Palmitate induces reactive oxygen species production and β-cell dysfunction by activating nicotinamide adenine dinucleotide phosphate oxidase through Src signaling.

[Aims/Introduction]Chronic hyperlipidemia impairs pancreatic β-cell function, referred to as lipotoxicity. We have reported an important role of endogenous reactive oxygen species (ROS) overproduction by activation of Src, a non-receptor tyrosine kinase, in impaired glucose-induced insulin secretion (GIIS) from diabetic rat islets. In the present study, we investigated the role of ROS production by Src signaling in palmitate-induced dysfunction of β-cells. [Materials and Methods]After rat insulinoma INS-1D cells were exposed to 0.6 mmol/L palmitate for 24 h (palmitate exposure); GIIS, ROS production and nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity were examined with or without exposure to10 μmol/L 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), a Src inhibitior, for 30 or 60 min. [Results]Exposure to PP2 recovered impaired GIIS and decreased ROS overproduction as a result of palmitate exposure. Palmitate exposure increased activity of NOX and protein levels of NOX2, a pathological ROS source in β-cells. Palmitate exposure increased the protein level of p47phox, a regulatory protein of NOX2, in membrane fraction compared with control, which was reduced by PP2. Transfection of small interfering ribonucleic acid of p47phox suppressed the augmented p47phox protein level in membrane fraction, decreased augmented ROS production and increased impaired GΙIS by palmitate exposure. In addition, exposure to PP2 ameliorated impaired GIIS and decreased ROS production in isolated islets of KK-Ay mice, an obese diabetic model with hyperlipidemia. [Conclusions]Activation of NOX through Src signaling plays an important role in ROS overproduction and impaired GΙIS caused by chronic exposure to palmitate, suggesting a lipotoxic mechanism of β-cell dysfunction of obese mice

The importance of central airway dilatation in patients with bronchiolitis obliterans

Background: Bronchiolitis obliterans (BO) is a clinical syndrome characterised by progressive small airway obstruction, causing significant morbidity and mortality. Central airway dilatation is one of its radiological characteristics, but little is known about the clinical and pathological associations between airway dilatation and BO. Methods: This retrospective study consecutively included patients who underwent lung transplantation due to BO at Kyoto University Hospital from 2009 to 2019. Demographic and histopathological findings of the resected lungs were compared between patients with and without airway dilatation measured by chest computed tomography (CT) at registration for lung transplantation. Results: Of a total of 38 included patients (median age, 30 years), 34 (89%) had a history of hematopoietic stem-cell transplantation, and 22 (58%) had airway dilatation based on CT. Patients with airway dilatation had a higher frequency of Pseudomonas aeruginosa isolation with greater residual volume than those without airway dilatation. Quantitative CT analysis revealed an increase in lung volume to predictive total lung capacity and a percentage of low attenuation volume <-950 HU at inspiration in association with the extent of airway dilatation. Airway dilatation on CT was associated with an increased number of bronchioles with concentric narrowing of the lumen and thickening of the subepithelium of the walls on histology. Conclusions: In patients with BO, airway dilatation may reflect increased residual volume or air trapping and pathological extent of obstructive bronchioles, accompanied by a risk of Pseudomonas aeruginosa isolation. More attention should be paid to the development of airway dilatation in the management of BO

Association between Alkaline Phosphatase and Anemia in Rural Japanese Men: The Nagasaki Islands study

Although bone metabolism is reportedly associated with production and maturation of blood corpuscles, and serum alkaline phosphatase (ALP) levels have been associated with bone metabolism, no published study has investigated the association between ALP and anemia. Furthermore, although ALP is known as an enzyme affected by alcohol consumption, there are no reports in the literature on associations between ALP and the risk of anemia in relation to drinking status. We conducted a cross-sectional study of 907 men aged 30-89 years undergoing a general health check-up to investigate the associations between ALP and anemia in relation to drinking status. Of the 907 participants, 120 men were diagnosed with anemia. The association between ALP and anemia was J-shaped. With the second quartile of ALP (194-228 IU/L) (Q2) as the reference group, the multivariable adjusted OR and 95%CI for anemia were 1.91 (95%CI: 0.96-3.82) for 277 IU/L (Q4). When the analysis was limited to non-drinkers, the associations became stronger with corresponding values of 3.34 (95%CI: 1.28-8.74), 3.18 (95%CI: 1.28-7.88) and 3.22 (95%CI:1.37-7.59). Not only lower but also higher levels of serum ALP are associated with anemia for men, especially non-drinkers. For analyses of associations between ALP and anemia, alcohol consumption should thus be considered a potential confounder

Association between white blood cell count and diabetes in relation to triglycerides-to-HDL cholesterol ratio in a Japanese population: The Nagasaki Islands study

Although our previous study found that diabetes combined with a high serum triglycerides to high-density lipoprotein cholesterol (TG-HDL) ratio constitutes a risk for atherosclerosis and chronic kidney disease (CKD), the association, in terms of TG-HDL ratio, between diabetes and white blood cell (WBC) count, which is an independent risk factor for atherosclerosis, has not been clarified. To investigate this association, we conducted a cross-sectional study of 3,998 Japanese subjects aged 30-89 years undergoing a general health check. We investigated the associations between WBC count and diabetes for all subjects, who were divided into tertiles according to TG-HDL level. Independent of classical cardiovascular risk factors, WBC count of both men and women was positively associated with diabetes combined with high but not with low TG-HDL. The multivariable odds ratios (ORs) and 95% confidence intervals (95%CIs) of 1SD (standard deviation) increment in WBC count (1,538/μL for men, 1,382/μL for women) for high TG-HDL diabetes and low TG-HDL diabetes were 1.39 (95%CI: 1.04-1.85) and 0.88 (95%CI: 0.66-1.19) for men, and 1.83 (95%CI: 1.45-2.33) and 0.91 (95%CI: 0.64-1.29) for women, respectively. In conclusion, for both men and women, WBC count is associated with high TG-HDL diabetes but not with low TG-HDL diabetes. These findings suggest that measuring WBC count is clinically relevant for estimating the risk of atherosclerosis and CKD in patients with diabetes categorized according to TG-HDL ratio

Association of serum gamma-glutamyltransferase (GGT) and diabetes with triglycerides-to-HDL cholesterol ratio in Japanese subjects: The Nagasaki Study

Background: Although we reported in a previous study that diabetes with a high serum triglycerides to high-density lipoproteincholesterol (TG-HDL) ratio constitutes a risk for atherosclerosis, associations in terms of TG-HDL ratio between diabetes and gamma-glutamyltransferase (GGT), which is also known as an independent risk factor for atherosclerosis, have not yet been clarified. The purpose of this study was to test the hypothesis that a positive association between GGT and diabetes may be confined to high TG-HDL. Methods: This was a cross-sectional study of 2,302 Japanese subjects who were undergoing a general health check in 2014. All subjects were divided into TG-HDL level tertiles and serum GGT and diabetes status were investigated. Results: Of 207 diabetes patients identified in this study, 94 had high TG-HDL, 63 intermediate TG-HDL, and 50 low TG-HDL. Independent of classical cardiovascular risk factors, serum GGT showed a positive association with diabetes in patients with high TG-HDL, but not in patients with intermediate and low TG-HDL diabetes. The multivariable adjusted odds ratios (OR) and 95% coincidence intervals (95%CI) of diabetes for 1 standard deviation (SD) increment of GGT were 1.64 (95%CI: 1.16-2.31) for high TG-HDL, 1.46 (95%CI: 0.95-2.26) for intermediate TG-HDL, and 1.04 (95%CI: 0.60-1.79) for low TG-HDL diabetes. Conclusion: Serum GGT is positively associated with diabetes in patients with high TG-HDL but not with intermediate or low TG-HDL diabetes. This finding may prove to be an efficient tool for estimating atherosclerotic risk in diabetes patients

Body mass index and triglyceride-to-HDL-cholesterol ratio in relation to risk of diabetes: The Nagasaki Islands study

Body mass index (BMI) is well known as an independent risk factor for insulin resistance. In addition, lower BMI and lower insulin levels are recognized as specific characteristics of Asian diabetes patients. Since the triglyceride-to-HDL-cholesterol ratio (TG-HDL) is positively associated with insulin level, but inversely associated with insulin sensitivity, we supposed that diabetes combined with high but not with low TG-HDL might be positively associated with BMI. We therefore conducted a cross-sectional study of 2,431 Japanese subjects (905 men and 1,526 women) aged 30-79 years, who underwent a general health check, to investigate associations between BMI, diabetes and its subtypes that we defined on the basis of TG-HDL levels, which in turn were categorized according to sex-specific tertiles. Among the 172 diabetic patients identified in the study group, 45 showed low TG-HDL and 82 high TG-HDL. We found a significant inverse association between low-TG-HDL diabetes and BMI, and a significant positive association between high-TG-HDL diabetes and BMI. The multivariable-adjusted odds ratio and 95%CI for a 1SD increment in BMI (3.03 kg/m2 for men and 3.44 kg/m2 for women) for low-TG-HDL diabetes was 0.53 (95%CI: 0.36-0.77) and 1.57 (95%CI: 1.24-2.01) for high-TG-HDL diabetes. These findings demonstrated that for Japanese subjects associations between diabetes and BMI are strongly influenced by the TG-HDL status. Since a previous study of ours found that diabetes combined with high TG-HDL ratios constitutes a risk for atherosclerosis, these findings may serve as an effective tool for estimating risk of atherosclerosis for diabetes patients

Discontinuation of methotrexate in rheumatoid arthritis patients achieving clinical remission by treatment with upadacitinib plus methotrexate (DOPPLER study)

Background: The administration of Janus kinase inhibitors as well as biological disease-modifying anti-rheumatic drugs has dramatically improved the clinical outcomes of patients with rheumatoid arthritis (RA). Previous trials have shown that upadacitinib, a Janus kinase inhibitor, can effectively improve disease activity and prevent progression of joint destruction in RA patients with inadequate responses to methotrexate (MTX). It remains unclear whether reduced disease activity can be maintained after discontinuation of MTX in patients treated with upadacitinib plus MTX. Thus, the aim of this study is to evaluate changes in disease activity after administration of upadacitinib plus MTX in RA patients who failed to achieve an adequate response to MTX and to determine whether clinical relapse can be avoided after discontinuation of MTX in those who achieved clinical remission.Methods/design: The proposed study is an interventional, multicenter, open-label, single-arm clinical trial with a 48-week follow-up. The cohort will include 155 RA patients with at least moderate disease activity during treatment with MTX. Patients will receive upadacitinib and MTX will be discontinued for those who achieve clinical remission. Disease activity will be evaluated longitudinally by measuring clinical disease activity indices and with musculoskeletal ultrasound (MSUS). The primary endpoint is the proportion of patients who sustain a disease activity score-28- C reactive protein score of ≤3.2 from week 24 to 48 after a disease activity score-28- C reactive protein score of <2.6 at week 24. Important secondary endpoints are changes from baseline MSUS scores. Serum levels of multiple biomarkers, including cytokines and chemokines, will be comprehensively analyzed.Discussion: The study results are expected to show the clinical benefit of the discontinuation of MTX after achieving clinical remission by treatment with upadacitinib plus MTX combination therapy. The strength of this study is the prospective evaluation of therapeutic efficacy using clinical disease activity indices and standardized MSUS, which can accurately and objectively evaluate disease activity at the joint level among patients drawn from multiple centers. Furthermore, parameters to predict clinical remission after administration of upadacitinib plus MTX combination therapy and nonclinical relapse after discontinuation of MTX will be screened by integrated multilateral assessments (i.e., clinical disease activity indices, MSUS findings, and serum biomarkers)

Efficacy and safety of selective JAK 1 inhibitor filgotinib in active rheumatoid arthritis patients with inadequate response to methotrexate: comparative study with filgotinib and tocilizumab examined by clinical index as well as musculoskeletal ultrasound assessment (TRANSFORM study): study protocol for a randomized, open-label, parallel-group, multicenter, and non-inferiority clinical trial

Background:Administration of Janus kinase (JAK) inhibitors and biological disease-modifying antirheumatic drugs has dramatically improved even the clinical outcomes in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). Dysregulation of JAK-STAT pathways via overproduction of cytokines, such as interleukin-6, is involved in the pathogenesis of RA. Filgotinib is a selective JAK1 inhibitor pending approval for use in RA. By inhibition of the JAK-STAT pathway, filgotinib is effective in suppressing disease activity and preventing the progression of joint destruction. Similarly, interleukin-6 inhibitors such as tocilizumab also inhibit the JAK-STAT pathways by inhibition of interleukin-6 signaling. We present the protocol for a study that will evaluate whether the effectiveness of filgotinib monotherapy is non-inferior to that of tocilizumab monotherapy in RA patients with an inadequate response to MTX.Methods:This study is an interventional, multicenter, randomized, open-label, parallel-group, and non-inferiority clinical trial with a 52-week follow-up. Study participants will be 400 RA patients with at least moderate disease activity during treatment with MTX. Participants will be randomized in a 1:1 ratio to administer filgotinib monotherapy or subcutaneous tocilizumab monotherapy switched from MTX. We will evaluate disease activity by measuring clinical disease activity indices and by using musculoskeletal ultrasound (MSUS). The primary endpoint is the proportion of patients who achieve an American College of Rheumatology 50 response at week 12. Secondary endpoints are changes from baseline in the MSUS scores. We will also comprehensively analyze serum levels of multiple biomarkers, such as cytokines and chemokines.Discussion:The study results are expected to show the non-inferiority of the effectiveness of filgotinib monotherapy to that of tocilizumab monotherapy in RA patients with inadequate response to MTX. The strength of this study is its prospective evaluation of therapeutic efficacy using not only clinical disease activity indices, but also MSUS, which accurately and objectively evaluates disease activity at the joint level among patients drawn from multiple centers with a standardized evaluation by MSUS. We will evaluate the effectiveness of both drugs by integrating multilateral assessments—clinical disease activity indices, MSUS findings, and serum biomarkers