BackgroundCombination therapy with canagliflozin and insulin was investigated in a prescribed substudy of the canagliflozin Cardiovascular Assessment Study (CANVAS); however, it was not evaluated in Japanese patients with type 2 diabetes mellitus (T2DM). Since the usage profile of insulin therapy and pathologic features of Japanese patients differ from those of Caucasian patients, we determined the clinical benefit of such a combination therapy in Japanese patients.MethodsPatients who had inadequate glycemic control despite insulin, diet and exercise therapies were randomized into placebo (n = 70) and canagliflozin 100 mg (n = 76) groups that were administered once daily in addition to their prior insulin therapy in this double-blind, placebo-controlled study. The primary endpoint was the change in glycated hemoglobin (HbA1c) levels from the baseline to week 16.ResultsThere was a statistically significant decrease in HbA1c levels from the baseline in the canagliflozin group (−0.97 ± 0.08 %) compared with the placebo group (0.13 ± 0.08 %) at week 16 [last observation carried forward (LOCF)]. The decrease in HbA1c levels in the canagliflozin group was independent of the insulin regimen (premixed, long-acting and long-acting plus rapid- or short-acting). Compared with the placebo group, canagliflozin significantly decreased fasting plasma glucose levels (−34.1 ± 4.8 vs −1.4 ± 5.0 mg/dL) and body weights (−2.13 ± 0.25 vs 0.24 ± 0.26 %), and significantly increased HDL cholesterol (3.3 ± 1.0 vs −0.5 ± 1.0 mg/dL) and HOMA2- %B (10.15 ± 1.37 vs 0.88 ± 1.42 %). The overall incidence of adverse events was similar between the two groups. The incidence and incidence per subject-year exposure of hypoglycemia (hypoglycemic symptoms and/or decreased blood glucose) were slightly higher in the canagliflozin group (40.0 % and 7.97) than in the placebo group (29.6 % and 4.51). However, hypoglycemic events in both groups were mild in severity and dose-reduction of insulin by <10 % from the baseline following hypoglycemic events decreased the incidence per subject-year exposure in the canagliflozin group. The incidence of hypoglycemia between the groups did not differ according to the insulin regimen.ConclusionCanagliflozin in combination with insulin was effective in improving glycemic control and reducing body weight and well tolerated by Japanese patients with T2DM.Trial Registration ClinicalTrials.gov identifier: NCT02220920Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0407-4) contains supplementary material, which is available to authorized users.

The silk gland of Bombyx mori is an organ specialized for the synthesis and secretion of silk proteins. We report here the resolution of silk gland proteins by 2-DE and the identification of many of those proteins. This was accomplished by dissecting the glands into several sections, with each exhibiting more than 400 protein spots by 2-DE, of which 100 spots were excised and characterized by in-gel digestion followed by PMF. Ninety-three proteins were tentatively identified. These were then categorized into groups involved in silk protein secretion, transport, lipid metabolism, defense, etc. Western blotting of a 2-DE gel using an antibody of the carotenoid binding protein confirmed the presence of this protein in the silk gland. Proteins including fibroin L-chain and P25 were found as multiple isoforms, some of which contained differential amounts of phosphate residues as analyzed by on-probe dephosphorylation. The current analysis contributes to our understanding of proteins expressed by the silk gland not only of the model lepidopteran B. mori, but also to proteins from other silk-producing insects such as Philosamia cynthia ricini.

Background Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis. Methods The efficacy and safety of vadadustat, compared with darbepoetin alfa, was determined in a phase 3 double-blind study in Japanese anemic patients on hemodialysis. Patients receiving erythropoiesis-stimulating agents (ESAs) were randomized and switched to either vadadustat or darbepoetin alfa for 52 weeks. Doses were adjusted to maintain a hemoglobin level of 10.0–12.0 g/dL. The primary endpoint was average hemoglobin level at weeks 20 and 24. Results Of 323 randomized patients, 120 and 135 completed the 52-week treatment period in the vadadustat and darbepoetin alfa groups, respectively. The average hemoglobin levels at weeks 20 and 24 (least square mean [LSM] and 95% confidence interval [CI]) were 10.61 (10.45–10.76) and 10.65 (10.50–10.80) g/dL in the vadadustat and darbepoetin alfa groups, respectively, demonstrating vadadustat’s non-inferiority to darbepoetin alfa (difference, −0.05 g/dL; 95% CI, −0.26–0.17). In both groups, the mean hemoglobin levels were maintained within the target range for 52 weeks. Furthermore, irrespective of patient backgrounds, the LSMs at week 52 were within the target range. The most common adverse events were nasopharyngitis, diarrhea, and shunt stenosis, which occurred at similar frequencies in both groups. No new safety concerns were identified. Conclusions Vadadustat was as well tolerated and effective as darbepoetin alfa in maintaining hemoglobin levels within the target range. The findings suggest that vadadustat can be an alternative to ESA in the management of anemia in Japanese hemodialysis patients receiving ESA (Clinical Trials.gov, NCT03439137).

BackgroundStandard care for treating anemia in patients with CKD includes use of erythropoiesis-stimulating agents, which sometimes involves increased risks of cardiovascular morbidity and mortality. Previous studies in patients with anemia and nondialysis-dependent CKD (NDD-CKD) found significantly elevated hemoglobin levels with use of vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, compared with placebo.MethodsIn this phase 3, open-label, active-controlled noninferiority trial, we randomized 304 Japanese adults with anemia in NDD-CKD (including erythropoiesis-stimulating agent users and nonusers) to oral vadadustat or subcutaneous darbepoetin alfa for 52 weeks. The primary efficacy end point was average hemoglobin at weeks 20 and 24. Safety data included adverse events (AEs) and serious AEs.ResultsA total of 151 participants received vadadustat and 153 received darbepoetin alfa. Least squares mean of the average hemoglobin at weeks 20 and 24 was 11.66 (95% confidence interval [95% CI], 11.49 to 11.84) g/dl for vadadustat and 11.93 (95% CI, 11.76 to 12.10) g/dl for darbepoetin alfa. The 95% CIs for both treatments were within the target hemoglobin range (11.0–13.0 g/dl), and the lower 95% confidence limit for the difference between groups (−0.50 g/dl) was above the predefined noninferiority margin (−0.75 g/dl), demonstrating noninferiority of vadadustat to darbepoetin alfa. Similar proportions of patients in each group reported AEs and serious AEs. The most frequent AEs with vadadustat were nasopharyngitis, diarrhea, and constipation.ConclusionsIn Japanese patients with NDD-CKD, vadadustat was noninferior to darbepoetin alfa, was effective up to week 52 in terms of average hemoglobin, and was generally well tolerated. These results suggest that vadadustat may be a potential treatment for anemia in this patient population.

Abstract:The telomere structures in Bombyx mori are thought to be maintained mainly by the transposition of the specialized telomeric retroelements SART and TRAS. The silkworm genome has telomeric TTAGG repeats and telomerase, but this telomerase displays little or no activity. Here, we report that the transcription of the telomeric retroelements SART1 and TRAS1 is suppressed by the silkworm Piwi subfamily proteins BmAgo3 and Siwi. The silkworm Piwi subfamily was found to be expressed predominantly in the gonads and early embryo, as in other model organisms, but in BmN4 cultured cells, these proteins formed granules that were separate from the nuage, which is a different behaviour pattern. The expression of TRAS1 was increased in BmN4 cells when BmAgo3 or Siwi were silenced by RNAi. Our results suggest that B. mori Piwi proteins are involved in regulating the transposition of telomeric retroelements, and that the functional piRNA pathway is conserved in BmN4 cultured cells.