Background
Hyperkalemia is associated with many chronic diseases and renin-angiotensin-aldosterone system inhibitor therapy. Sodium zirconium cyclosilicate (SZC), an oral, highly selective ...cation-exchanger, is approved for the treatment of hyperkalemia.
Methods
This phase 3, multicenter, open-label, single-arm, flexible-dose study assessed the safety and efficacy of SZC in Japanese patients with hyperkalemia during a correction phase of up to 3 days and long-term (1 year) maintenance phase (NCT03172702).
Results
Overall, 150 patients received treatment during both study phases; the study population was generally representative of hyperkalemic Japanese patients in clinical practice. Most patients (78.7%) had three doses of SZC during the correction phase. All but one patient received SZC for ≤ 48 h before transitioning to the maintenance phase. In the maintenance phase, mean (standard deviation; SD) exposure to the study drug was 319.4 (98.1) days and mean (SD) dose was 7.38 (2.85) g/day. Adverse events (AEs) were reported in 131 patients (87.3%); most were mild. The most common treatment-related AEs as evaluated by investigators were constipation (6.7%), peripheral edema (4.0%), and hypertension (2.7%). In the correction phase, 78.7% of patients were normokalemic at 24 h and 98.7% within 48 h; ≥ 65.5% maintained normokalemia throughout the maintenance phase.
Conclusion
After a year of exposure, SZC treatment was well tolerated by Japanese patients and potassium levels were well controlled.
To determine the impact of blood glucose profile, involving fluctuation and excursion of blood glucose levels, on glycated proteins, we evaluated the association among the daily profile of blood ...glucose, and glycated albumin (GA) and HbA1c levels in patients with type 1 diabetes (n = 93) and type 2 diabetes (n = 75). GA levels were strongly correlated with HbA1c levels in type 1 (r = 0.85, P<0.0001) and type 2 diabetes (r = 0.61, P<0.0001), respectively. HbA1c levels were similar between patients with type 1 and type 2 diabetes, while GA levels were significantly higher in type 1 diabetes. Thus the ratio of GA levels to HbA1c levels was significantly higher in type 1 diabetes than that in type 2 diabetes (3.32 0.36 vs. 2.89 0.44, p<0.001). The degrees of GA levels and HbA1c levels correlated with maximum and mean blood glucose levels in patients with type 1 and type 2 diabetes. Stepwise multivariate analysis revealed that GA levels independently correlated with maximum blood glucose levels in type 1 diabetes (F = 43.34, P<0.001) and type 2 diabetes (F = 41.57, P<0.001). HbA1c levels also independently correlated with maximum blood glucose levels in type 1 diabetes (F = 34.78, P<0.001), as well as being correlated with mean blood glucose levels in type 2 diabetes (F = 11.28, P<0.001). In summary, GA could be a better marker for glycemic control than glycated hemoglobin in diabetic patients, especially for evaluating glycemic excursion, which is considered to be a major cause of diabetic angiopathy.
Aims
Most risk calculators that predict future cardiovascular disease (CVD) by baseline profiles are originally developed for primary prevention, but some studies applied the calculators to secondary ...prevention. We compared the impact of baseline profiles on the future CVD risk between patients with diabetes with and without a CVD history.
Methods
We analyzed a multicenter prospective cohort of 6338 Japanese patients with diabetes aged 40–74 years, including those with (
n
= 634) and without a CVD history (
n
= 5704). The future risk of CVD was investigated using the competing risk model, with adjustment for non-cardiovascular mortality.
Results
During the median follow-up of 6.9 years, 413 CVD events were observed. The 8-year cumulative incidence rates of CVD were 21.5% and 7.2% in patients with and without a CVD history, respectively. A higher systolic blood pressure and lower high-density lipoprotein cholesterol levels were independently associated with a future CVD risk in patients without a CVD history (both
P
< 0.05), whereas they were not associated in those with a CVD history. The
P
values for interaction were 0.040 and 0.005, respectively. The male sex, an older age, a longer duration of diabetes, higher hemoglobin A1c levels, and higher low-density lipoprotein cholesterol levels were common independent risk factors regardless of CVD history (all
P
< 0.05).
Conclusions
The prognostic impact of metabolic profiles on CVD risk would not be identical between patients with and without a CVD history, suggesting that it might be inappropriate to apply CVD risk calculators developed for primary prevention to patients with a CVD history.
Reactive oxygen species (ROS) are induced under diabetic conditions and are likely associated with the development of type 2 diabetes. It is also known that ROS production is facilitated in the ...presence of copper ion through the Fenton reaction. The aim of this study was to examine the involvement of copper ion in the pathogenesis of type 2 diabetes and to evaluate the potential usefulness of a copper chelating agent for the treatment of type 2 diabetes. First, both serum copper ion and ROS levels in diabetic C57BL/KsJ-db/db mice were significantly higher compared to those in nondiabetic mice. Second, we treated diabetic db/db mice with a copper chelating agent tetrathiomolybdate and examined the effects on the development of type 2 diabetes. As the results, both serum copper ion and ROS levels were significantly decreased by the treatment, which were equivalent to those in non-diabetic mice. Consequently, the treatment with a copper chelating agent reduced insulin resistance and ameliorated glucose intolerance in diabetic db/db mice. In addition, serum triglyceride levels were also decreased by the treatment. In conclusion, our present results suggest that copper ion is involved in the development of type 2 diabetes and thereby a potential therapeutic target for diabetes.
Type 2 diabetes is one of the most prevalent and serious metabolic diseases in the world, and insulin resistance and pancreatic β-cell dysfunction are the hallmarks of the disease. In this study, we ...have shown that endoplasmic reticulum (ER) stress, which is provoked under diabetic conditions, plays a crucial role in the insulin resistance found in diabetes by modifying the expression of oxygen-regulated protein 150 (ORP150), a molecular chaperone that protects cells from ER stress. Sense ORP overexpression in the liver of obese diabetic mice significantly improved insulin resistance and markedly ameliorated glucose tolerance. Conversely, expression of antisense ORP150 in the liver of normal mice decreased insulin sensitivity. The phosphorylation state of IRS-1 and Akt, which are key molecules for insulin signaling, and the expression levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, key enzymes of gluconeogenesis, were also altered by ORP150 overexpression. This is the first report showing that ER stress plays a crucial role in the insulin resistance found in diabetes and thus could be a potential therapeutic target for diabetes.
It has been shown that oxidative stress and activation of the c-Jun N-terminal kinase (JNK) pathway induce the nucleocytoplasmic translocation of the pancreatic transcription factor PDX-1, which ...leads to pancreatic β-cell dysfunction. In this study, we have shown that the forkhead transcription factor Foxo1/FKHR plays a role as a mediator between the JNK pathway and PDX-1. Under oxidative stress conditions, Foxo1 changed its intracellular localization from the cytoplasm to the nucleus in the pancreatic β-cell line HIT-T15. The overexpression of JNK also induced the nuclear localization of Foxo1, but in contrast, suppression of JNK reduced the oxidative stress-induced nuclear localization of Foxo1, suggesting the involvement of the JNK pathway in Foxo1 translocation. In addition, oxidative stress or activation of the JNK pathway decreased the activity of Akt in HIT cells, leading to the decreased phosphorylation of Foxo1 following nuclear localization. Furthermore, adenovirus-mediated Foxo1 overexpression reduced the nuclear expression of PDX-1, whereas repression of Foxo1 by Foxo1-specific small interfering RNA retained the nuclear expression of PDX-1 under oxidative stress conditions. Taken together, Foxo1 is involved in the nucleocytoplasmic translocation of PDX-1 by oxidative stress and the JNK pathway.
Brachial-ankle pulse wave velocity (baPWV) is a method to estimate arterial stiffness, which reflects the stiffness of both the aorta and peripheral artery; it would be applicable to general ...practice, since its measurementis automated. The aim of this study was to evaluate whether baPWV can be predictors of future cardiovascular events (CVE) in diabetic patients.
We prospectively evaluated the association between baPWV or carotid intima-media thickness (carotid IMT) at baseline and new onset of CVE in 1040 type 2 diabetic patients without CVE. The predictability of baPWV and/or carotid IMT for identifying patients at high risk for CVE was evaluated by time-dependent receiver-operating-characteristic (ROC) curve analysis.
During a median follow-up of 7.5 years, 113 had new CVD events. The cumulative incidence rates of CVE were significantly higher in patients with high baPWV values (≥1550 cm/s) as compared to those with low baPWV values (<1550 cm/s) (p < 0.001, log-rank test). Similarly, the cumulative incidence rate of CVE was significantly higher in patients with higher maximum carotid IMT (maxIMT) values (≥1.0 mm) as compared to those with lower maxIMT values (<1.0 mm) (p < 0.001, log-rank test). Subjects with both "high PWV" and "high IMT" had a significantly higher risk of developing CVE as compared to those with either "high PWV" or "high IMT," as well as those with neither. A multivariate Cox proportional hazards regression model revealed that both baPWV (HR = 1.30, 95%CI: 1.07-1.57; p = 0.009) and maxIMT (HR = 1.20, 95%CI: 1.01-1.41; p = 0.033) were independent predictors for CVE, even after adjustment for the conventional risk factors. Time-dependent ROC curve analyses revealed that the addition of maxIMT to the Framingham risk score resulted in significant increase in AUC (from 0.60 95%CI: 0.54-0.67 to 0.63 95%CI: 0.60-0.82; p = 0.01). Notably, the addition of baPWV to the Framingham risk score and maxIMT resulted in further and significant (p = 0.02) increase in AUC (0.72 95%CI: 0.67-0.78).
Evaluation of baPWV, in addition to carotid IMT and conventional risk factors, improved the ability to identify the diabetic individuals with high risk for CVE.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Authors would like to correct the typo in author name of the last author. The author name is corrected from "
Yamazaki
" to "
Yamasaki
" in the original publication.
Pancreatic and duodenal homeobox factor-1 (PDX-1) plays a crucial role in pancreas development, β-cell differentiation, and maintenance of mature β-cell function. PDX-1 expression is maintained in ...pancreatic precursor cells during pancreas development but becomes restricted to β-cells in mature pancreas. In mature β-cells, PDX-1 transactivates the insulin and other genes involved in glucose sensing and metabolism such as GLUT2 and glucokinase. MafA is a recently isolated β-cell-specific transcription factor which functions as a potent activator of insulin gene transcription. Furthermore, these transcription factors play an important role in induction of insulin-producing cells in various non-β-cells and thus could be therapeutic targets for diabetes. On the other hand, under diabetic conditions, expression and/or activities of PDX-1 and MafA in β-cells are reduced, which leads to suppression of insulin biosynthesis and secretion. It is likely that alteration of such transcription factors explains, at least in part, the molecular mechanism for β-cell glucose toxicity found in diabetes.
Patients with chronic kidney disease (CKD) are at an increased risk not only for end-stage kidney disease (ESKD) but also for cardiovascular disease (CVD). In this review article, we summarize the ...current evidence of CKD as a high-risk condition for CVD based on reports from Japan and other countries to draw attention to the close clinical association between CKD and CVD. Several epidemiologic studies have shown that the presence of CKD and reduced renal function are independent predictors of CVD also in Japan. According to a post-hoc analysis of CASE-J, the power of CKD as a predictor of CVD is as strong as diabetes mellitus and a previous history of ischemic heart disease. CKD worsens classical risk factors including hypertension and dyslipidemia, and dyslipidemia is associated with increased thickness and stiffness of large arteries independent of major confounders. A post-hoc analysis of MEGA indicates that lipid-lowering therapy with statins reduces the risk of CVD, and that it appears to be more efficacious in patients with than without CKD. These reports from Japan and other countries suggest that CKD should be regarded as a high-risk condition comparable to diabetes mellitus, and that strict control of dyslipidemia would be beneficial in preventing CVD, at least early stages of CKD.
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