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.
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.
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.
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.
Endothelial function deteriorates after glucose ingestion. This may be attributed to hyperglycemia-induced oxidative stress. Acute endurance exercise might improve postprandial endothelial function by enhancing glucoregulation and reducing postprandial hyperglycemia.
To determine if endurance exercise performed 17h prior to high-sugar food ingestion attenuates postprandial impairment in endothelial function.
Healthy men and women (n=13; age: 48±17y) were studied on 2 occasions: after ≥48h with no exercise (CON) and 17h after a 60-min bout of endurance exercise (EX). During each trial, brachial artery flow-mediated dilation (FMD) was used to assess endothelial function before and after the ingestion of a candy bar and soft drink. Glucose, insulin, and thiobarbiturate reactive substances (TBARS), as a marker of oxidative stress, were measured in blood obtained during each FMD measurement. Insulin sensitivity index (ISI) was calculated from the glucose and insulin data.
FMD decreased significantly after food ingestion in both trials. However, prior exercise shifted the entire FMD curve upward (main treatment effect: p=0.0002), resulting in a greater area under the curve for FMD (774±122 vs. 607±122 % · min, p=0.01). Prior exercise shifted the glucose and insulin curves downward (main treatment effects: p=0.05 and p=0.0007, respectively) and increased ISI (10.8±0.7 vs. 9.2±0.7, p=0.01). TBARS did not differ between trials.
Postprandial endothelial function was improved by endurance exercise performed ~17 hours earlier. This effect was accompanied by exercise-induced improvements in insulin action and reductions in glycemia but did not correspond with reductions in oxidative stress, as assessed by TBARS.
endothelial function; acute exercise; postprandial; hyperglycemia
Alpha glucosidase inhibitor (GI) attenuates postprandial hyperglycemia (PPH) and reduces the risk of cardiovascular events in patients with impaired glucose tolerance or type 2 diabetes. Dipeptidyl peptidase 4 (DPP-4) inhibitors also attenuate PPH. PPH is one of the factors leading to endothelial dysfunction which is an early event in the pathogenesis of atherosclerosis. Furthermore, DPP-4 inhibitors protect endothelial function through a GLP-1-dependent mechanism. However, the impact of these two types of drugs on endothelial dysfunction in patients with type 2 diabetes has not been fully elucidated. We compared the effects of sitagliptin, a DPP-4 inhibitor, and voglibose, an alpha GI, on endothelial function in patients with diabetes.
We conducted a randomized prospective multicenter study in 66 patients with type 2 diabetes who did not achieve the treatment goal with sulfonylurea, metformin or pioglitazone treatment; 31 patients received sitagliptin treatment and 35 patients, voglibose treatment. The flow-mediated dilatation (FMD) of the brachial artery was measured in the fasting state at baseline and after 12 weeks of treatment. The primary endpoint was a change in FMD (ΔFMD) from the baseline to the end of follow-up. The effects of sitagliptin and voglibose on FMD were assessed by ANCOVA after adjustment for the baseline FMD, age, sex, current smoking, diabetes duration and body mass index. Secondary efficacy measures included changes in HbA1c, GIP, GLP-1, C-peptide, CD34, lipid profile, oxidative stress markers, inflammatory markers and eGFR and any adverse events.
ΔFMD was significantly improved after 12 weeks of treatment in both groups, and there was no significant difference in ΔFMD between the two groups. There were no significant differences in changes in HbA1c, GIP, GLP-1, C-peptide, lipid profile, oxidative stress marker, inflammatory marker and eGFR between the two groups. Compared with voglibose, sitagliptin significantly increased the circulating CD34, a marker of endothelial progenitor cells. Adverse events were observed in 5 patients in only the voglibose group (diarrhea 1, nausea 1, edema 2 and abdominal fullness 1).
Sitagliptin improved endothelial dysfunction just as well as voglibose in patients with type 2 diabetes. Sitagliptin had protective effects on endothelial function without adverse events.
registered at http://www.umin.ac.jp/ctrj/ under UMIN000003951
Dipeptidyl peptidase 4 (DPP-4) inhibitors; Alpha glucosidase inhibitor; Endothelial function; Flow-mediated dilatation; CD34
Postprandial hyperlipidemia impairs endothelial function and participates in the development of atherosclerosis. We investigated the postprandial effects of a dipeptidyl peptidase IV inhibitor, alogliptin, on endothelial dysfunction and the lipid profile.
A randomized cross-over trial design in 10 healthy volunteers (8 males and 2 females, 35 ± 10 years) was performed. The postprandial effects before and after a 1-week treatment of 25 mg/day alogliptin on endothelial function were assessed with brachial artery flow-mediated dilation (FMD) and changing levels of lipids, apolipoprotein B48 (apoB-48), glucose, glucagon, insulin, and glucagon-like peptide-1 (GLP-1) during fasting and at 2, 4, 6, and 8 h after a standard meal loading test.
Alogliptin treatment significantly suppressed the postprandial elevation in serum triglyceride (incremental area under the curve [AUC]; 279 ± 31 vs. 182 ± 32 mg h/dl, p = 0.01), apoB-48 (incremental AUC; 15.4 ± 1.7 vs. 11.7 ± 1.1 μg h/ml, p = 0.04), and remnant lipoprotein cholesterol (RLP-C) (incremental AUC: 29.3 ± 3.2 vs. 17.6 ± 3.3 mg h/dl, p = 0.01). GLP-1 secretion was significantly increased after alogliptin treatment. Postprandial endothelial dysfunction (maximum decrease in%FMD, from −4.2 ± 0.5% to −2.6 ± 0.4%, p = 0.03) was significantly associated with the maximum change in apoB-48 (r = −0.46, p = 0.03) and RLP-C (r = −0.45, p = 0.04).
Alogliptin significantly improved postprandial endothelial dysfunction and postprandial lipemia, suggesting that alogliptin may be a promising anti-atherogenic agent.
Dipeptidyl peptidase IV inhibitor; Postprandial lipid; Triglyceride-rich lipoprotein; Endothelial dysfunction; Alogliptin
Impaired glucose tolerance (IGT) is associated with increased cardiovascular risk. The pathophysiological mechanisms linking post-challenge hyperglycemia to accelerated atherosclerosis, however remain to be elucidated.
A prospective, open, randomised, cross-over study was performed to investigate the effect of 2 mg repaglinide on hyperglycemia and endothelial function during an oral glucose tolerance test (75 g glucose) in 12 subjects with diagnosed IGT. Blood samples for determination of plasma glucose were drawn fasting, 1 and 2 hours after glucose ingestion. Endothelial function was assessed by measuring flow-mediated dilatation (FMD) of the brachial artery with high-resolution ultrasound.
Administration of repaglinide resulted in a significant reduction of plasma glucose at 2 hours (172.8+/-48.4 vs. 138.3+/-41.2 mg/dl; p < 0.001). The flow-mediated dilatation (FMD) 2 hours after the glucose-load was significantly reduced in comparison to fasting in the control group (6.21+/-2.69 vs. 7.98+/-2.24 %; p = 0.028), whereas after theadministration of repaglinide the FMD was not significantly different to fasting values (7.24+/-2.57 vs. 8.18+/-2.93 %; p = n.s.). Linear and logistic regression analysis revealed that only the change of glucose was significantly correlated to the change of FMD observed (p < 0.001). Regression analysis after grouping for treatment and time confirmed the strong negative association of the changes of plasma glucose and FMD and indicate that the effect of repaglinide observed is based on the reduction glycemia.
In subjects with IGT, the endothelial dysfunction observed after a glucose challenge is related to the extent of hyperglycemia. Reduction of hyperglycemia by repaglinide reduces endothelial dysfunction in a glucose dependent manner.
The association of prediabetic states with endothelial dysfunction measured by flow‐mediated dilation (FMD) or endothelial biomarker levels remains controversial. We examined data from 5 ethnic groups to determine the association between glucose categories and FMD or endothelial biomarkers. We determined whether these associations vary by ethnic group or body mass index.
Methods and Results
We used data from 3516 participants from 5 race/ethnic groups with brachial FMD, endothelial biomarkers, and glucose category (normal, impaired fasting glucose [IFG], and diabetes) measures. There were significant ethnic differences in FMD, biomarker levels, and the prevalence of IFG and diabetes. However, all 5 ethnic groups showed similar patterns of higher FMD for the IFG group compared with the normal glucose and diabetes groups, which was most significant among whites and Asian Indians. Associations between glucose categories and endothelial biomarkers were more uniform, with the IFG and diabetes groups having higher biomarker levels than the normal glucose group. These associations did not change with further adjustment for fasting insulin levels. Whites with normal BMI had higher FMD values with higher glucose levels, but those with BMI in the overweight or obese categories had the inverse association (P for interaction=0.01).
The discordance of IFG being associated with higher FMD but more abnormal endothelial biomarker levels is a novel finding. This higher FMD for the IFG group was most notable in whites of normal BMI. The higher FMD among those with impaired fasting glucose may reflect differences in insulin signaling pathways between the endothelium and skeletal muscle.
biomarkers; diabetes; endothelium; ethnicity; insulin resistance
Postprandial hypertriglyceridemia impairs endothelial function and plays an important role in the development of atherosclerosis. The aim of the present study was to examine the postprandial effects of the dipeptidyl peptidase-4 inhibitor vildagliptin and the α-glucosidase inhibitor voglibose on endothelial dysfunction and lipid profiles following a single administration. A randomized cross-over trial using 11 normoglycemic individuals was performed. The postprandial effects of a single administration of vildagliptin (50 mg) or voglibose (0.3 mg) on endothelial function were analyzed using brachial artery flow-mediated dilation (FMD) and lipid profiles during fasting and 1.5 and 3 h after an oral cookie-loading test. Compared with voglibose, vildagliptin significantly suppressed postprandial endothelial dysfunction, (%FMD, −1.6±0.9 vildagliptin vs. −4.0±0.7 voglibose; P=0.01) and the postprandial incremental increase in the triglyceride level (28±18 vildagliptin vs. 51±26 mg/dl voglibose; P=0.01) 3 h after a cookie-loading test. In addition, vildagliptin significantly increased the levels of glucagon-like peptide-1 compared with voglibose 3 h after a loading cookie test (4.4±0.6 vs. 2.9±0.7 pmol/l, respectively; P=0.04). No significant differences in the levels of glucose, apolipoprotein B-48, glucagon or insulin were observed between vildagliptin and voglibose treatments. In conclusion, a single administration of vildagliptin attenuated postprandial endothelial dysfunction and postprandial hypertriglyceridemia, suggesting that vildagliptin may be a promising antiatherogenic agent.
endothelial function; postprandial lipemia; dipeptidyl peptidase 4
Presence of Diabetes Mellitus increases the risk of subclinical atherosclerosis. In this study was aimed to determine the influence of hypertension (HTN) on surrogate markers of atherosclerosis in a population of patients with early type 2 diabetes.
125 diabetic subjects drawn from Dr. Shariati outpatient’s clinic list and 153 non- diabetic subjects who were the relatives in law of diabetic participants were recruited. Participants with type 2 diabetes were free of clinical evidence of cardiovascular disease and renal involvement. Two groups of diabetic and control were further divided into two subgroups of hypertensive (known case of HTN or blood pressure ≥140/90 mmHg) and normotensive, and anthropometric characteristics, metabolic biomarkers as well as markers of subclinical atherosclerosis including Carotid intima media thickness (CIMT), flow mediated dilation (FMD) and Ankle Brachial Index (ABI) were measured.
Diabetic group with a mean age of 49.9 ± 7.5 years had significantly higher CIMT (0.64 ± 0.14 vs 0.76 ± 0.19, p = 0.001) and lower FMD (16.5 ± 8.1 vs 13.3 ± 7.1, p = 0.003) and ABI (1.2 ± 0.1 vs 1.1 ± 0.1, p = 0.01) than control with mean age of 52.9 ± 10.1 years. 34% of control and 59.2% of diabetic were hypertensive. Fasting blood sugar, insulin levels and calculated insulin resistance index of HOMA IR. of hypertensive subjects were higher than normotensive subjects in both groups of diabetic and non-diabetic. Similar pattern was presented for measured inflammatory mediators of hs-CRP and IL-6. Among subclinical atherosclerosis markers, only CIMT was significantly different between hypertensive and normotensive subjects in both groups. In adjusted linear regression analysis, a constant significant association existed between age and CIMT, ABI and FMD in non-diabetic, while in diabetic, age only correlated with CIMT and not the other two markers. In multiple regression model, HTN was recognized as a risk factor for increasing CIMT (OR = 2.93, 95% CI = 1.03-8.33, p = 0.04) but not attenuating FMD or ABI.
Since FMD and CIMT may measure a different stage of subclinical atherosclerosis in diabetic patients, influence of HTN on these markers might be different.
Diabetes melitus; Subclinical atherosclerosis; CIMT; FMD; ABI; Hypertension
Arterial and venous thrombosis have always been regarded as different pathologies and epidemiological studies have examined the association between venous thrombosis and indicators of atherosclerosis and/or arterial thromboembolic events. We measured the flow-mediated dilation (FMD), a well-known marker of arterial endothelial dysfunction, in young–middle-aged and old-aged patients with and without unprovoked deep venous thrombosis (DVT). The aim of this study was to investigate whether DVT was a significant predictor for impaired FMD, considering all the patients and young–middle-aged (age < 65 years) and old-aged (age ≥ 65 years) patients separately. FMD was measured in the brachial artery on a population of 120 subjects with the same atherosclerosis risk factors, 68 male and 52 female, 70 young–middle-aged subjects (mean age ± SD 49.5 ± 10.5 years) and 50 old-aged subjects (76.2 ± 7.7 years). Patients with DVT showed a significant decrease of FMD compared to patients without DVT (6.8 ± 5.5% vs. 10.9 ± 3.5%, p < 0.001). Moreover, old-aged patients showed a significant decrease of FMD compared to the young–middle-aged subjects (7.4 ± 4.1% vs. 9.8 ± 5.3%, p = 0.005). In the whole study population, DVT was strongly associated with FMD (risk factors adjusted β = −4.14, p < 0.001). A significant interaction between age and the presence of DVT on predicting FMD was found (p = 0.003) suggesting a differential behavior of DVT as predictor of FMD. In young–middle-aged group, multivariate model confirmed that DVT was the most significant predictor of continuous FMD (β = −6.06, p < 0.001). On the contrary, DVT was no more a predictor of FMD in the old age group (β = −0.73, p=0.556). Furthermore, old-aged patients without DVT showed a statistically significant decrease of FMD compared to the young–middle-aged subjects without DVT (8.2±2.1% vs. 12.6±2.7%, p<0.001) and old-aged patients with DVT showed a not statistically significant decrease of the FMD compared to the young–middle-aged patients with DVT (6.7±5.3% vs. 6.8±5.7%, p = 0.932). In conclusion, young–middle-aged patients with spontaneous DVT show an impaired FMD, whereas this impairment in old-aged subjects is evident independently from the presence or absence of DVT. Aging per se may be associated with physiologic abnormalities in the systemic arteries and with endothelial dysfunction.
Endothelial dysfunction; Venous thrombosis; Atherosclerosis; Flow-mediated dilation; Aging; Life Sciences; Molecular Medicine; Geriatrics/Gerontology; Cell Biology
To study the effect of exercise and a high fat meal (HFM) on endothelial function.
Postprandial lipemia and exercise oppose each other in terms of cardiovascular risk, however the mechanism of their interaction is not well understood.
Endothelial function was assessed by brachial artery flow mediated dilation (FMD), in eight healthy men before and after a HFM preceded (16–18 hrs) by rest, a single bout of continuous moderate intensity exercise (CME), and high intensity interval exercise (HIIE).
Before the HFM, initial brachial artery diameters were similar in all trials (0.43±0.04 cm), but after the HFM basal diameter decreased only in the control (0.39±0.03) and CME (0.38±0.04) trials. Prior to the HFM, FMD/shear was improved by a single bout of CME (+20%, p<0.01) and HIIE (+45%, p<0.01, group differences, p<0.01), with no effect in the control trial. After the HFM (30, 120, and 240 mins), FMD decayed to a lesser extent with CME, but in a similar fashion to the control trial. In contrast FMD in the HIIE trial remained elevated following the exercise despite a clear meal-induced lipemia. Although, there were no correlations between vascular function and food-induced markers of cardiovascular risk, antioxidant status was strongly correlated with FMD (r=0.9, p<0.001).
These findings reveal a clinically relevant protective effect of acute exercise upon the vasculature that is clearly exercise intensity dependent and tightly related to exercise-induced antioxidant capacity.
Interval training; endothelial function; high-fat meal
The aim of this study was to compare the effects of nateglinide and acarbose on glycemic excursions and postprandial glucose profiles with different types of meals (standardized carbohydrate and mixed meals) in drug-naïve type 2 diabetic patients. A randomized, parallel-group prospective design clinical trial was conducted and a total of 39 drug-naïve patients (16 males and 23 females, aged 56.7±10.2 years) were enrolled. The patients were randomly divided into group A [nateglinide 120 mg three times daily (t.i.d.), n=19] and group B (acarbose 50 mg t.i.d., n=20). The standardized carbohydrate and mixed-meal tests were performed at baseline and at the end of study. Continuous glucose monitoring system (CGMS) data were recorded. Various parameters that measure glucose variability were derived from the CGMS data. In the standardized carbohydrate meal tests, the postprandial glucose excursions (PPGEs) were significantly decreased in the two groups after 12 weeks of treatment (P<0.05), whereas the decrease was more prominent in the acarbose compared to the nateglinide group (P=0.138). In the mixed-meal tests, the mean sensor glucose values [24-h mean blood glucose (MBG)] were significantly decreased in the two groups after 12 weeks of treatment (P<0.05) and the parameters of glucose excursions, including standardized deviation (SD), largest amplitude of glycemic excursion (LAGE), mean of daily differences (MODD) and mean amplitude of glycemic excursion (MAGE), were reduced in the two groups. However, the decreases in SD and LAGE in the nateglinide group were statistically significant, whereas in the acarbose group only the decreases in LAGE were statistically significant. The efficiency of nateglinide or acarbose in lowering postprandial 120-min hyperglycemia were similar in the standardized carbohydrate meal test. However, acarbose was more efficient in lowering postprandial 30- and 60-min hyperglycemia (P<0.05) compared to nateglinide. The fasting and postprandial total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) had a tendency to decrease from the baseline after 12 weeks of treatment with nateglinide, whereas fasting and postprandial high-density lipoprotein cholesterol (HDL-C) had a tendency to increase. Acarbose did not affect the fasting or postprandial lipid profiles after 12 weeks of treatment (P>0.05). In conclusion, nateglinide and acarbose effectively improved postprandial glycemic control, although acarbose was shown to be more efficient in controlling early (30 and 60 min) postprandial glucose excursions in the carbohydrate meal test, whereas nateglinide was shown to be superior to acarbose in controlling postprandial glucose excursions in the mixed-meal test.
type 2 diabetes mellitus; glycose excursion; postprandial glucose; acarbose; nateglinide
Endothelial dysfunction is an independent predictor of future cardiac events.
We evaluated the relationship between flow-mediated dilation (FMD) in brachial artery and coronary risk factors in 93 patients (70 males, mean age: 62±8 years) with ACS treated with primary angioplasty (PCI). The patients were divided into 2 subgroups: 43 patients with diabetes mellitus type 2 (DM) and 50 non-diabetics (non-DM). Patients were examined on the 3rd day after ACS and after 6 months. FMD on the 3rd day were significantly lower in DM than in non-DM (5.8±2.2% vs. 8.8±4.9%, p=0.0007) and after 6 months (6.2±2.6% vs. 9.4±4.4%, p<0.0001). It was also observed that the improvement of FMD in both groups after a 6-month follow-up inversely correlated with the increase of left ventricular end-diastolic volume (LVEDV) (r=−0.41, p<0.001).
There was an inverse relationship between FMD and age (r=−0.26, p<0.01), BMI (r=−0.26, p<0,005), total cholesterol (r=−0.56, p<0.001) and LDL cholesterol (r=−0.53, p<0.001). There was no relationship between triglycerides, hypertension and history of smoking. In the DM group, FMD negatively correlated with HbA1c (r=−0.68, p<0.001). Restenosis rate was significantly higher in the DM group (19% vs. 6%, p<0.001) but there was no relationship between FMD and restenosis.
Impaired FMD is more significant in diabetics than in non-diabetic patients with ACS. Lack of improvement of FMD after acute coronary syndrome can be a predictor of detrimental left ventricular remodeling in patients with ACS.
flow-mediated dilatation; endothelium; diabetes mellitus; acute coronary syndrome; left ventricular remodeling
To investigate the effect of an exercise intervention on flow-mediated dilation (FMD) and circulating endothelial biomarkers in adults with type 2 diabetes (T2DM)
Sedentary adults (n=140), aged 40–65, with T2DM and untreated pre- or Stage I hypertension or treated hypertension were randomized to a 6-month, supervised, exercise program (3×week) or a sedentary control. Assessments included BMI, body and visceral fat, blood pressure, lipids, HbA1c, insulin sensitivity (QUICKI), fitness, FMD, E-selectin, P-selectin, intracellular and vascular cellular adhesion molecules (ICAM, VCAM), and tissue plasminogen activator (tPA). Intervention effects were compared by t-tests. Pearson’s correlations were calculated between changes in cardiovascular risk factors and endothelial outcomes.
Exercisers significantly improved BMI (−0.6 kg/m2), body fat % (−1.4%), HbA1c (−0.5%), and fitness (2.9 mL/kg·min) vs. controls (p<0.05). However, there were no differences between groups in changes in FMD, E-selectin, P-selectin, ICAM, VCAM, or tPA. Among exercisers, changes in cardiovascular risk factors correlated with several biomarkers. Decreased P-selectin correlated with decreased BMI (r=0.29, p=0.04) and increased HDL cholesterol (r=−0.36, p=0.01). Decreased ICAM correlated with decreased triglycerides and HbA1c (r=0.30, p=0.04; r=0.31, p=0.03) and increased QUICKI (r=−0.28, p=0.05). Decreased tPA correlated with decreased total body and visceral fat (r=0.28, p=0.05; r=0.38, p=0.008) and increased QUICKI (r=−0.38, p=0.007).
While exercise resulted in improved fitness, body composition, and glycemic control, there were no changes in FMD or circulating endothelial biomarkers. The associations of changes in cardiovascular risk factors and endothelial biomarkers suggest that improvement in risk factors could mediate the exercise-induced improvements in endothelial function seen in prior studies.
Endothelial function; adhesion molecules; exercise; type 2 diabetes; vasodilation
Postprandial elevation of triglyceride-rich lipoproteins impairs endothelial function, which can initiate atherosclerosis. We investigated the effects of bezafibrate on postprandial endothelial dysfunction and lipid profiles in patients with metabolic syndrome.
Ten patients with metabolic syndrome were treated with 400 mg/day bezafibrate or untreated for 4 weeks in a randomized crossover study. Brachial artery flow-mediated dilation (FMD) and lipid profiles were assessed during fasting and after consumption of a standardized snack. Serum triglyceride and cholesterol contents of lipoprotein fractions were analyzed by high-performance liquid chromatography.
Postprandial FMD decreased significantly and reached its lowest value 4 h after the cookie test in both the bezafibrate and control groups, but the relative change in FMD from baseline to minimum in the bezafibrate group was significantly smaller than that in the control group (-29.0 ± 5.9 vs. -42.9 ± 6.2 %, p = 0.04). Bezafibrate significantly suppressed postprandial elevation of triglyceride (incremental area under the curve (AUC): 544 ± 65 vs. 1158 ± 283 mg h/dl, p = 0.02) and remnant lipoprotein cholesterol (incremental AUC: 27.9 ± 3.5 vs. 72.3 ± 14.1 mg h/dl, p < 0.01). High-performance liquid chromatography analysis revealed that postprandial triglyceride content of the chylomicron and very low-density lipoprotein fractions was significantly lower in the bezafibrate group than in the control group (p < 0.05).
Bezafibrate significantly decreased postprandial endothelial dysfunction, and elevations of both exogenous and endogenous triglycerides in patients with metabolic syndrome, suggesting that bezafibrate may have vascular protective effects in these patients.
Clinical trial registration
Unique Identifiers: UMIN000012557
Atherosclerosis; Bezafibrate; Triglyceride; Endothelium; Vasodilation
A low-carbohydrate diet (LCD) achieves good glycemic control in type 2 diabetes (T2DM) compared with a high-carbohydrate diet. With respect to energy metabolism, acute metabolic responses to high-carbohydrate meals (HCMs) have not been determined in LCD patients with T2DM.
Subjects and methods
We enrolled 31 subjects with T2DM (mean age: 62 yrs, mean hemoglobin A1c level: 6.9%), of whom 13 were on a strict LCD (26% carbohydrate diet), and 18 a moderate one (44% carbohydrate diet). Two isocaloric meals were administered to all subjects in a randomized crossover design. The carbohydrate:protein:fat ratios of HCMs and low-carbohydrate meals (LCMs) were 59:20:21 and 7:20:73, respectively. Serum β-hydroxybutyrate, acetoacetate, free fatty acids (FFAs), triglyceride and insulin, and plasma glucose concentrations were measured for 120 minutes after the intake of each meal.
HCMs rapidly decreased postprandial β-hydroxybutyrate, acetoacetate and FFA concentrations within 2 hours in all patients in combination with rapid increases in serum insulin and plasma glucose, while LCMs increased or did not change β-hydroxybutyrate, acetoacetate and FFAs (P < 0.001 for all). HCMs did not change postprandial triglyceride concentrations over 2 hours, while LCMs gradually increased them (P < 0.001).
HCMs sharply and rapidly decreased postprandial β-hydroxybutyrate and acetoacetate concentrations in strict LCD subjects over 2 hours, but only slightly decreased them in moderate LCD subjects (P < 0.001, difference between strict and moderate LCD subjects). The parameter Δketone bodies (level at 120 minutes - level at baseline) was significantly correlated with the insulinogenic index (Spearman's r = 0.503 for β-hydroxybutyrate and 0.509 for acetoacetate), but not with total insulin secretory capacity. Moreover, HCMs slightly decreased postprandial triglyceride levels in strict LCD subjects but somewhat increased them in the moderate LCD subjects (P = 0.002). The parameter Δtriglyceride was significantly correlated with background dietary %carbohydrate (Spearman's r = 0.484).
HCMs rapidly decreased postprandial ketone body concentrations in T2DM patients treated with a LCD. The decreases were more remarkable in strict than in moderate LCD subjects. HCMs slightly decreased postprandial triglyceride levels in strict LCD subjects. The parameter Δketone bodies was significantly correlated with the insulinogenic index, as was Δtriglyceride with background dietary %carbohydrate.
Hyperglycemia and elevated free fatty acids (FFA) are implicated in the development of endothelial dysfunction. Infusion of soy-bean oil-based lipid emulsion (Intralipid®) increases FFA levels and results in elevation of blood pressure (BP) and endothelial dysfunction in obese healthy subjects. The effects of combined hyperglycemia and high FFA on BP, endothelial function and carbohydrate metabolism are not known. Twelve obese healthy subjects received four random, 8-h IV infusions of saline, Intralipid 40 mL/h, Dextrose 10% 40 mL/h, or combined Intralipid and dextrose. Plasma levels of FFA increased by 1.03±0.34 mmol/L (p=0.009) after Intralipid, but FFAs remained unchanged during saline, dextrose, and combined Intralipid and dextrose infusion. Plasma glucose and insulin concentrations significantly increased after dextrose and combined Intralipid and dextrose (all, p<0.05) and were not different from baseline during saline and lipid infusion. Intralipid increased systolic BP by 12±9 mmHg (p<0.001) and diastolic BP by 5±6 mmHg (p=0.022), and decreased flow-mediated dilatation (FMD) from baseline by 3.2%±1.4% (p<0.001). Saline and dextrose infusion had neutral effects on BP and FMD. The co-administration of lipid and dextrose decreased FMD by 2.4%±2.1% (p=0.002) from baseline, but did not significantly increase systolic or diastolic BP. Short-term Intralipid infusion significantly increased FFA and BP; in contrast, FFA and BP were unchanged during combined infusion of Intralipid and dextrose. Combined Intralipid and dextrose infusion resulted in endothelial dysfunction similar to Intralipid alone.
We examined the relationship of several cardiovascular risk factors (CVRF) to brachial artery flow-mediated dilatation (FMD) in Chinese subjects.
This was a cross-sectional study. In 2,511 Chinese adults (age 46.86±9.52 years, 1,891 men and 620 women) recruited from people who underwent health screening at The Third Xiangya Hospital, patients’ CVRF [age, body mass index (BMI), waist circumference (WC), blood pressure (BP), cholesterol parameters, creatinine (Cr), uric acid (UA), glucose level and smoking] and prevalence of present disease (hypertension, diabetes mellitus, coronary heart disease and hyperlipidemia) were investigated.
Multivariate analysis revealed that FMD negative correlated with age (β=–0.29, P<0.001), gender (β=–0.12, P<0.001), BMI (β=–0.12, P=0.001), WC (β=–0.10, P=0.011), systolic BP (SBP) (β=–0.12, P<0.001), fasting glucose (β=–0.04, P=0.009), total cholesterol (TC) (β=–0.04, P=0.014), smoking (β=–0.05, P=0.003), and baseline brachial artery diameter (β=–0.35, P<0.001). FMD decreased with increasing age in both genders. In women, FMD was higher than men and age-related decline in FMD was steepest after age 40; FMD was similar in men above 55 years old.
In Chinese subjects, FMD may be a usefully marker of CVRF. Age, gender, BMI, WC, SBP, fasting glucose, TC, smoking, and baseline brachial artery diameter were independent variables related to the impairment of FMD. The influence of CVRF on endothelial function is more in women than men.
Endothelial function; brachial artery flow-mediated dilatation (FMD); cardiovascular risk factors (CVRF)
The aim of this study was to evaluate the functional changes of the arterial endothelium and smooth muscle after a high-voltage electrical injury (HVEI), using flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD).
Twenty-five male patients injured in the upper extremities by current due to contact with more than 20,000 volts were enrolled in the study. FMD and NMD were measured on the brachial artery within 48 hours after HVEI, and follow-up FMD and NMD were evaluated six weeks later. In addition, we enrolled an age, sex and body mass index matched healthy control group consisting of 25 individuals. Including FMD and NMD, all the variables of the control group were investigated one time and compared with the initial and six week follow-up data of the HVEI group.
A significantly lower initial FMD was seen in the HVEI group compared with the control group (2.1 ± 1.2% versus 13.6 ± 3.4%, P < 0.01). At the six week follow-up, the FMD of the HVEI group had significantly improved compared to the initial FMD (2.1 ± 1.2% versus 5.1 ± 2.1%, P < 0.01), but it was still lower than the FMD of the control group (5.1 ± 2.1% versus 13.6 ± 3.4%, P < 0.01). A significantly lower NMD was seen both initially and at the six week follow-up compared with the NMD of the control group (7.3 ± 4.7% versus 20.4 ± 4.1%, P < 0.01 and 11.4 ± 6.7% versus 20.4 ± 4.1%, P < 0.01, respectively). The FMD study of the contralateral arm which was uninjured by HVEI was available in six patients. In those patients, the six week follow-up FMD was significantly improved in the HVEI arm compared with the initial FMD (1.8 ± 0.6% versus 4.4 ± 1.6%, P < 0.01). However, in the contralateral uninjured arm, there was no difference between the initial and the six week follow-up FMDs (5.5 ± 1.4% versus 6.9 ± 2.2%, P = 0.26).
After HVEI, the endothelial and smooth muscle functions of the brachial artery were significantly decreased for at least six weeks. Long term cautious care might be needed for all victims of HVEI, because there is a chance of increased risk of thrombosis or stenosis in the injured arm.
high-voltage electrical injury; endothelium; smooth muscle; arterial function; flow-mediated dilation; nitrate-mediated dilation
The variability of postprandial plasma glucose is an independent risk factor for diabetes. The type and amount of carbohydrate may be important determinants of glycemic control. The aim of the study was to compare the effects of different proportions of carbohydrate in breakfast on postprandial blood glucose fluctuations in impaired glucose regulation (IGR) and normal glucose tolerance (NGT) subjects.
Subjects and Methods
This is a cross-sectional study of two groups including 55 subjects with IGR and 78 individuals with NGT. Their recorded breakfast was sorted into low-carbohydrate (LC) (carbohydrate <45%), medium-carbohydrate (MC) (carbohydrate 45–65%), and high-carbohydrate (HC) (carbohydrate >65%) meals according to the proportion of carbohydrate. Glucose concentrations were continuously measured with a continuous glucose monitoring system, and parameters such as the incremental area under the curve (iAUC) of glucose and postprandial glucose excursion (PPGE) were calculated to evaluate postprandial glucose fluctuations.
The postprandial fluctuations of glucose increased gradually with increased proportions of carbohydrate in breakfast in both IGR and NGT subjects. For the MC and HC meals, iAUC, PPGE, postprandial glucose spike (PGS), and mean blood glucose were significantly greater than those in the NGT group (P<0.05), respectively. The median time to PGS and the time period in which glucose concentrations decreased to baseline after the MC and HC meals in the IGR group were significantly longer than those in the NGT group (P<0.01), respectively. Compared with the NGT subjects for the HC meal, the IGR subjects consuming the MC meal had greater PGS, range of glucose concentrations, SD, and PPGE (P<0.05).
The proportion of carbohydrate in breakfast contributes to glucose excursions in the NGT and IGR subjects. In the IGR subjects, a HC meal should be avoided and a LC meal should be recommended to prevent development of diabetes.
Women with polycystic ovary syndrome (PCOS) may represent a large underappreciated segment of female population who is at increased cardiovascular risk because of the presence of cluster of metabolic abnormalities. The aim of our study was to assess atherosclerotic risk factors in women with PCOS.
Materials and Methods:
In a cross-sectional study, 50 women with PCOS and 50 age and weight-matched healthy controls were enrolled. Endothelial dysfunction by flow-mediated dilatation (FMD) of brachial artery, highly sensitive C-reactive protein (hs CRP), and carotid intima media thickness (CIMT) were measured in both cases and control groups.
The mean age of women with PCOS was 26.82 ± 3.26 years and Body-mass index (BMI) of 26.2 ± 4.8 kg/ m2. Thirty-six (72%) patients were overweight or obese,54% had central obesity and 12% had impaired glucose tolerance. Among the markers of atherosclerosis, hsCRP levels were nonsignificantly higher in patients with PCOS than in controls. The FMD was 12.18 ± 2.3% vs 8.3 ± 2.23% in patients with PCOS and controls respectively (P=0.01). CIMT was significantly different in two study groups (0.68 ± 0.11 in PCOS vs 0.52 ± 0.02 in normal subjects, (P=0.01). FMD had significant negative correlation with homeostasis model assessment (HOMA) index (r = −0.32, P=0.02) and hs CRP (r = −0.37, P=0.04) while hs CRP was correlated with BMI (r = 0.54, P=0.005), HOMA (r = 0.38, P=0.02) and FMD (r = -0.33, P=0.01). CIMT was significantly different in women with PCOS and control subjects, and it had significant correlation with age (r = 0.42, P=0.03), BMI (r = 0.36, P=0.01), waist circumference (r = 0.52, P=0.001) and HOMA (r = 0.31, P=0.04).
Women with PCOS definitely have increased risk for future cardiovascular events. Clinicians should consider early cardiovascular screening and interventions to control all modifiable cardiovascular risk factors.
Atherosclerosis; cardiovascular risk; metabolic syndrome; polycystic ovary syndrome
The aim of the present study was to investigate the association between cardiovascular risk factors and endothelial dysfunction in patients with mixed connective tissue disease (MCTD) and to determine which biomarkers are associated with atherosclerotic complications, such as cardiovascular disease.
Fifty MCTD patients and 38 healthy age-matched and sex-matched controls were enrolled in this study. In order to describe endothelial dysfunction, we assessed flow-mediated dilation (FMD), nitrate-mediated dilation (NMD) and carotid artery intima-media thickness (IMT). We investigated FMD of the brachial artery after reactive hyperemia and NMD after sublingual nitroglycerin administration, while the IMT of the common carotid artery was determined by ultrasound. Anti-U1 ribonucleoprotein (anti-U1RNP) antibodies, anti-cardiolipin (anti-CL) antibodies, anti-endothelial cell antibody (AECA) and endothelial cell markers, such as soluble thrombomodulin (TM) and von Willebrand factor antigen (vWFAg), were assessed.
The endothelium-dependent vasodilation (FMD) was significantly impaired in patients with MCTD, as compared with controls (%FMD: 4.7 ± 4.2% vs. 8.7 ± 5.0%; P < 0.001), while the percentage NMD did not differ (%NMD: 14.3 ± 6.6% vs. 17.1 ± 6.7%; P = 0.073). Mean carotid IMT values were higher in patients than in controls (IMT: MCTD, 0.64 ± 0.13 mm vs. controls, 0.53 ± 0.14 mm; P < 0.001). FMD negatively correlated with disease duration, the levels of apolipoprotein A1, the paraoxonase-1 activity, and systolic blood pressure in MCTD patients. The percentage FMD was significantly lower in MCTD patients with cardiovascular diseases (CVD), than in those without CVD (%FMD: 3.5 ± 2.9 vs. 5.8 ± 4.8, P < 0.0002), while percentage NMD did not differ between patients with and without CVDs. Serum levels of autoantibodies (anti-U1RNP, AECA and anti-CL) were significantly higher in MCTD patients and differed between MCTD patients with and without CVD. Endothelial cell markers such as soluble TM (12.2 ± 8.1 ng/ml vs. 3.2 ± 1.3 ng/ml; P < 0.001) and vWFAg (224.1 ± 115% vs. 89.4 ± 27.1%, P < 0.001) were the highest in MCTD patients with CVD.
FMD is a reliable sensitive marker of endothelial cell dysfunction in MCTD. Beside the traditional risk factors, anti-U1RNP, AECA and anti-CL antibodies may be important not only in the pathogenesis of MCTD but in the induction of endothelial cell activation, and may play crucial roles in the development of early atherosclerosis in MCTD.
We evaluated the prevalence of endothelial dysfunction as measured by flow-mediated dilatation (FMD) of the brachial artery and carotid intima-media thickness (c-IMT) in relationship to vascular inflammatory biomarkers in preadolescent children with type 1 diabetes.
RESEARCH DESIGN AND METHODS
We studied 21 type 1 diabetic children (aged 8.3 ± 0.3 years with diabetes duration of 4.3 ± 0.4 years) and 15 group-matched healthy siblings (aged 7.6 ± 0.3 years). Fasting plasma glucose (FPG), lipid profile, HbA1c, high-sensitivity C-reactive protein (hs-CRP), fibrinogen, homocysteine, and erythrocyte (red blood cell [RBC]) folate were evaluated in all subjects. Each subject underwent c-IMT and brachial artery FMD percentage (FMD%) measurements using high-resolution vascular ultrasound.
Type 1 diabetic children had higher FPG (173.4 ± 7.9 mg/dL vs. 81.40 ± 1.7 mg/dL; P < 0.0001), HbA1c (8.0 ± 0.2% vs. 5.0 ± 0.1%; P < 0.0001), and hs-CRP (1.8 ± 0.3 vs. 0.70 ± 0.2; P = 0.017) than control children without significant differences in BMI, homocysteine, and fibrinogen levels; RBC folate content; and c-IMT between the groups. Children with type 1 diabetes had lower FMD% than control children (7.1 ± 0.8% vs. 9.8 ± 1.1%; P = 0.04), whereas c-IMT did not differ between groups.
Preadolescent children with type 1 diabetes and mean diabetes duration of 4 years displayed evidence of low-intensity vascular inflammation and attenuated FMD measurements. These data suggest that endothelial dysfunction and systemic inflammation, known harbingers of future cardiovascular risk, are present even in preadolescent children.
Abnormal postprandial elevation of plasma glucose and lipids plays an important role in the pathogenesis of diabetes and strongly predicts cardiovascular mortality. In patients suffering from type 2 diabetes (T2D) postprandial state is associated with oxidative stress, cardiovascular risk and, probably, with impairment of both secretion and the effect of gastrointestinal peptides. Evaluating postprandial changes of gastrointestinal hormones together with changes in oxidative stress markers may help to understand the mechanisms behind the postprandial state in diabetes as well as suggest new preventive and therapeutical strategies.
A standard meal test has been used for monitoring the postprandial concentrations of gastrointestinal hormones and oxidative stress markers in patients with T2D (n = 50) compared to healthy controls (n = 50). Blood samples were drawn 0, 30, 60, 120 and 180 minutes after the standard meal.
Both basal and postprandial plasma concentrations of glucose and insulin proved to be significantly higher in patients with T2D, whereas plasma concentrations of ghrelin showed significantly lower values during the whole meal test. In comparison with healthy controls, both basal and postprandial concentrations of almost all other gastrointestinal hormones and lipoperoxidation were significantly increased while ascorbic acid, reduced glutathione and superoxide dismutase activity were decreased in patients with T2D. A positive relationship was found between changes in GIP and those of glucose and immunoreactive insulin in diabetic patients (p<0.001 and p<0.001, respectively) and between changes in PYY and those of glucose (p<0.01). There was a positive correlation between changes in GIP and PYY and changes in ascorbic acid in patients with T2D (p<0.05 and p<0.001, respectively).
Apart from a positive relationship of postprandial changes in GIP and PYY with changes in ascorbic acid, there was no direct link observed between gastrointestinal hormones and oxidative stress markers in diabetic patients.
Cardiovascular disease is more common in patients with chronic kidney disease (CKD) than in the general population. Endothelial dysfunction is an early predictor of cardiovascular events.
We conducted a cross-sectional study in CKD patients to explore the association of metabolic syndrome (MetS) components with endothelial cell function.
We evaluated clinical and laboratory data in 161 CKD patients from stage 1 to stage 5. Endothelial function was estimated by flow-mediated dilatation (FMD) of the brachial artery and expressed as percentage change relative to baseline diameter. MetS was defined according to the National Cholesterol Education Program-Adult Treatment Panel III criteria.
Patients were grouped into two groups according to whether or not they had MetS. FMD was significantly lower in the MetS group than in the group without MetS (P = 0.012). In a Pearson’s correlation analysis, FMD was significantly negatively correlated with waist circumference in women (r = −0.223, P = 0.03) and fasting blood glucose (r = −0.186, P = 0.001). Multiple linear regression analysis showed that fasting blood glucose was an independently associated factor for FMD.
MetS and some components of MetS (waist circumference in women and fasting blood glucose) are closely associated with a decreased FMD in CKD patients.
metabolic syndrome; endothelial dysfunction; flow-mediated dilatation; chronic kidney disease
In the present study, we tested the hypothesis that age-associated vascular endothelial dysfunction is exacerbated by IFG (impaired fasting plasma glucose) and that regular aerobic exercise prevents this effect. Data were analysed from a cohort of 131 non-smoking men and women without overt clinical disease. Compared with young adult controls (age=24±1 years, n = 29; values are means ± S.E.M.), brachial artery FMD (flow-mediated dilation), a measure of conduit artery EDD (endothelium-dependent dilation), was 33% lower [7.93±0.33 against 5.27±0.37%Δ (% change), P < 0.05] in MA/O (middle-aged/older) adults with NFG (normal fasting plasma glucose) (≤99 mg/dl, 62±1 years, n = 35). In MA/O adults with IFG (100–125 mg/dl, 64±1 years, n = 28), FMD was 30% lower (3.37±0.35%Δ) than in their peers with NFG and 58% lower than young controls (P < 0.05). Brachial artery FMD was greater (6.38±0.35%Δ) in MA/O adults with NFG who regularly performed aerobic exercise (>45 min/day for ≥5 days/week, 62±1 years, n = 23) compared with their non-exercising peers and only slightly less than young controls (P < 0.05). Most importantly, FMD was completely preserved in MA/O adults with IFG who regularly performed aerobic exercise (6.99±0.69%Δ, 65±1 years, n = 16). In the pooled sample, fasting plasma glucose was inversely related to FMD (r = – 0.42, P < 0.01) and was the strongest independent predictor of FMD (R2 = 0.32). Group differences in FMD were not affected by other subject characteristics or brachial artery properties, including brachial artery dilation to sublingual NTG (nitroglycerine, i.e. endothelium-independent dilation). IFG exacerbates age-associated vascular endothelial dysfunction and this adverse effect is completely prevented in MA/O adults who regularly perform aerobic exercise.
aging; flow-mediated dilation; physical fitness; prediabetic state