Apolipoprotein B-48 as a determinant of endothelial function in obese subjects with type 2 diabetes mellitus: effect of fenofibrate treatment

ObjectiveElevated triglyceride-rich lipoproteins may contribute to endothelial dysfunction in obese diabetic subjects. We investigated the association between plasma concentrations of chylomicron-related particles and endothelial function, and the corresponding responses to fenofibrate treatment.MethodsPlasma apolipoprotein (apo) B-48 and remnant-like particle (RLP)-cholesterol concentrations were measured in 28 obese subjects with T2DM. Flow-mediated endothelium-dependent dilation (FMD) and glyceryl-trinitrate mediated dilatation (GTNMD) in the brachial artery during reactive hyperaemia were examined by high-resolution ultrasound technique.ResultsIn univariate analysis, plasma apoB-48 and RLP-cholesterol concentrations were inversely associated with brachial artery FMD (r = ?0.425 and ?0.423, respectively, P < 0.05), but not with GTNMD. In regression models including BMI and HOMA score, plasma apoB-48 was an independent predictors (P < 0.05) of brachial artery FMD (β coefficient = ?0.384). Replacing HOMA-IR score with plasma triglyceride, adiponectin or CRP concentrations did not alter the findings. The subjects were then randomized to a 12-week treatment period of either 200 mg micronized fenofibrate or matching placebo. Compared with the placebo group, fenofibrate treatment (200 mg daily for 12 weeks) achieved significant increase in FMD (+34%) and reduction in plasma triglyceride (?42%), apoB-48 (?52%) and RLP-cholesterol (?51%) concentrations. The increase in FMD with fenofibrate was significantly associated with the corresponding decrease in plasma apoB-48 (r = ?0.644, P < 0.02) concentrations.ConclusionsOur findings demonstrate an association between changes in lipid metabolism and improvement in endothelial function in patients with diabetic dyslipidaemia treated with fenofibrate that may involve the effect of apoB-48 on endothelium-dependent vasodilator function.     

Vitamin D deficiency and endothelial dysfunction in non-dialysis chronic kidney disease patients

BackgroundCardiovascular (CV) events are common in patients with chronic kidney disease (CKD) but inadequately explained by traditional risk factors. Vitamin D deficiency is highly prevalent in CKD and has been proposed to be a non-traditional risk factor, but its relationship with vascular function is unknown.Methods and resultsThe aim of this study was to investigate the relationship between vitamin D levels and endothelial function in non-diabetes patients with mild to moderate CKD. Endothelial function was measured non-invasively using brachial artery flow mediated dilation (FMD). 25 hydroxy vitamin D levels were measured using electrochemiluminescence immunoassay.In 50 CKD patients (age 56 ± 11 years, BMI 25 ± 4 kg/m², 46% females, 14% smokers, 86% hypertensives, 52% with dyslipidaemia) the mean vitamin D level was 53 ± 33 nmol/L (21 ± 13 ng/L). The mean FMD was 3.8 ± 2.4%. Decreasing 25 hydroxy vitamin D levels were associated with decreasing FMD [r = 0.44, p = 0.001]. In multivariate analysis the association remained independent after adjustment with traditional risk factors (adjusted beta 0.451; t = 3.46; p < 0.002).Patients with low vitamin D (≤37.5 nmol/L) demonstrated low FMD compared to patients with vitamin D values >37.5 nmol/L (4.4 ± 2.5% vs. 2.5 ± 1.6%; p = 0.007); however the traditional risk factors were similar between the two groups.ConclusionThis is the first demonstration of an association of vitamin D deficiency with abnormal vascular endothelial function in non-dialysis CKD patients. Further studies with intervention and exploration of the mechanism are needed to establish a cause effect relationship.     

Role of add-on zileuton on total exhaled, large airway, and small airway/alveolar nitric oxide in moderate-severe persistent adult asthmatics on fluticasone 250 μg/Salmeterol 50 μg

BackgroundMeasuring non-invasive exhaled biomarkers of inflammation may be important in monitoring asthma therapy.ObjectiveEvaluate exhaled nitric oxide with add-on leukotriene synthesis inhibitor in moderate-severe persistent asthmatics on combination controllers.MethodsIn a non-randomized, non-placebo, single-blind, fixed sequence, pilot study, we evaluated 22 non-smoking, stable, moderate-severe adult asthmatics on maintenance inhaled fluticasone 250 μg/salmeterol 50 μg (F/S) via MDI bid ≥ 1 yr, with add-on oral zileuton 600 mg qid. Exhaled fractional nitric oxide (FENO) gas exchange, large airway NO, small airway/alveolar NO concentration (CANO), Juniper score and lung function were measured. Asthmatics were studied at baseline only on F/S bid (visit 1), on F/S bid pre and 2 h post first dose zileuton 600 mg (visit 2), and post 4 weeks (visit 3) F/S bid plus zileuton 600 mg qid. Values were compared at each visit and to healthy non-smoking age matched healthy controls with normal lung function.ResultsThree asthmatics stopped zileuton prematurely (headache and/or nausea) and 19 (12F) age 55 ± 17 yr (mean ± SD) completed the 4-week study. Baseline forced expiratory lung volume in 1 sec (FEV₁) was 1.6 ± 0.7L (53 ± 19% pred) (mean ± SD), FEV₁ over FVC ratio was 64 ± 11% and post 180 μg albuterol FEV₁ was 1.8 ± 0.7 L (56 ± 21% pred), and FEV₁ over FVC ratio was 67 ± 12%. Baseline Juniper scores were mild (10 ± 10) and similar (p = ns) at all visits. Baseline FENO@50 mL/s was 48 ± 27 ppb (mean ± SD), and FENO@100 mL/s was 29 ± 16 ppb, and were similar (p = ns) at all visits. Large airway NO flux was 2.0 ± 1.3 nL/s (52% asthmatics abnormal) and small airway/alveolar NO was 8.0 ± 4.0 ppb (79% asthmatics abnormal) and were similar (p = ns) at all visits. Compared to baseline, post 26 ± 6 days Zileuton, mean FEV₁ (L)% predicted increased 3.3% predicted (p = 0.03), and FEV₁ over FVC ratio increased 2.2% (p = 0.03).ConclusionIn stable, moderate-severe persistent adult asthmatics, large airway NO flux, small airway/alveolar CANO, and Juniper airway scores, were not significantly different on F/S bid vs F/S bid plus Zileuton for 4 weeks, despite significant small increase in FEV₁ over FVC ratio and FEV₁% predicted.     

Decreased heparin cofactor II activity is associated with impaired endothelial function determined by brachial ultrasonography and predicts cardiovascular events

BackgroundHeparin cofactor II (HCII) could inactivate thrombin after binding to dermatan sulfate at injured arterial walls, and has been shown to be a novel and independent antiatherosclerotic factor. However, the relation between plasma HCII activity and peripheral vascular endothelial function remains unclear.MethodsA total of 199 patients (mean age, 63 ± 14 years) were enrolled and followed up for a median period of 24 months. Endothelial function was assessed using brachial ultrasonography to determine endothelium dependent flow-mediated vasodilation (FMD). Cox regression analyses were conducted for the 199 subjects, with cardiovascular events being defined as myocardial infarction (MI), percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), ischemic stroke, and peripheral artery revascularization.ResultsA total of 31 patients (16%) had cardiovascular events. Patients with cardiovascular events had significantly lower HCII activity (112 ± 34 versus 127 ± 34%, p = 0.027) and lower antithrombin III (ATIII) activity (82 ± 12 versus 88 ± 13%, p = 0.014) than those without events. By multivariate analysis, age (p = 0.012), hsCRP (p = 0.020) and HCII activity (p = 0.035) were correlated with FMD. Kaplan-Meier analysis was performed and showed plasma HCII (p = 0.036) and ATIII activities (p = 0.005) were predictors of cardiovascular events. By Cox regression analysis, plasma HCII activity (p = 0.026) could be an independent predictor of future cardiovascular events, but not ATIII.ConclusionsThe present study demonstrates that plasma HCII activity is positively correlated with endothelial vasodilator function. Furthermore, plasma HCII activity could be a predictor of future cardiovascular events in patients with suspected coronary artery disease, suggesting its role in atherosclerosis.     

Arterial endothelial function and wall thickness in familial hypercholesterolemia and familial combined hyperlipidemia and the effect of statins. A systematic review and meta-analysis

BackgroundTo evaluate the impact of familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCH) on arterial properties and the effects of statins.MethodsWe meta-analyzed 51 studies providing data for 4,057 FH patients and 732 FCH patients with random-effects models, meta-regression analysis and publication bias analysis. The main outcomes of interest were (1) brachial artery flow-mediated dilation (FMD), (2) intima-media thickness (IMT), and (3) change of IMT and FMD after treatment with statins.ResultsCompared to normolipidemic controls, FH patients had lower FMD [pooled mean difference (MD): ?5.31%, 95% CI ?7.09 to ?3.53%, P < 0.001] and higher carotid IMT (pooled MD: 0.12 mm, 95% CI 0.09–0.15 mm, P < 0.001) and femoral IMT (pooled MD: 0.35 mm, 95% CI 0.18–0.51 mm, P < 0.001). FCH patients had lower FMD and increased IMT (pooled MD: ?3.60%, 95% CI ?6.69 to ?0.50%, P = 0.023; and 0.06 mm, 95% CI 0.04–0.08 mm, P < 0.001, respectively). Total and LDL-cholesterol was a significant determinant of FMD and carotid IMT in FCH patients and of FMD and femoral IMT in FH patients. In FH patients, statins improved FMD (pooled MD of change: 5.39%, 95% CI 2.86–7.92%, P < 0.001) and decreased carotid IMT (pooled MD of change: ?0.025 mm, 95% CI ?0.042 to ?0.009 mm, P = 0.003). Changes of both FMD and IMT with statins correlated with the duration × treatment intensity product in FH patients (both P < 0.01). Additionally, statins improved FMD in FCH patients (pooled MD of change: 2.06%, 95% CI 0.43–3.69%, P = 0.013). No significant publication bias was detected.ConclusionArterial properties are impaired in subjects with FH or FCH. Statins improve arterial function and structure in FH patients in a treatment intensity-related manner.     

Time course of asymmetric dimethylarginine (ADMA) and oxidative stress in fructose-hypertensive rats: a model related to metabolic syndrome

ObjectiveAsymmetric dimethylarginine (ADMA) is an endogenous modulator of endothelial function and oxidative stress, and increased levels of this molecule have been reported in some metabolic disorders and cardiovascular diseases. The aim of this work was to analyze the time course of dimethylarginine compounds and oxidative stress levels and the relationship between these and cardiovascular function in fructose-hypertensive rats.Methods and results90 male Sprague–Dawley rats were randomized into 2 groups, fed for 3 months with standard (C) chow supplemented or not with fructose (F, 60%). After sacrifice at different weeks (W), the aorta and plasma were harvested to assess the vascular and biochemical parameters. Our work showed that the plasma levels of ADMA in the fructose-fed rats increased after 2 weeks of the diet (1.6 ± 0.3 μM vs. 1.2 ± 0.3 μM, p < 0.05) with no changes in plasma levels of either SDMA or l-arginine and after an increase in glycemia. Levels of vascular oxidative stress, estimated in aortic segments using an oxidative fluorescence technique, were higher in the F group (W2: 1.14 ± 0.2% vs. 0.33 ± 0.02%, p < 0.01). An increase in expression levels of nitrotyrosine (3-fold) and iNOS (2-fold) were noted in the fructose-fed rats. After 1 month, this was associated with a significant increase in NAD(P)H oxidase activity. Concerning vascular function, a 15% decrease in maximal endothelium-dependent relaxation was found in the aorta of the F group. Our work showed that the presence of exogenous L-MMA, an inhibitor of NO synthase, was associated with a significant reduction in endothelium-dependent relaxation in isolated aorta rings of the C group; this effect was not observed in the vessels of fructose-fed rats.ConclusionOur findings suggest that the elevated levels of ADMA observed could in part be secondary to the early development of oxidative stress associated with the development of hypertension.     

Effects of fenofibrate therapy on circulating adipocytokines in patients with primary hypertriglyceridemia

BackgroundWe investigated effects of fenofibrate therapy on endothelial dysfunction and adipocytokine profiles.MethodsA randomized, single-blind, placebo-controlled, cross-over study was conducted in 53 patients with primary hypertriglyceridemia. We administered placebo or fenofibrate 160 mg daily for 8 weeks.ResultsWhen compared with placebo, fenofibrate therapy substantially lowered plasma levels of TNF-α by 6 ± 3% (P = 0.014) and hsCRP from 1.10 to 0.90 mg/l (P = 0.004). When compared with placebo, fenofibrate therapy increased plasma levels of adiponectin by 17 ± 4% (P = 0.001), insulin sensitivity by 4 ± 1% (as assessed by QUICKI, P = 0.009), and decreased plasma levels of leptin and resistin by 4 ± 7% (P = 0.022) and 10 ± 3% (P = 0.001), respectively. There were correlations between percent changes in QUICKI and percent changes in adiponectin levels (r = 0.279, P = 0.043) or leptin (r = ?0.280, P = 0.042).ConclusionsFenofibrate therapy significantly reduced pro-inflammatory biomarkers and improved adipocytokines levels and insulin sensitivity in hypertriglyceridemic patients.     

Circulating angiogenic cell populations, vascular function, and arterial stiffness

ObjectiveSeveral bone marrow-derived cell populations have been identified that may possess angiogenic activity and contribute to vascular homeostasis in experimental studies. We examined the extent to which lower quantities of these circulating angiogenic cell phenotypes may be related to impaired vascular function and greater arterial stiffness.MethodsWe studied 1948 Framingham Heart Study participants (mean age, 66 ± 9 years; 54% women) who were phenotyped for circulating angiogenic cells: CD34+, CD34+/KDR+, and early outgrowth colony forming units (CFU). Participants underwent non-invasive assessments of vascular function including peripheral arterial tone (PAT), arterial tonometry, and brachial reactivity testing.ResultsIn unadjusted analyses, higher CD34+ and CD34+/KDR+ concentrations were modestly associated with lower PAT ratio (β = ?0.052 ± 0.011, P < 0.001 and β = ?0.030 ± 0.011, P = 0.008, respectively) and with higher carotid-brachial pulse wave velocity (β = 0.144 ± 0.043, P = 0.001 and β = 0.112 ± 0.043, P = 0.009), but not with flow-mediated dilation; higher CD34+ was also associated with lower carotid-femoral pulse wave velocity (β = ?0.229 ± 0.094, P = 0.015). However, only the association of lower CD34+ concentration with higher PAT ratio persisted in multivariable analyses that adjusted for standard cardiovascular risk factors. In all analyses, CFU was not associated with measures of vascular function or arterial stiffness.ConclusionsIn our large, community-based sample of men and women, circulating angiogenic cell phenotypes largely were not associated with measures of vascular function or arterial stiffness in analyses adjusting for traditional risk factors.     

Gender differences in short-term effects of atorvastatin on lipid profile, fibrinolytic parameters, and endothelial function

Background and aimLittle is known about the impact of gender on short-term effects of atorvastatin. We investigated the gender differences in the short-term lipid-lowering and pleiotropic effects of atorvastatin therapy.Methods and resultsSeventy-two consecutive patients including 48 women with primary hypercholesterolemia, were assigned prospectively to treatment with atorvastatin (10 mg/day) for 3 months. We measured fasting lipid concentrations, thiobarbituric acid reactive substances (TBARS) as marker of lipid peroxide, fibrinolytic parameters, and endothelial function by flow-mediated vasodilation of the brachial artery (FMD), at baseline and after 3 months of therapy. We assessed the impact of gender on temporal differences in these parameters.In men, atorvastatin decreased total, low-density lipoprotein (LDL), and small, dense LDL-cholesterol concentrations, and increased FMD after 3 months. In women, atorvastatin decreased TBARS, triglyceride, and total, LDL, small, dense LDL, and remnant-like lipoprotein particle-cholesterol concentrations, and increased FMD after 3 months. Fibrinolytic parameters did not change significantly in either men or women. With respect to the percent change in those parameters after 3 months, TBARS (−17.6 ± 12.4 vs. −0.4 ± 18.8%, p < 0.01) and small, dense LDL-cholesterol (−96.7 ± 8.3 vs. −68.6 ± 29.7%, p < 0.01) decreased to a greater degree in women, although the relative changes in other parameters were similar between men and women.ConclusionsWe found gender differences in some of the lipid altering changes, including TBARS and small, dense LDL-cholesterol concentrations, after short-term atorvastatin therapy, which were greater in women. However, short-term atorvastatin therapy may be beneficial in improving endothelial function equally in both men and women.     

Endothelium-dependent vasodilation, insulin resistance and the metabolic syndrome in an elderly cohort: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study

BackgroundOnly a few previous studies have investigated endothelium-dependent vasodilation in the metabolic syndrome (MetS). In the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study, different techniques to assess vasodilation in conduit and resistance arteries were evaluated in relation to the MetS and insulin resistance.MethodsIn this population-based study, 1016 subjects aged 70 were evaluated by the invasive forearm technique with acetylcholine (EDV), brachial artery ultrasound to assess flow-mediated vasodilation (FMD) and pulse wave analysis with a beta-2 receptor agonist challenge, terbutaline.ResultsEDV was lower in subjects with the MetS (NECP/ATP III-criteria, prevalence 23%) compared to those without (p < 0.0001), and declined with increasing number of MetS criteria (p < 0.0001), after adjustment for coronary heart disease, stroke and cardiovascular medication. Also a reduced pulse wave response (p = 0.015), but not FMD (p = 0.64), was seen in those with the MetS. EDV and the pulse wave response, but not FMD, were inversely related to insulin resistance evaluated by the HOMA index. Also endothelium-independent vasodilation (EIDV) induced by intra-brachial infusion of sodium nitroprusside was impaired in subjects with MetS and in insulin resistance.ConclusionsVasodilation evaluated with the invasive forearm technique and pulse wave analysis with a beta-2 agonist, but not FMD, was reduced in elderly subjects with the MetS and was related to insulin resistance. Also EIDV showed the same pattern, suggesting a general deterioration in vasoreactivity mainly in resistance arteries in elderly subjects with the MetS.     

The FTO gene modifies weight, fat mass and insulin sensitivity in women with polycystic ovary syndrome, where its role may be larger than in other phenotypes

AimGenome-wide association studies have shown that variation in the FTO gene predisposes to obesity and related traits that are common features of polycystic ovary syndrome (PCOS). The aim of the present study was to assess the effect of FTO variation on obesity, insulin sensitivity, and metabolic and hormonal profiles in PCOS.MethodsWe examined 136 PCOS women (mean body mass index [BMI]: 28.28 ± 6.95 kg/m², mean age: 25.36 ± 5.48 years). Anthropometric measurement, euglycaemic–hyperinsulinaemic clamp and oral glucose tolerance tests and sex hormone assessments were performed. The study group was genotyped for the FTO rs9939609 polymorphism.ResultsBMI (29.0 ± 6.9 kg/m² vs 26.1 ± 6.8 kg/m²; P = 0.023), body weight (80.1 ± 20.7 kg vs 72.6 ± 20.2 kg; P = 0.048), fat mass (29.7 ± 1 6.6 kg vs 24.6 ± 17.7 kg; P = 0.045) and waist circumference (89.8 ± 16.7 cm vs 83.2 ± 17.1 cm; P = 0.028) were higher in carriers of at least one copy of the A allele. Differences in these parameters were more significant when comparing AA and TT homozygotes. Women with the AA genotype also had decreased insulin sensitivity (P = 0.025) and follicle-stimulating hormone (P = 0.036). In logistic-regression analyses, the association of the FTO gene polymorphism with insulin sensitivity was no longer significant when BMI was included in the model.ConclusionVariation in the FTO gene modifies weight, adiposity and other measures of obesity and insulin sensitivity in PCOS. The examined FTO gene variant appears to have a greater impact on obesity and related traits in PCOS than in other phenotypes. The effect on insulin sensitivity appears to be secondary to its influence on obesity and body fat.     

Effects of a phytosterol-enriched dairy product on lipids, sterols and 8-isoprostane in hypercholesterolemic patients: a multicenter Italian study

Background and aimsPlant sterols, added to several food sources, lower serum cholesterol concentrations. Plant sterol-induced cholesterol lowering is paralleled by a mild decrease in plasma levels of the antioxidant β-carotene, the amount of this decrease being considered clinically non-significant. Whether the effect on lipid profile of daily consumption of plant sterol-enriched low-fat fermented milk (FM) is paralleled by a concomitant variation in a reliable marker of the oxidative burden like plasma isoprostane levels is unresolved.Methods and resultsThe effect of plant sterol consumption on plasma lipid and isoprostane levels of hypercholesterolemic patients was evaluated in a multicenter, randomized double blind study. Hypercholesterolemic patients consumed a FM daily for 6 weeks. Subjects were randomized to receive either 1.6 g of plant sterol-enriched FM (n = 60) or control FM product (n = 56). After 6 weeks of plant sterol-enriched FM consumption, LDL cholesterol was reduced from 166.2 ± 2.0 to 147.4 ± 2.8 mg/dL (p = 0.01). A significant reduction was observed for total cholesterol (from 263.5 ± 2.6 to 231.0 ± 3.2 mg/dL, p = 0.01). There was greater LDL cholesterol lowering among hypercholesterolemic patients with higher LDL cholesterol at baseline. We found a reduction of plasma 8-isoprostane in patients taking plant sterol-enriched FM (from 43.07 ± 1.78 to 38.04 ± 1.14 pg/ml, p = 0.018) but not in patients taking the control product (from 42.56 ± 2.12 to 43.19 ± 2.0 pg/ml, p = NS). Campesterol and β-sitosterol levels were not influenced by phytosterol consumption.ConclusionsDaily consumption of low-fat plant sterol dairy product favourably changes lipid profile by reducing LDL-cholesterol, and may also have an anti-oxidative effect through a reduction of plasma isoprostanes.     

Angiotensin II receptor antagonism with telmisartan increases number of endothelial progenitor cells in normotensive patients with coronary artery disease: A randomized,double-blind,placebo-controlled study

IntroductionCirculating endothelial progenitor cells (EPCs) provide an endogenous repair mechanism of the dysfunctional endothelium and therefore can play a crucial role in the pathophysiology of coronary artery disease (CAD). Angiotensin II receptor antagonism has been shown to be able to increase EPCs in hypertension but its effect in patients with CAD is unknown. Aim of this study was to evaluate whether telmisartan, an angiotensin II receptor antagonist, can modify the number of subpopulations of EPCs and may in turn affect the endothelial function of normotensive patients with CAD.MethodsIn a prospective double-blind parallel group study, 40 normotensive patients with CAD were randomly treated with telmisartan (80 mg) or placebo for 4 weeks at time of coronary angiography. Measurements of EPCs and assessment of flow-mediated dilatation (FMD) of the brachial artery was performed before and after therapy.ResultsAbsolute number of EPCs was similar at baseline in the telmisartan and placebo groups. After 4 weeks treatment, CD34+/KDR+/CD45? cells increased significantly in the telmisartan group (from 0.010 ± 0.003 to 0.014 ± 0.004%, P = 0.0001) but not in the placebo group (from 0.009 ± 0.004 to 0.009 ± 0.005%, NS). Similarly, CD133+/KDR+/CD45? cells raised significantly with telmisartan (from 0.003 ± 0.002 to 0.006 ± 0.002%, P = 0.0001) but not with placebo (from 0.004 ± 0.003 to 0.003 ± 0.002%, NS). Also, CD14+/CD45+ cells increased significantly with telmisartan (from 0.005 ± 0.002 to 0.008 ± 0.002%, P = 0.0001) and were unchanged with placebo (0.006 ± 0.002 vs. 0.005 ± 0.003%, NS). FMD improved significantly in patients who received telmisartan (10.4 ± 3.9%, P = 0.0015 vs. baseline) but did not change in the placebo group (5.9 ± 2.8%; P = 0.32 vs. baseline; telmisartan vs. placebo, P = 0.002). A significant positive correlation was found in the telmisartan group between the improvement in FMD and the increase in CD34+/KDR+/CD45? cells and CD133+/KDR+/CD45? cells (r = 0.55, P < 0.01, and r = 0.49, P < 0.05, respectively).ConclusionAngiotensin II receptor antagonism with telmisartan increases the number of regenerative EPCs and improves endothelial function in normotensive patients with CAD. These novel effects are interrelated and can explain, at least in part, why telmisartan has beneficial cardiovascular effects independent of its blood pressure lowering action.     

Multicentre, randomised, controlled study of the impact of continuous sub-cutaneous glucose monitoring (GlucoDay) on glycaemic control in type 1 and type 2 diabetes patients

AimThis randomised study was designed to investigate the impact of continuous glucose monitoring (CGM) for 48 h on glycaemic control with a 3-month follow-up in patients with type 1 (T1D) or type 2 (T2D) diabetes.MethodsA total of 48 patients with poor glycaemic control (HbA_1c: 8–10.5%) underwent CGM for 48 h using the GlucoDay^® system (A. Menarini Diagnostics), after which they were randomly assigned to treatment adjustments based on either their CGM profile (CGM group) or their usual self-monitoring of blood glucose (SMBG group). HbA_1c measurement and 48-h CGM were repeated 3 months later.ResultsAltogether, 34 patients with either T1D (n = 9) or T2D (n = 25) completed the study; seven patients chose to leave the study, and seven patients in the CGM group were excluded because their baseline CGM graphs were not interpretable. HbA_1c levels decreased significantly in the CGM group (n = 14, –0.63 ± 0.27%; P = 0.023), but not in the controls (n = 20, –0.28 ± 0.21%; P = 0.30). In T2D patients, the improvement associated with CGM vs SMBG was due to HbA_1c decreases (mean: –0.63 ± 0.34%; P = 0.05 vs –0.31 ± 0.29%; P = 0.18, respectively). However, HbA_1c did not change significantly with CGM in T1D patients. Comparisons of CGM data at baseline and after 3 months showed no significant changes in glucose control, glucose variability or hypoglycaemia. No major adverse events related to the GlucoDay^® system were reported.ConclusionThis is the first randomised study showing that CGM improves glycaemic control in patients with T2D.     

Relationship between serum levels of osteocalcin and atherosclerotic disease in type 2 diabetes

AimsTo analyze the relationship between serum levels of osteocalcin and parameters of atherosclerosis in patients with type 2 diabetes mellitus (T2DM).MethodsThis cross-sectional study of 78 patients with T2DM evaluated intima–media thickness, and the prevalence of coronary heart disease, atherosclerotic plaques and aortic calcifications. Serum osteocalcin levels were also determined by radioimmunoassay.ResultsThe patients’ mean age was 57.8 ± 6.4 years (duration of diabetes: 13.4 years; mean HbA_1c level: 8.01%), and 37.2% had coronary heart disease, 56% had an abnormal intima–media thickness, 26.9% had carotid plaques and 32.1% had aortic calcifications. Coronary heart disease was associated with higher levels of osteocalcin in male vs female patients (1.95 ± 1.36 vs 0.93 ± 0.86 ng/mL, respectively; P = 0.006). Also, higher concentrations of osteocalcin were found in female patients with vs without abnormal intima–media thicknesses (2.17 ± 1.84 vs 1.25 ± 0.67 ng/mL, respectively; P = 0.042), carotid plaques (2.86 ± 2.10 vs 1.43 ± 1.09 ng/mL, respectively; P = 0.03) and aortic calcifications (2.85 ± 1.97 vs 1.26 ± 0.83 ng/mL, respectively; P = 0.002). Serum osteocalcin levels were associated with coronary heart disease on multivariate logistic regression (odds ratio: 2.27, 95% confidence interval: 1.21–4.25; P = 0.01).ConclusionIn T2DM patients, serum osteocalcin levels were associated with parameters of atherosclerosis, suggesting that osteocalcin is involved not only in bone metabolism, but also in atherosclerotic disease.     

Effects of pentoxifylline on intestinal bacterial overgrowth, bacterial translocation and spontaneous bacterial peritonitis in cirrhotic rats with ascites

BackgroundProphylaxis of spontaneous bacterial peritonitis with norfloxacin has been associated to development of antibiotic resistance. We investigated whether pentoxifylline compared to norfloxacin reduces bacterial translocation and spontaneous bacterial peritonitis in rats with CCl₄-induced cirrhosis and ascites.MethodAfter development of cirrhosis and ascites, animals were randomly allocated to receive pentoxifylline (16 mg/kg/d every 8 h, oral route, n = 13) or placebo (n = 12) for 15 days. An additional group of 8 cirrhotic rats was given norfloxacin (5 mg/kg/d for 15 days). Six healthy rats served as controls. Cecal flora and the prevalence of bacterial translocation and spontaneous bacterial peritonitis were analysed. Serum and ascitic fluid levels of TNF-alpha and cecal levels of malondialdehyde were also measured.ResultsPentoxifylline in comparison to placebo reduced intestinal bacterial overgrowth (21% vs. 67%, p = 0.04), bacterial translocation to cecal lymph nodes (23% vs. 75%, p = 0.03) and prevented spontaneous bacterial peritonitis (0% vs. 33%, p = 0.04) by Enterobacteriaceae. Norfloxacin administration induced similar results. Pentoxifylline (0.18 ± 0.10 nmol/mg), but not norfloxacin (0.25 ± 0.13; p = 0.02), significantly reduced cecal mucosal levels of malondialdehyde compared to placebo (0.33 ± 0.16; p = 0.03).ConclusionIn cirrhotic rats with ascites: (a) pentoxifylline as well as norfloxacin reduced intestinal bacterial overgrowth and bacterial translocation and prevented spontaneous bacterial peritonitis; (b) pentoxifylline, but not norfloxacin, reduced oxidative stress in cecal mucosal.     

Digitoxin Prolongs Survival of Female Rats With Heart Failure Due to Large Myocardial Infarction

BackgroundWe analyzed whether digitoxin affects the survival of rats with congestive heart failure.Methods and ResultsThe influence of digitoxin (0.1 mg·100 g·day, orally) on the survival of infarcted female rats (n = 170) randomized as Control Infarcted (CI, n = 85) or Digitoxin (D, n = 85) was evaluated for 280 days. Mean survival was 235 ± 7 days for CI and 255 ± 5 days for D (log-rank test: P = .0602). Digitoxin did not affect survival in rats with congestive heart failure from myocardial infarction <40% of the left ventricle, but did prolong survival in rats with infarction ≥40%. The log-rank test defined higher mortality (P = .0161) in CI >40% (56%) than in D >40% (34%), with a hazard ratio of 2.03. Pulmonary water content and papillary muscle mechanics were analyzed in CI (n = 7) and D (n = 14) survivors. Significant differences were observed regarding pulmonary water content (CI: 82 ± 0.3; D: 80 ± 0.3%; P = .0014), developed tension (CI: 2.7 ± 0.3; D: 3.8 ± 0.3 g/mm²; P = .0286) and +dT/dt (CI: 24 ± 3; D: 39 ± 4 mg mm²·s; P = .0109).ConclusionIn conclusion, long-term digitoxin administration reduced cardiac impairment after myocardium infarction, attenuated myocardial dysfunction, reduced pulmonary congestion, and provided the first evidence regarding the efficiency of digitoxin in prolonging survival in experimental cardiac failure.     

Endothelial function and arterial stiffness in normotensive normoglycemic first-degree relatives of diabetic patients are independent of the metabolic syndrome

Background and aimThe aim of the present study was to investigate endothelial function and arterial stiffness in normotensive normoglycemic first-degree relatives (offspring) of diabetic subjects and to explore the relationship with the metabolic syndrome and its components.Methods and resultsForty-five healthy normotensive normoglycemic subjects (aged 18–42 years), 29 first-degree relatives of diabetic subjects (FDR) and 16 with no parental history of type 2 diabetes mellitus were studied. Endothelial function was measured as flow-mediated dilation of the brachial artery (FMD) and arterial stiffness as carotid-femoral pulse wave velocity (PWV). Insulin resistance was calculated by homeostasis model assessment (HOMA). Plasma levels of inflammation markers (hsCRP, TNF-α, IL-1β, CD40L, VCAM, and ICAM) were evaluated.Normotensive normoglycemic FDR presented a 33% lower flow-mediated dilation than the control group (9.8 ± 5.2 vs. 16.2 ± 7.6%, p < 0.01). FMD was reduced in FDR, with or without insulin resistance, whereas arterial stiffness was significantly increased only in FDR with insulin resistance. To investigate the role of FDR status independently of altered components of the metabolic syndrome, subjects with no altered components of the metabolic syndrome were compared according to their FDR status: FDR subjects with no altered components of the metabolic syndrome presented a blunted endothelial function (lower FMD: 11.2 ± 1.6 vs. 16.8 ± 2.0%, p < 0.05) and stiffer large arteries (higher PWV: 9.6 ± 0.3 vs. 8.8 ± 0.3 m/s, p < 0.05) than controls.ConclusionNormoglycemic first-degree relatives of diabetic subjects have blunted endothelial function and increased stiffness of the large arteries. These alterations are already present at a very young age, before any alteration in glycemic control or blood pressure values can be detected, and are independent of the presence of the metabolic syndrome and its altered components.     

A meta-analysis of randomized trials and adjusted observational studies of drug-eluting stents versus coronary artery bypass grafting for unprotected left main coronary artery disease

BackgroundAcute coronary syndrome (ACS) is an independent risk factor for late stent thrombosis which might be related to the impaired vascular healing after drug-eluting stent (DES) due to the disruption of plaques and thrombus formation. Therefore, we investigated the vascular response after various DES implantations between ACS and stable angina pectoris (SAP) using optical coherence tomography (OCT).MethodsNinety-one patients [49 ACS: 20 sirolimus-eluting (SES), 12 paclitaxel-eluting (PES) and 17 zotarolimus eluting stent (ZES) and 42 SAP: 15 SES, 12 PES and 15 ZES] underwent OCT at 9 months after stent implantation. Neointimal coverage and malapposition were evaluated in 21,939 struts in 2269-mm stented segments.ResultsIn the ACS group, the incidence of uncovered and malapposed struts was significantly higher (8.9 ± 13.7 vs 2.9 ± 6.2%, p = 0.01 and 2.2 ± 5.6 vs 0.5 ± 2.0%, p = 0.02). Among the three DESs tested, SES showed a significantly higher rate of uncovered struts in the ACS group (17.3 ± 13.4 vs 4.4 ± 6.2%, p = 0.003). PES had a trend toward higher rate of uncovered and malapposed struts in the ACS groups (6.7 ± 7.6 vs 4.0 ± 9.0%, p = 0.13) while ZES was similar in both groups.ConclusionThe patterns of neointimal coverage and malapposition at 9 months after DES implantation were different between ACS and SAP, and variable among the DES type between two groups. Therefore, the present study suggests that vascular response after DES implantation might be influenced by both clinical presentation and type of DES.     

Inflammatory cytokines in insulin-treated patients with type 2 diabetes

ObjectiveAn association between type 2 diabetes mellitus and inflammation has been described in several studies. The aim of this study was to search for the presence of low-grade inflammation in a special group of insulin-treated patients with type 2 diabetes, and to investigate a possible correlation between inflammation and obesity, glucose homeostasis and insulin requirement (IU insulin/kg body weight, BW).MethodsWe studied 85 subjects with type 2 diabetes that were receiving insulin treatment (group A) and 32 receiving sulfonylurea treatment (group B), and 57 subjects without diabetes (group C). Interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α), and the soluble TNF-α receptors sTNFR-60 and sTNFR-80 were measured in serum samples taken from all patients.ResultsThe mean serum cytokine levels in group A vs. group B were: IL-6, 8.54 ± 11 vs. 2.71 ± 1.9 pg/ml (p = 0.000); TNF-α, 14.33 ± 24 vs. 5.12 ± 15 pg/ml (p = 0.016); sTNFR60, 3.9 ± 2.8 vs. 2.36 ± 1.4 ng/ml (p = 0.000); and sTNFR80, 11.9 ± 7 vs. 9.4 ± 6 ng/ml (p = 0.080). The mean serum cytokine levels in group A vs. group C were: IL-6, 8.54 ± 11 vs. 4.74 ± 7 pg/ml (p = 0.017); TNF-α, 14.33 ± 24 vs. 5.94 ± 3.4 pg/ml (p = 0.003); sTNFR60, 3.9 ± 2.8 vs. 2.54 ± 1.4 ng/ml (p = 0.000); and sTNFR80, 11.9 ± 7 vs. 10.85 ± 8 ng/ml (p = 0.470). A positive association between waist circumference and IL-6 (r = 0.165, p = 0.030) and sTNFR-60 (r = 0.276, p = 0.000) was detected. A significant correlation coefficient was observed between haemoglobin A1c (HbA1c) and both IL-6 (r = 0.278, p = 0.000) and sTNFR-60 (r = 0.293, p = 0.000), when the groups were studied as one. No correlation between inflammation and units of insulin/kg BW was found. In conclusion, low-grade chronic inflammation, as estimated by the relative levels of inflammatory cytokines, was present in patients with type 2 diabetes that were receiving insulin treatment, with significantly higher cytokine levels recorded compared to sulfonylurea-treated patients. In addition, an association between inflammation and both obesity and glucose homeostasis was detected.