Do incretins improve endothelial function?

An impaired endothelial function has been recognized in the early stage of atherosclerosis, and is a major factor affecting the future development of cardiovascular events. Type 2 diabetes mellitus (T2DM) is widely prevalent, and is one of the most important risk factors for cardiovascular disease. T2DM is associated with increases in both morbidity and mortality, particularly from cardiovascular disease. New therapies based on the incretin hormone and its actions are now becoming widely used, and appear to offer advantages over conventional therapies by keeping the body weight steady and limiting hypoglycemia, while also achieving attractive glycemic control. However, there is little data available about the effects of incretins on the cardiovascular system. This review will focus on the effects of incretin therapies, including glucagon-like peptide-1 (GLP-1) analogs and dipeptidyl peptidase (DPP)-4 inhibitors, on the endothelial function, and will discuss the potential mechanisms underlying these effects

Asynchronous Rhythm of Steroidogenic Factor 1 and Period Homolog 2 mRNA Expression in Mouse Y1 Adrenocorticol Tumor Cells

The relationship between the expression of Steroidogenic factor 1 (Sf1) and the circadian-related gene, period homolog 2 (Per2), in the adrenal cortex is still unknown. We show here that in Y1 adrenocortical tumor cells, expression of steroidogenic-related genes such as P450scc mRNA and Sf1 mRNA were asynchronous with Per2 mRNA. SF1 promoter analyses showed that the E-box element functions in a rhythmic pattern. Rhythmic expression of Upstream factor 1 mRNA, correlated well with Sf1 mRNA expression. We propose that tumorigenesis of adrenocortical lesions cause disruption of synchronous expression of steroidogenic-related and circadian-related genes

Postprandial hyperglycemia as an etiological factor in vascular failure

Postprandial hyperglycemia is characterized by hyperglycemic spikes that induce endothelial dysfunction, inflammatory reactions and oxidative stress, which may lead to progression of atherosclerosis and occurrence of cardiovascular events. Emerging data indicate that postprandial hyperglycemia or even impaired glucose tolerance may predispose to progression of atherosclerosis and cardiovascular events. There is evidence that postprandial hyperglycemia, but not fasting hyperglycemia, independently predicts the occurrence of cardiovascular events. We proposed a concept of 'vascular failure' as a comprehensive syndrome of vascular dysfunction extending from risk factors to advanced atherosclerotic disease. Postprandial hyperglycemia is therefore one of the very important pathophysiological states contributing to vascular failure. Accordingly, controlling postprandial hyperglycemia should be the focus of future clinical investigation as a potential target for preventing vascular failure

Postprandial endothelial dysfunction in subjects with new-onset type 2 diabetes: an acarbose and nateglinide comparative study

<p>Abstract</p> <p>Background</p> <p>Postprandial hyperglycemia is believed to affect vascular endothelial function. The aim of our study was to compare the effects of acarbose and nateglinide on postprandial endothelial dysfunction.</p> <p>Methods</p> <p>We recruited a total of 30 patients with newly diagnosed type 2 diabetes (19 men and 11 women, age 67.8 ± 7.3 years). Patients were randomly assigned to 3 groups receiving either 300 mg/day acarbose, 270 mg/day nateglinide, or no medication. A cookie test (consisting of 75 g carbohydrate, 25 g butter fat, and 7 g protein for a total of 553 kcal) was performed as dietary tolerance testing. During the cookie test, glucose and insulin levels were determined at 0, 30, 60, and 120 min after load. In addition, endothelial function was assessed by % flow-mediated dilation (FMD) of the brachial artery at 0 and 120 min after cookie load.</p> <p>Results</p> <p>Postprandial glucose and insulin levels were similar in the 3 groups. Postprandial endothelial dysfunction was similar in the 3 groups before treatment. After 12 weeks of intervention, postprandial FMD was significantly improved in the acarbose group compared with the control group (6.8 ± 1.3% vs 5.2 ± 1.1%, p = 0.0022). Area under the curve (AUC) for insulin response was significantly increased in the nateglinide and control groups; however, no significant change was observed in the acarbose group.</p> <p>Conclusions</p> <p>Our results suggest that acarbose improves postprandial endothelial function by improvement of postprandial hyperglycemia, independent of postprandial hyperinsulinemia. Acarbose may thus have more beneficial effects on postprandial endothelial function in patients with type 2 diabetes than nateglinide.</p

Longitudinal association among endothelial function, arterial stiffness and subclinical organ damage in hypertension

ObjectivesTo examine the longitudinal mutual association between endothelial dysfunction and arterial stiffness, and also to determine which of the two variables was more closely associated with the progression of subclinical organ damage.MethodsThe brachial-ankle pulse wave velocity (baPWV), carotid intima-media thickness (CIMT), estimated glomerular filtration rate, microalbuminuria and flow-mediated vasodilatation of the brachial artery (FMD) were measured three times at 1.5-year intervals in 674 Japanese patients receiving antihypertensive treatment.ResultsThe change of the baPWV during the study period was larger in the subjects with baseline FMD values in the lowest tertile as compared to those with baseline FMD values in the highest tertile. The change of the CIMT was smaller in the subjects with baseline baPWV values in the lowest tertile than in those with baseline baPWV values in the highest tertile. After the adjustment, the FMD value at the baseline was inversely associated with the baPWV at the end of the study period (beta = − 0.07, p = 0.01), although, the reverse association was not significant. The baPWV, but not the FMD value, at the baseline was associated with the CIMT (beta = 0.06, p = 0.04) measured at the end of the study period.ConclusionsIn hypertension, endothelial dysfunction was associated with the progression of arterial stiffness, although the reverse association was not confirmed. The increased arterial stiffness rather than endothelial dysfunction may be more closely associated with the progression of atherosclerotic vascular damage, and the endothelial dysfunction-arterial stiffness-atherosclerosis continuum may be important in hypertension

A detection method for latent circadian rhythm sleep-wake disorder

Background Individuals with typical circadian rhythm sleep-wake disorders (CRSWDs) have a habitual sleep timing that is desynchronized from social time schedules. However, it is possible to willfully force synchronisation against circadian-driven sleepiness, which causes other sleep problems. This pathology is distinguishable from typical CRSWDs and is referred to here as latent CRSWD (LCRSWD). Conventional diagnostic methods for typical CRSWDs are insufficient for detecting LCRSWD because sufferers have an apparently normal habitual sleep timing. Methods We first evaluated the reliability of circadian phase estimation based on clock gene expression using hair follicles collected at three time points without sleep interruption. Next, to identify detection criteria for LCRSWD, we compared circadian and sleep parameters according to estimated circadian phases, at the group and individual level, between subjects with low and high Pittsburgh Sleep Quality Index (PSQI) scores. To validate the reliability of identified detection criteria, we investigated whether the same subjects could be reproducibly identified at a later date and whether circadian amelioration resulted in sleep improvement. Findings We successfully validated the reliability of circadian phase estimation at three time points and identified potential detection criteria for individuals with LCRSWD attributed to delayed circadian-driven sleepiness. In particular, a criterion based on the interval between the times of the estimated circadian phase of clock gene expression and getting out of bed on work or school days was promising. We also successfully confirmed the reproducibility of candidate screening and sleep improvement by circadian amelioration, supporting the reliability of the detection criteria. Interpretation Although several limitations remain, our present study demonstrates a promising prototype of a detection method for LCRSWD attributed to delayed circadian-driven sleepiness. More extensive trials are needed to further validate this method

Effects of canagliflozin on WBC counts

Aims/Introduction: Clinical evidence is lacking about the influence of sodium–glucose cotransporter 2 inhibitors on white blood cell (WBC) counts, a commonly used and widely available marker of inflammation. The aim of the present analysis was to assess the effect of canagliflozin relative to glimepiride on WBC counts. Materials and Methods: This was a post-hoc subanalysis of the CANDLE trial (Effects of Canagliflozin in Patients with Type 2 Diabetes and Chronic Heart Failure: A Randomized Trial; UMIN000017669), an investigator-initiated, multicenter, open-label, randomized, controlled trial. A total of 233 patients with type 2 diabetes and concomitant heart failure were randomly assigned to either canagliflozin (n = 113) or glimepiride (n = 120) treatment for 24 weeks. Overall, patient baseline characteristics were as follows: mean ± standard deviation age, 68.6 ± 10.1 years; hemoglobin A1c, 7.0 ± 0.9%; left ventricular ejection fraction, 56.7 ± 14.4%; and median N-terminal pro-brain natriuretic peptide, 252 pg/mL (interquartile range 96–563 pg/mL). The mean baseline WBC counts were 6704 cells/μL (95% confidence interval 6,362–7,047) in the canagliflozin group and 6322 cells/μL (95% confidence interval 5,991–6,654) in the glimepiride group. There were no significant differences between treatment groups in terms of changes in WBC counts from baseline to weeks 4 and 12. In contrast, a group difference (canagliflozin minus glimepiride) from baseline to week 24 was significant (mean difference − 456 cells/μL [95% confidence interval −774 to −139, P = 0.005]). Conclusions: Our findings suggest that 24 weeks of treatment with canagliflozin, relative to glimepiride, reduced WBC counts in patients with type 2 diabetes and heart failure

An out-of-lab trial: a case example for the effect of intensive exercise on rhythms of human clock gene expression

Background: Although out-of-lab investigation of the human circadian clock at the clock gene expression level remains difficult, a recent method using hair follicle cells might be useful. While exercise may function as an entrainment cue for circadian rhythms, it remains unclear whether exercise affects human circadian clock gene expression. Methods: Efforts to observe apparent effects of exercise on clock gene expression require that several specific conditions be met: intense exercise should be habitually performed at a relatively uncommon time of day over an extended period; and any relative phase shift thereby observed should be validated by comparison of exercise and no-exercise periods. Wake-up and meal times should be kept almost constant over the experimental period. The present study was conducted using a professional fighter who met these strict criteria as subject. Facial hair samples were collected at 4-h intervals around the clock to ascertain rhythms of clock gene expression. Results: During a period in which nighttime training (from 20:00 to 22:00) was habitually performed, circadian clock gene expression was phase-delayed by 2 to 4 h compared with that during a no-exercise period. Maximum level and circadian amplitude of clock gene expression were not affected by the nighttime training. Conclusion: Our trial observations illustrate the possibility that heavy physical exercise might strongly affect the circadian phase of clock gene expression. Exercise might be therefore effective for the clinical care of circadian disorders. The results also suggest that athletes may require careful scheduling of heavy physical exercise to maintain normal circadian phase and ensure optimal athletic performance

Comparing the Effects of Canagliflozin vs. Glimepiride by Body Mass Index in Patients with Type 2 Diabetes and Chronic Heart Failure : A Subanalysis of the CANDLE Trial

Background: We present results of a 24-week comparative study of the effects of the sodium–glucose cotransporter 2 (SGLT2) inhibitor canagliflozin vs. the sulfonylurea glimepiride, by baseline body mass index (BMI), in patients with type 2 diabetes and chronic heart failure. Methods: We conducted a post hoc analysis of the CANDLE trial. This subanalysis evaluated NT-proBNP, BMI, and other laboratory parameters, according to the subgroups stratified by BMI ≥ 25 kg/m2 vs. BMI < 25 kg/m2. Results: A group ratio of proportional changes in the geometric means of NT-proBNP was 0.99 (p = 0.940) for the subgroup with BMI ≥ 25 kg/m2 and 0.85 (p = 0.075) for the subgroup with BMI < 25 kg/m2, respectively. When baseline BMI was modeled as a continuous variable, results for patients with BMI < 30 kg/m2 showed a slightly smaller increase in NT-proBNP in the canagliflozin group vs. the glimepiride group (p = 0.295); that difference was not seen among patients with BMI ≥30 kg/m2 (p = 0.948). Irrespective of obesity, the canagliflozin group was associated with significant reduction in BMI compared to the glimepiride group. Conclusion: There was no significant difference in the effects of canagliflozin, relative to glimepiride, on NT-proBNP concentrations irrespective of baseline obesity. UMIN clinical trial registration number: UMIN000017669

Heterogeneous Effects of Intensive Glycemic and Blood Pressure on Cardiovascular Events Among Diabetes by Living Arrangements

糖尿病患者における厳格な血糖・血圧管理の効果が、居住形態によって異なることが明らかに. 京都大学プレスリリース. 2024-07-03.Background: Although living alone versus with others is a key social element for cardiovascular prevention in diabetes, evidence is lacking about whether the benefit of intensive glycemic and blood pressure (BP) control differs by living arrangements. We thus aim to investigate heterogeneity in the joint effect of intensive glycemic and BP control on cardiovascular events by living arrangements among participants with diabetes. Methods and results: This study included 4731 participants with diabetes in the ACCORD-BP (Action to Control Cardiovascular Risk in Diabetes-Blood Pressure) trial. They were randomized into 4 study arms, each with glycated hemoglobin target (intensive, <6.0% versus standard, 7.0-7.9%) and systolic BP target (intensive, <120 mm Hg versus standard <140 mm Hg). Cox proportional hazard models were used to estimate the joint effect of intensive glycemic and BP control on the composite cardiovascular outcome according to living arrangements. At a mean follow-up of 4.7 years, the cardiovascular outcome was observed in 445 (9.4%) participants. Among participants living with others, intensive treatment for both glycemia and BP showed decreased risk of cardiovascular events compared with standard treatment (hazard ratio [HR], 0.68 [95% CI, 0.51-0.92]). However, this association was not found among participants living alone (HR, 0.96 [95% CI, 0.58-1.59]). P for interaction between intensive glycemic and BP control was 0.53 among participants living with others and 0.009 among those living alone (P value for 3-way interaction including living arrangements was 0.049). Conclusions: We found benefits of combining intensive glycemic and BP control for cardiovascular outcomes among participants living with others but not among those living alone. Our study highlights the critical role of living arrangements in intensive care among patients with diabetes