Thioredoxin reductase 1 suppresses adipocyte differentiation and insulin responsiveness

Recently thioredoxin reductase 1 (TrxR1), encoded by Txnrd1, was suggested to modulate glucose and lipid metabolism in mice. Here we discovered that TrxR1 suppresses insulin responsiveness, anabolic metabolism and adipocyte differentiation. Immortalized mouse embryonic fibroblasts (MEFs) lacking Txnrd1 (Txnrd1−/−) displayed increased metabolic flux, glycogen storage, lipogenesis and adipogenesis. This phenotype coincided with upregulated PPARγ expression, promotion of mitotic clonal expansion and downregulation of p27 and p53. Enhanced Akt activation also contributed to augmented adipogenesis and insulin sensitivity. Knockdown of TXNRD1 transcripts accelerated adipocyte differentiation also in human primary preadipocytes. Furthermore, TXNRD1 transcript levels in subcutaneous adipose tissue from 56 women were inversely associated with insulin sensitivity in vivo and lipogenesis in their isolated adipocytes. These results suggest that TrxR1 suppresses anabolic metabolism and adipogenesis by inhibition of intracellular signaling pathways downstream of insulin stimulationThis study was supported by funding to ESJA from Karolinska Institutet, The Swedish Research Council, The Swedish Cancer Society, to MR from the Strategic Research Program in Diabetes and to ACG from Diabetesfonden and a “Ramón y Cajal” fellowship (RYC-2014-15792) from Spanish Ministerio de Economía y Competitivida

Is There a Relationship between Abdominal Aortic Aneurysms and Alpha1-antitrypsin Deficiency (PiZ)?

AbstractObjective:to determine if the frequency of α1AT deficiency (PiZ) is increased in patients with abdominal aortic aneurysm (AAA), and, to investigate whether aneurysmal stiffness and other clinical characteristics differ in AAA patients with and without α1AT deficiency.Methods:we identified α1AT-deficient individuals by a monoclonal-antibody ELISA technique, in 102 consecutive patients with AAA. Positive ELISA samples were further phenotyped by isoelectric focusing to differentiate between the heterozygosity (PiZ) and homozygosity (PiZZ) state. Aneurysmal diameter and stiffness was measured using echotracking sonography and blood pressure measurements.Results:the frequency of heterozygous α1AT deficiency (PiZ) in patients with AAA was similar to that in the general population (6.8% and 4.7%, respectively,p>0.3). The frequency of popliteal and femoral aneurysm was similar in male PiZ-carriers and non-carriers with AAA, as were age at diagnosis of AAA, aneurysmal diameter, aneurysmal stiffness, and presence of factors that may be associated with AAA (i.e. smoking, hypertension, diabetes mellitus, and family history of AAA). Occurrence of ischaemic heart disease was more frequent in male non-PiZ-carriers than in male PiZ-carriers with AAA (p=0.03).Conclusions:the frequency of α1AT deficiency (PiZ) was not increased in our series of patients with AAA and patients in whom the two disorders coexisted did not appear to have different clinical characteristics except for the lower occurrence of ischaemic heart disease among the PiZ-carriers

The association between glucose abnormalities and heart failure in the population-based Reykjavik study

To access publisher full text version of this article. Please click on the hyperlink in Additional Link fieldOBJECTIVE: Diabetes is an independent risk factor for heart failure, whereas the relation between heart failure and abnormal glucose regulation (AGR) needs further evaluation. We studied this combination in the Reykjavik Study. RESEARCH DESIGN AND METHODS: The Reykjavik Study, a population-based cohort study during 1967-1997, recruited 19,381 participants aged 33-84 years who were followed until 2002. Oral glucose tolerance tests and chest X-rays were obtained from all participants. Cases were defined in accordance with World Health Organization criteria for type 2 diabetes or AGR (impaired glucose tolerance or impaired fasting glucose) and European Society of Cardiology guidelines for heart failure. RESULTS: The overall prevalence of type 2 diabetes and heart failure was 0.5% in men and 0.4% in women, while AGR and heart failure were found in 0.7% of men and 0.6% of women. Among participants with normal glucose regulation, heart failure was diagnosed in 3.2% compared with 6.0 and 11.8% among those with AGR and type 2 diabetes, respectively. The prevalence of type 2 diabetes in the age-group 45-65 years increased in both sexes during the period (P for trend = 0.007). The odds ratio was 2.8 (95% CI 2.2-3.6) for the association between type 2 diabetes and heart failure and 1.7 (1.4-2.1) between AGR and heart failure. CONCLUSIONS: There is a strong association between any form of glucometabolic perturbation and heart failure. Future studies in this field should focus on all types of glucose abnormalities rather than previously diagnosed diabetes only

Enantioselective Narasaka-Heck Cyclizations:Synthesis of Tetrasubstituted Nitrogen-Bearing Stereocenters

A SPINOL-derived P,N-ligand system enables Pd-catalyzed 5-exo cyclization of oxime esters with trisubstituted alkenes to generate dihydropyrroles in up to 86% yield and 95 : 5 e.r.</p

Influence on Plasma β-N-Acetyl-D-glucosaminidase of Reticuloendothelial Stimulation and Depression: An Experimental Study in Rats

Peer Reviewe

Applying REWIND cardiovascular disease criteria to SUSTAIN 6 and PIONEER 6: An exploratory analysis of cardiovascular outcomes with semaglutide

In the REWIND trial, dulaglutide reduced cardiovascular (CV) risk versus placebo in patients with type 2 diabetes in both the “established CV disease” (CVD) and “CV risk factor” subgroups. The SUSTAIN 6 and PIONEER 6 trials of semaglutide used different criteria for established CVD from those used in REWIND. The present post hoc analysis assessed the effect of semaglutide on major adverse CV events (MACE) in a pooled population of SUSTAIN 6 and PIONEER 6 patients, re-categorized into CV risk subgroups using the REWIND CVD criteria. In the pooled analysis (n = 6480), a lower percentage of patients were in the established CVD subgroup, when using the REWIND CVD criteria, compared with the original trial CVD criteria (66.5% vs. 83.8%, respectively). After re-categorization, the risk of MACE was significantly lower with semaglutide versus placebo in the established CVD subgroup (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.59, 0.92) and nonsignificantly lower in the CV risk factor subgroup (HR 0.84, 95% CI 0.55, 1.28) (P-interaction = 0.60). These results suggest that the CV effects of semaglutide may extend to patients with type 2 diabetes across the CV risk continuum

Concentrations of canine prostate specific esterase, CPSE, at baseline are associated with the relative size of the prostate at three-year follow-up

BackgroundEnlargement of the prostate is associated with prostatic diseases in dogs, and an estimation of prostatic size is a central part in the diagnostic workup. Ultrasonography is often the method of choice, but biomarkers constitute an alternative. Canine prostate specific esterase (CPSE) shares many characteristics with human prostate specific antigen (PSA) and is related to prostate size. In men with clinical symptoms of prostatic disease, PSA concentrations are related to prostate growth. The aims of the present follow-up study were to evaluate if the concentration of CPSE is associated with future growth of the prostate, and if analysis of a panel of 16 steroids gives further information on prostatic growth. Owners of dogs included in a previous study were 3 years later contacted for a follow-up study that included an interview and a clinical examination. The prostate was examined by ultrasonography. Serum concentrations of CPSE were measured, as was a panel of steroids.ResultsOf the 79 dogs included at baseline, owners of 77 dogs (97%) were reached for an interview, and 22 were available for a follow-up examination. Six of the 79 dogs had clinical signs of prostatic disease at baseline, and eight of the remaining 73 dogs (11%) developed clinical signs between baseline and follow-up, information was lacking for two dogs. Development of clinical signs was significantly more common in dogs with a relative prostate size of >= 2.5 at baseline (n=20) than in dogs with smaller prostates (n=51). Serum concentrations of CPSE at baseline were not associated with the change in prostatic size between baseline and follow-up. Serum concentrations of CPSE at baseline and at follow-up were positively associated with the relative prostatic size (S-rel) at follow-up. Concentrations of corticosterone (P = 0.024), and the class corticosteroids (P = 0.0035) were positively associated with the difference in S-rel between baseline and follow-up.ConclusionsThe results support the use of CPSE for estimating present and future prostatic size in dogs >= 4years, and the clinical usefulness of prostatic size for predicting development of clinical signs of prostatic disease in the dog. The association between corticosteroids and prostate growth warrants further investigation

Trends in HbA1c thresholds for initiation of hypoglycemic agents:Impact of changed recommendations for older and frail patients

Aims: Less strict glycated hemoglobin (HbA1c) thresholds have been recommended in older and/or frail type 2 diabetes (T2D) patients than in younger and less frail patients for initiating hypoglycemic agents since 2011. We aimed to assess trends in HbA1c thresholds at initiation of a first hypoglycemic agent(s) in T2D patients and the influence of age and frailty on these trends. Materials and methods: The groningen initiative to analyze type 2 diabetes treatment (GIANTT) database was used, which includes primary care T2D patients from the north of the Netherlands. Patients initiating a first non-insulin hypoglycemic agent(s) between 2008 and 2014 with an HbA1c measurement within 120 days before initiation were included. The influence of calendar year, age, or frailty and the interaction between calendar year and age or frailty were assessed using multilevel regression analyses adjusted for confounders. Results: We included 4588 patients. The mean HbA1c threshold at treatment initiation was 7.4% up to 2010, decreasing to 7.1% in 2011 and increasing to 7.4% in 2014. This quadratic change over the years was significant (P 0.05). Conclusions: HbA1c thresholds at initiation of a first hypoglycemic agent(s) changed significantly over time, showing a decrease after 2010 and an increase after 2012. The HbA1c threshold at initiation was not influenced by age or frailty, which is in contrast with recommendations for more personalized treatment