 ng/L [IQR 14.4; 27.9]) than in participants without DPN (15.4 ng/L [IQR 11.7; 20.1]). There were no unadjusted s-NfL differences between controls (17.6 ng/L [IQR 12.7; 19.8]) and participants with or without DPN. Higher original and axonal NCS sum z-scores were associated with 10% higher s-NfL (10.2 and 12.1% [95% CI’s 4.0; 16.8 and 6.6; 17.9] per 1 SD). The AUC of s-NfL for DPN was 0.63 (95% CI 0.52; 0.73).ConclusionsS-NfL is unlikely to be a reliable biomarker for the presence of DPN. S-NfL is however associated to the severity of the nerve damage underlying DPN

Habitual physical activity is associated with lower fasting and greater glucose-induced GLP-1 response in men.

RATIONALE: The hormone glucagon-like peptide-1 (GLP-1) decreases blood glucose and appetite. Greater physical activity (PA) is associated with lower incidence of type 2 diabetes. While acute exercise may increase glucose-induced response of GLP-1, it is unknown how habitual PA affects GLP-1 secretion. We hypothesised that habitual PA associates with greater glucose-induced GLP-1 responses in overweight individuals. METHODS: Cross-sectional analysis of habitual PA levels and GLP-1 concentrations in 1326 individuals (mean (s.d.) age 66 (7) years, BMI 27.1 (4.5) kg/m2) from the ADDITION-PRO cohort. Fasting and oral glucose-stimulated GLP-1 responses were measured using validated radioimmunoassay. PA was measured using 7-day combined accelerometry and heart rate monitoring. From this, energy expenditure (PAEE; kJ/kg/day) and fractions of time spent in activity intensities (h/day) were calculated. Cardiorespiratory fitness (CRF; mL O2/kg/min) was calculated using step tests. Age-, BMI- and insulin sensitivity-adjusted associations between PA and GLP-1, stratified by sex, were evaluated by linear regression analysis. RESULTS: In 703 men, fasting GLP-1 concentrations were 20% lower (95% CI: -33; -3%, P = 0.02) for every hour of moderate-intensity PA performed. Higher CRF and PAEE were associated with 1-2% lower fasting GLP-1 (P = 0.01). For every hour of moderate-intensity PA, the glucose-stimulated GLP-1 response was 16% greater at peak 30 min (1; 33%, P rAUC0-30 = 0.04) and 20% greater at full response (3; 40%, P rAUC0-120 = 0.02). No associations were found in women who performed PA 22 min/day vs 32 min/day for men. CONCLUSION: Moderate-intensity PA is associated with lower fasting and greater glucose-induced GLP-1 responses in overweight men, possibly contributing to improved glucose and appetite regulation with increased habitual PA.S B was supported by the UK Medical Research Council (MC_UU_12015/3) and the NIHR Biomedical Research Centre Cambridge (IS-BRC-1215-20014)