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Short-Term Low-Carbohydrate High-Fat Diet in Healthy Young Males Renders the Endothelium Susceptible to Hyperglycemia-Induced Damage, An Exploratory Analysis

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Postprandial hyperglycemia has been linked to elevated risk of cardiovascular disease. Endothelial dysfunction and/or damage may be one of the mechanisms through which this occurs. In this exploratory study, we determined whether acute glucose ingestion would increase markers of endothelial damage/activation and impair endothelial function before and after a short-term low-carbohydrate high-fat diet (HFD) designed to induce relative glucose intolerance. Nine healthy young males (body mass index 23.2 ± 2 kg/m2) consumed a 75 g glucose drink before and <24 hours after consuming seven days of an iso-energetic HFD consisting of ~70% energy from fat, ~10% energy from carbohydrates, and ~20% energy from protein. CD31+/CD42b- and CD62E+ endothelial microparticles (EMPs) were enumerated at fasting, 1 hour (1 h), and 2 hours (2 h) post-consumption of the glucose drink. Flow-mediated dilation (FMD), arterial stiffness, and diameter, velocity, and flow of the common and internal carotid, and vertebral arteries were assessed in the fasting state and 1 h post glucose consumption. After the HFD, CD31+/CD42b- EMPs were elevated at 1 h compared to 2 h (p = 0.037), with a tendency for an increase above fasting (p = 0.06) only post-HFD. CD62E EMPs followed the same pattern with increased concentration at 1 h compared to 2 h (p = 0.005) post-HFD, with a tendency to be increased above fasting levels (p = 0.078). FMD was reduced at 1 h post glucose consumption both pre- (p = 0.01) and post-HFD (p = 0.005). There was also a reduction in FMD in the fasting state following the HFD (p = 0.02). In conclusion, one week of low-carbohydrate high-fat feeding that leads to a relative impairment in glucose homeostasis in healthy young adults may predispose the endothelium to hyperglycemia-induced damage.
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nutrients
Article
Short-Term Low-Carbohydrate High-Fat Diet in
Healthy Young Males Renders the Endothelium
Susceptible to Hyperglycemia-Induced Damage,
An Exploratory Analysis
Cody Durrer 1, Nia Lewis 1, Zhongxiao Wan 1, Philip N. Ainslie 1, Nathan T. Jenkins 2
and Jonathan P. Little 1 ,*
1School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, BC V1V 1V7,
Canada; cdurrer@live.com (C.D.); nialewis_26@hotmail.co.uk (N.L.); zhxwan@suda.edu.cn (Z.W.);
philip.ainslie@ubc.ca (P.N.A.)
2Department of Kinesiology, University of Georgia, Athens, GA 30602, USA; jenkinsn@uga.edu
*Correspondence: jonathan.little@ubc.ca; Tel.: +1-250-807-9876
Received: 22 December 2018; Accepted: 20 February 2019; Published: 26 February 2019


Abstract:
Postprandial hyperglycemia has been linked to elevated risk of cardiovascular disease.
Endothelial dysfunction and/or damage may be one of the mechanisms through which this occurs.
In this exploratory study, we determined whether acute glucose ingestion would increase markers
of endothelial damage/activation and impair endothelial function before and after a short-term
low-carbohydrate high-fat diet (HFD) designed to induce relative glucose intolerance. Nine healthy
young males (body mass index 23.2
±
2 kg/m
2
) consumed a 75 g glucose drink before and
<24 hours
after consuming seven days of an iso-energetic HFD consisting of ~70% energy from fat, ~10%
energy from carbohydrates, and ~20% energy from protein. CD31+/CD42b- and CD62E+ endothelial
microparticles (EMPs) were enumerated at fasting, 1 hour (1 h), and 2 hours (2 h) post-consumption of
the glucose drink. Flow-mediated dilation (FMD), arterial stiffness, and diameter, velocity, and flow
of the common and internal carotid, and vertebral arteries were assessed in the fasting state and 1 h
post glucose consumption. After the HFD, CD31+/CD42b- EMPs were elevated at 1 h compared
to 2 h (p= 0.037), with a tendency for an increase above fasting (p= 0.06) only post-HFD. CD62E
EMPs followed the same pattern with increased concentration at 1 h compared to 2 h (p= 0.005)
post-HFD, with a tendency to be increased above fasting levels (p= 0.078). FMD was reduced at 1 h
post glucose consumption both pre- (p= 0.01) and post-HFD (p= 0.005). There was also a reduction in
FMD in the fasting state following the HFD (p= 0.02). In conclusion, one week of low-carbohydrate
high-fat feeding that leads to a relative impairment in glucose homeostasis in healthy young adults
may predispose the endothelium to hyperglycemia-induced damage.
Keywords: high-fat diet; microparticles; EMPs; flow-mediated dilation; FMD
1. Introduction
Impaired glucose tolerance and type 2 diabetes mellitus (T2DM) are associated with increased
risk of cardiovascular disease (CVD; [
1
]) Accumulating evidence indicates that elevated postprandial
hyperglycemia is an independent risk factor for CVD and cardiovascular mortality in individuals
with, and without, T2DM [
2
]. The etiology of elevated postprandial hyperglycemia and increased
cardiovascular risk has not been firmly established [
3
] but endothelial dysfunction is hypothesized to
be the major mechanistic link [
4
]. Specifically, studies have shown that acute glucose infusion [
5
] or
ingestion [
6
] can cause impairment in flow-mediated dilation (FMD) of the brachial artery in humans.
Nutrients 2019,11, 489; doi:10.3390/nu11030489 www.mdpi.com/journal/nutrients
Nutrients 2019,11, 489 2 of 13
Such impairment in endothelial function caused by acute glucose excursions appears to be exacerbated
in conditions of glucose dysregulation, such that individuals with impaired glucose tolerance or T2DM
experience a greater decline in FMD in response to glucose ingestion [
7
]. Experimental studies in
humans [
6
] and mechanistic studies in cell culture [
8
] suggest that glycemic fluctuations may impair
endothelial function by increasing oxidative stress and promoting an inflammatory response. As such,
it is hypothesized that over time, repeated exposure to elevated postprandial hyperglycemia results in
cumulative endothelial damage that contributes to increased risk of CVD.
Although FMD is a well-established indicator of peripheral vascular function that is linked
to CVD risk [
9
], it does not provide details into the cellular or molecular responses of endothelial
cells. Endothelial microparticles (EMPs) are small (~100–1000 nm in diameter) vesicles shed from the
plasma membrane of endothelial cells in response to activation, apoptosis, or damage. Circulating
levels of EMPs are elevated in atherosclerosis, hypertension, T2DM, and metabolic syndrome [
10
],
and as such are regarded as biomarkers for endothelial damage and dysfunction. EMPs can be
characterized by the surface proteins associated with events triggering their release. CD31+/CD42b-
EMPs are believed to be shed from apoptotic endothelial cells, whereas CD62E+ (E-selectin) EMPs
indicate inflammatory activation of the endothelial cell of origin. Thus, measurement of circulating
CD31+/CD42b- and CD62E+ EMPs can provide direct insight into damage and inflammation of the
vascular endothelium [11].
The primary purpose of this exploratory investigation was to determine whether acute glucose
ingestion would increase EMP release and impair FMD in humans. In order to perturb glucose
tolerance, we studied the impact of a 75-gram oral glucose tolerance test (OGTT) drink before and
after a 7-day low-carbohydrate high-fat diet (HFD) in young healthy male participants. Short-term
HFDs have previously been shown to promote relative glucose intolerance in healthy human
participants [12,13]
, and therefore allowed us to determine whether glucose ingestion impacted EMP
release in the context of relative increase in postprandial hyperglycemia using a within-subjects
design. This approach has the advantage of limiting the influence of baseline vascular dysfunction
and endothelial damage that would have confounded a cross-sectional study comparing individuals
of differing glucose tolerance status. Since high-fat feeding in animal models has been linked to
endothelial damage and dysfunction [
14
], this design also provided the opportunity to determine the
impact of short-term HFD on basal EMP levels and FMD. In addition, cerebral blood flow (CBF) is
altered in response to HFDs in animals [
15
], however, data on extracranial CBF in humans is lacking.
For this reason, we took this opportunity to assess CBF as an exploratory outcome.
2. Materials and Methods
2.1. Participants
Participants were enrolled in an interdisciplinary study that was also investigating the effects of
high-fat feeding and glucose ingestion on inflammatory signalling and immune function in peripheral
blood mononuclear cells [
13
,
16
]. Participants were excluded from the study if they (1) had a diagnosed
metabolic disorder such as diabetes, metabolic syndrome, hypothyroidism, or any other condition
known to affect metabolism; (2) had a history of mental health disorders such as depression, substance
abuse, attention deficit hyperactivity disorder, or any other condition known to impact cognitive
function; (3) had a history of inflammatory disorders such as rheumatoid arthritis, Crohn’s disease,
irritable bowel syndrome, etc.; (4) had been prescribed any anti-inflammatory medication that they
were unable to avoid for the duration of the study; (5) were already consuming a low-carbohydrate diet
(e.g., “Atkins”, “Protein Power Plan”, “Paleo diet”, etc.); (6) had any dietary restrictions that would
inhibit adherence to the study diet; (7) were unable to abstain from drugs (prescription and recreational)
or alcohol for the duration of the study; (8) were unable to travel to and from the university in order
to make their testing appointments; (9) had a body mass index (BMI: mass in kg divided by height
in meters squared) > 30 kg/m
2
; (10) were not between the ages of 18–30 years old. All participants
Nutrients 2019,11, 489 3 of 13
that were enrolled in the primary study also took part in this exploratory study. Recruitment was
done via poster advertisement on the University campus and word of mouth. The study was fully
explained to the participants prior to starting and written informed consent was obtained. Procedures
were approved by the University of British Columbia Clinical Research Ethics Board.
2.2. Study Design
The study involved three visits to the laboratory over approximately two weeks. On the first visit,
the study was explained and written informed consent was obtained. Participants were provided with
a 3-day food record detailing their typical diet during two weekdays and one weekend day (Table 1).
Diet records were collected and analyzed prior to the second visit. During the second visit, all baseline
measures were recorded. Participants reported to the lab for this visit following an overnight (
8 hour)
fast. Pre-testing included blood sampling and vascular function testing carried out in a fasted state and
following consumption of a 75-gram oral glucose tolerance test (OGTT) drink. Following pre-testing,
participants were provided with individualized meal plans and prepackaged food for the next seven
days. Participants returned to the lab on the morning of the eighth day in a fasted state and repeated
the pre-testing at the same time of day.
Table 1. Pre- and post-HFD (high-fat diet) macronutrient and energy intake.
Variable Pre-HFD Post-HFD
Energy intake (kcal/day) 2584 ±456 2417 ±267
Fat intake (% daily energy) 37 ±6 71 ±0.6
Carbohydrate intake (% daily intake) 46 ±9 11 ±0.9
Protein intake (% daily intake) 17 ±3 18 ±0.6
kcal, kilocalories
2.3. Diet
Total energy intake and macronutrient profile of participant’s usual diets were determined from
the 3-day food records using FoodWorks Diet Analysis software (The Nutrition Company, Long Valley,
NJ, USA). Individualized low-carbohydrate high-fat diets (HFD; supplying ~70% energy from fat, ~20%
energy from protein, and ~10% energy from carbohydrates) isocaloric to usual intake (determined via
3-day diet records collected pre-HFD) were designed and prepared for each participant. Participants
were provided with individualized meal plans and prepackaged food for the seven-day intervention
and were instructed to only drink water during the study period. Participants were instructed to record
their diet during the intervention and these records were analyzed post-HFD to confirm compliance
(Table 1). Participants were instructed to maintain current levels of physical activity during the study.
2.4. Oral Glucose Tolerance Test
Following an overnight fast, participants reported to the laboratory for blood work and vascular
function measurements. A baseline blood sample (pre-HFD) was obtained from an antecubital vein
by venipuncture and collected into a 4-mL EDTA vacutainer tube (Becton-Dickinson, Franklin Lakes,
NJ, USA). Baseline fasting vascular function tests were performed (see below) and participants were
provided with a 75-gram oral glucose tolerance test (OGTT) drink (82.5 g dextrose monohydrate
dissolved in 250 mL water). Blood samples were taken by venipuncture at 60 and 120 minutes
post-OGTT. Tubes were placed on ice and, within 10 minutes, centrifuged for plasma collection at
1200 g for 15 minutes at 4 C.
Nutrients 2019,11, 489 4 of 13
2.5. Cardiovascular Measurements
2.5.1. Blood Pressure and Heart Rate
Continuous beat-to-beat measures of arterial blood pressure (BP; finger photoplethysmography;
Finapres Medical Systems, Biomedical Instruments, The Netherlands) and heart rate (HR; 3-lead
ECG; ML132, ADInstruments, Colorado Springs, CO, USA) were recorded. Manual blood pressure
recordings were taken at rest to calibrate the finger photoplethysmography measures. All data were
sampled continuously using an analogue-digital converter (PowerLab/4S ML750; ADInstruments,
Dunedin, New Zealand) interfaced with a computer and displayed in real time during testing.
Data were stored for subsequent off-line analysis using commercially available software (Chart v7,
ADInstruments, Dunedin, New Zealand). Baseline measures of BP and HR were averaged over
1 minute following 15-minutes of supine rest.
2.5.2. Flow-Mediated Dilation
Brachial artery vascular function was assessed by endothelium-dependent FMD according to
international guidelines [
17
]. A 10-MHz multifrequency linear array probe attached to a high-resolution
ultrasound machine (Terason 3000
TM
, Teratech, Burlington, MA, USA) was used to image the brachial
artery in the right arm. One minute of diameter and flow recordings preceded forearm cuff inflation
(>200 mmHg) for 5 minutes. Diameter and flow recordings resumed 30 seconds prior to cuff deflation
and continued for 3 minutes thereafter.
Custom-designed edge-detection and wall-tracking software, which is largely independent
of investigator bias, was utilised for the analysis brachial diameter and brachial blood flow
velocity [
17
,
18
]. This software provides continuous and simultaneous diameter, velocity, and shear
rate (SR;
4 x velocity/diameter
) measurements, as well as post-hoc calculation of FMD and vasodilator
capacity. This semi-automated software provides higher reproducibility of diameter measurements
and reduces both observer error and bias with a reported intra-observer coefficient of variation (CV)
for FMD% of 6.7% [
18
]. Data are presented as absolute (millimetres) and relative (percentage) rises
from the preceding baseline diameter and are calculated based on standardized algorithms applied
by the software [
17
]. In accordance with procedural recommendations [
19
21
], we also measured the
post-deflation area under the shear rate curve in order to best interpret any changes in FMD. All FMD
analyses were completed in a blinded fashion.
2.5.3. Extracranial Cerebral Blood Flow
Continuous diameter, velocity, and blood flow recordings in the right common carotid artery
(CCA), right internal carotid artery (ICA), and right vertebral artery (VA) were obtained using a 10-MHz
multifrequency linear array probe attached to a high-resolution ultrasound machine (Terason 3000,
Teratech, Burlington, MA, USA). The CCA and ICA were measured at least 1.5–2 cm from the carotid
bifurcation, whilst ensuring there was no evidence of turbulent or retrograde flow. The right VA
was measured between the transverse process of C4 and the subclavian artery, but always at the
same location within each subject. Average diameter and blood velocity recordings were made for
~30 seconds (see below), and care was taken to ensure probe position was stable so that the angle of
insonation did not vary from 60 degrees. The sample volume was positioned in the centre of the vessel
and adjusted to cover the width of the vessel diameter. Measurement settings for each extracranial
artery within each individual were standardized for all measurement sets.
All images were directly stored as an AVI file for offline analysis. Custom-designed edge-detection
and wall-tracking software was utilised for the analysis of CCA, ICA, and VA diameter, velocity blood
flow at 30 Hz [
17
]. Mean blood flow was determined as half the time averaged maximum velocity [
18
]
multiplied by the cross-sectional lumen area. This method has been adopted previously by others and
is used instead of the intensity weighted mean because the latter is more susceptible to noise and other
Nutrients 2019,11, 489 5 of 13
distorting influences [
22
,
23
]. Global cerebral blood flow (CBF) was estimated assuming symmetrical
bilateral flow in the ICA and VA [22,23] as: global CBF = (ICAFlow + VAFlow)×2.
2.5.4. Arterial Stiffness
Adhering to the international guidelines [
24
], hand held-tonometry (SPT-301 Millar Instruments,
Houston, TX, USA) was employed to assess central (carotid-femoral pulse wave velocity; PWV)
and peripheral (carotid-radial PWV) arterial stiffness. Twenty reproducible carotid-femoral artery
waveforms and 20 separate carotid-radial artery waveforms were recorded simultaneously using
mechanotransducers, which were applied directly to the skin and over the area of greatest pulsation.
The distance from the sternal notch to the individual carotid, femoral, and radial artery pulse sites
were measured along the surface of the body using a measuring tape. This technique was used as
it has been shown to have the best agreement with aortic PWV measured invasively using cardiac
catheterization [
25
]. The foot to foot method was used to determine pulse transit time, using a bandpass
filter (5–30 Hz) to identify the foot or “notch” of the carotid-femoral and -radial waveform, and the
difference in time from R interval to systolic upstroke at each location. Pulse distance was determined
by subtracting the distance from carotid measurement to the sternal notch from the distance from
the sternal notch to the femoral and radial pulse site measurement. Pulse-wave velocity was then
determined by dividing distance by pulse transit time.
2.6. Plasma Analysis
2.6.1. Glucose and Insulin
As previously reported [
13
], fingerstick blood glucose and plasma insulin was assessed throughout
the OGTT. Fingerstick blood glucose was assessed following a
8-hour overnight fast immediately
before and 15, 30, 60, and 120 minutes after consumption of the 75-g glucose drink using a OneTouch
®
UltraMini
®
meter (Lifescan, Milpitas, CA, USA). Insulin was assessed in plasma samples collected at
fasting as well as 60 minutes and 120 minutes post-OGTT drink consumption via ELISA (Mercodia,
Sweden) according to the manufacturer’s instructions.
2.6.2. EMPs
Circulating EMPs were measured in platelet poor plasma via flow cytometry (MACSQuant
Analyzer, Miltenyi Biotec, Bergisch Gladbach, Germany) as described previously [
26
]. Frozen plasma
samples were thawed at room temperature for 20 minutes and centrifuged at 1500 g for 15 minutes
at room temperature. The top two-thirds of plasma were then further centrifuged again at 1500 g for
15 minutes to obtain platelet-poor plasma. The top 100
µ
L of platelet poor plasma was then incubated
with fluorochrome labeled antibodies specific for CD62E (CD62E-phycoerythrin (PE), BD Biosciences
(Mississauga, ON, Canada) Cat. No. 551145), CD31 (CD31-V450, BD Biosciences, Cat. No. 561653),
and CD42b (CD42b-APC, BD Biosciences, Cat. No. 551061) for 20 minutes in the dark at 4
C. Samples
were then fixed with 93
µ
L of 2% paraformaldehyde and diluted up to 500
µ
L with sterile, 0.2-um
filtered, phosphate buffered saline. A size gate was determined using 0.9 um National Institute of
Standards and Technology-traceable polystyrene beads (Cat. No. 64019, Polysciences Inc., Warrington,
PA, USA). Unstained and fluorescence minus one control were used to differentiate between true
events and background/debris. EMPs were identified as CD62E+ and CD31+/CD42b- events within
the microparticle size gate.
2.7. Data Analyses
Linear mixed effects analyses of the effect of HFD and glucose consumption on FMD, EMPs,
glucose, insulin, and the vascular measures were performed using R [
27
] and the lme4 package [
28
].
As fixed effects, HFD and OGTT timepoint (glucose consumption) were entered into the model along
with the interaction term. Random intercepts for subject were used. Visual inspections of residuals
Nutrients 2019,11, 489 6 of 13
plots were used to assess homoscedasticity and normality. In instances where heteroscedasticity was
noted, log-transformations of the data were used to satisfy this assumption. p-Values were obtained
by likelihood ratio tests of the full models with the effect in question compared to models without
the effect in question. All individuals were included in the analyses. Significant interactions and
main effects of glucose consumption were followed up with Fisher least significant difference (LSD)
post-hoc tests. Results are reported as means and standard deviations, or mean differences (fasting
vs. post-OGTT or pre-HFD vs. post-HFD) with 95% confidence intervals. Cohen’s deffect sizes were
calculated for significant pairwise comparisons.
3. Results
3.1. Dietary Intervention
Nine healthy male subjects (21
±
3 years, 76
±
4 kg, 181
±
9 cm, BMI 23.2
±
2 kg/m
2
) participated
in this study. All participants complied with the HFD intervention, as described previously [13].
3.2. Oral Glucose Tolerance Test
Fingerstick blood glucose and plasma insulin have been reported previously [
13
]. One week of
HFD caused a relative impairment in glucose homeostasis in young healthy male subjects, as indicated
by a significantly higher glucose area under the curve (AUC) in response to the 75-g OGTT drink
following 7 days of HFD. Blood glucose measured at 30, 60, and 120 minutes post-OGTT were also
significantly higher post-HFD when compared to baseline [
13
]. There was no effect of HFD on insulin
during the OGTT. There was a main effect of time on plasma insulin with fasting (4.5
±
1.6 mU/L),
60-minute (40.1
±
26.7 mU/L), and 120-minute (22.8
±
13.3 mU/L) post-OGTT consumption levels all
being significantly different from each other (all p< 0.05).
3.3. Cardiovascular Measures
3.3.1. Blood Pressure and Heart Rate
There were no effects of the diet or OGTT on systolic or diastolic blood pressure (Table 2). However,
there were significant main effects of glucose consumption and HFD on mean arterial pressure. Mean
arterial pressure was reduced (
3.2 mmHg, 95% CI [
6.3,
0.1], Cohen’s d=
0.44) at 60 minutes
post-OGTT compared to fasting (p= 0.044). Mean arterial pressure was also reduced (
3.6 mmHg,
95% CI [6.64, 0.47], Cohen’s d=0.49) post-HFD compared to pre-HFD (p= 0.025).
Table 2.
Cardiovascular measures before and after a one-week HFD both fasting and 60 minutes
(1 h) post-OGTT.
Pre-HFD Post-HFD p-Value
Variable Fasting 1 h Fasting 1 h Time Condition Interaction
Systolic Blood Pressure (mmHg) 120.2 ±10 116.7 ±11.6 117.3 ±9 113.8 ±7.9 0.07 0.14 1
Diastolic Blood Pressure (mmHg) 72.2 ±7.6 67.8 ±8.5 66.9 ±8.5 65.3 ±7.2 0.14 0.06 0.46
Mean Arterial Pressure (mmHg) 88.2 ±5.4 84.1 ±6.5 83.7 ±7.8 81.5 ±6.6 0.04 0.03 0.52
Resting Heart Rate (BPM) 60.0 ±9.5 59.7 ±12.2 56.7 ±7.7 60.8 ±8.9 0.11 0.35 0.05
Central PWV (m/s) 5.7 ±0.5 5.8 ±0.4 5.6 ±0.8 5.4 ±0.5 0.59 0.16 0.34
Peripheral PWV (m/s) 7.8 ±1.5 7.4 ±1.2 7.1 ±0.6 7.2 ±1.1 0.53 0.03 0.26
CCA Diameter (cm) 0.68 ±0.03 0.70 ±0.03 0.69 ±0.04 0.70 ±0.04 0.04 0.96 0.71
CCA Velocity (cm/s) 35.52 ±6.82 35.06 ±4.20 34.27 ±3.86 33.48 ±4.97 0.61 0.22 0.94
CCA Flow (mL/s) 6.70 ±1.22 6.90 ±0.80 6.54 ±1.07 6.50 ±1.06 0.53 0.23 0.68
ICA Diameter (cm) 0.53 ±0.03 0.55 ±0.04 0.52 ±0.04 0.54 ±0.03 0.01 0.06 0.53
ICA Velocity (cm/s) 38.61 ±7.62 35.19 ±3.80 38.11 ±7.79 34.86 ±4.87 0.02 0.75 0.95
ICA Flow (mL/s) 4.35 ±1.09 4.15 ±0.82 4.00 ±0.87 3.97 ±0.62 0.41 0.06 0.53
VA Diameter (cm) 0.40 ±0.04 0.42 ±0.04 0.39 ±0.04 0.41 ±0.04 0.005 0.10 0.38
VA Velocity (cm/s) 19.86 ±4.53 19.40 ±3.94 20.33 ±3.26 20.02 ±3.50 0.41 0.24 0.87
VA Flow (mL/s) 1.32 ±0.51 1.37 ±0.53 1.26 ±0.39 1.36 ±0.40 0.16 0.46 0.60
mmHG, millimeters of mercury; PWV, pule wave velocity; BPM, beats per minute; m/s, meters per second; cm,
centimeters; cm/s, centimeters per second; mL/s, milliliters per second; CCA, common carotid artery; ICA, internal
carotid artery; VA, vertebral artery.
Nutrients 2019,11, 489 7 of 13
3.3.2. FMD
Baseline brachial artery diameters were similar prior to and after the HFD (pre-HFD: 0.41 cm,
95% CI [0.37, 0.44]; post-HFD: 0.42 cm, 95% CI [0.36, 0.47]; p= 0.62). In addition, there were no
differences in shear rate area under the curve (SRAUC) post-HFD or post glucose consumption (both
p> 0.05). The linear mixed-effects analysis revealed a significant effect of condition (p< 0.001) and
time (
p= 0.002
) on FMD (Figure 1). Post-hoc tests were conducted to compare pre-HFD and post-HFD
between timepoints, as well as pre-HFD vs. post-HFD at each timepoint. FMD showed a significant
decrease pre-HFD (
0.58%, 95% CI [
0.18,
0.98], p= 0.01, Cohen’s d=
1.29), and post-HFD (
0.58%,
95% CI [
0.23,
0.93], p= 0.005, Cohen’s
d=1.12
) in response to acute glucose ingestion. FMD
was also lower post-HFD compared to pre-HFD in the fasting state (
0.71%, 95% CI [
0.16,
1.27],
p= 0.02
, Cohen’s d=
0.75) and had a tendency to be lower post-OGTT (
0.72%, 95% CI [0.015,
1.45],
p= 0.053, Cohen’s d=0.99).
Nutrients 2019, 11, x FOR PEER 7 of 14
Figure 1. Flow-mediated dilation (FMD) assessed in the fasting state (Fasting) and 1-hour (1 h)
following consumption of a 75-g glucose drink pre and post 7-day high fat diet (HFD). Data are
expressed as the mean ± standard deviation (gray lines and large circles) and individually (solid and
dashed black lines and small circles). Significant difference from Fasting to 1 h is denoted as * (p <
0.05), significant difference pre vs. post HFD is denoted as # (p < 0.05).
3.3.3. Extracranial Cerebral Blood Flow
There were no differences in blood flow in CCA, ICA, or VA (all p > 0.05). Accordingly, global
CBF was also unaltered by the diet intervention or acute OGTT (p > 0.05). There was a significant
effect of time for ICA diameter (p = 0.01), VA diameter (p = 0.005), and CCA diameter (p = 0.044),
which revealed that ICA, VA, and CCA diameters were all larger (ICA: 0.017 cm, 95% CI [0.0044,
0.029], Cohen’s d = 0.52; VA: 0.015 cm, 95% CI [0.0049, 0.026], Cohen’s d = 0.60; CCA: 0.012 cm, 95%
CI [0.00031, 0.024], Cohen’s d = 0.18) at 60 minutes vs. fasting. There was no effect of HFD on any
vessel diameters (all p > 0.05). There were no differences in either CCA or VA velocity, however,
there was a main effect of time for ICA velocity, where velocity was slower at 60 minutes compared
to fasting (3.33 cm/s, 95% CI [5.98, 0.69]; p = 0.015, Cohen’s d = 0.08).
3.3.4. Arterial Stiffness
There was a significant main effect of diet for peripheral PWV (p = 0.027), with lower PWV
post-HFD (0.47 ms
-1
, 95% CI [0.89, 0.06], Cohen’s d = 0.48). Central PWV was unaltered by diet
(p = 0.15) and both central and peripheral PWV were unaltered by the OGTT (p > 0.05).
Table 2. Cardiovascular measures before and after a one-week HFD both fasting and 60 minutes (1 h)
post-OGTT.
Pre-HFD Post-HFD p-Value
Variable Fasting 1 h Fasting 1 h Time Condition Interaction
Systolic Blood Pressure
(mmHg) 120.2 ± 10 116.7 ± 11.6 117.3 ± 9 113.8 ± 7.9 0.07 0.14 1
Diastolic Blood Pressure 72.2 ± 7.6 67.8 ± 8.5 66.9 ± 8.5 65.3 ± 7.2 0.14 0.06 0.46
Figure 1.
Flow-mediated dilation (FMD) assessed in the fasting state (Fasting) and 1-hour (1 h)
following consumption of a 75-g glucose drink pre and post 7-day high fat diet (HFD). Data are
expressed as the mean
±
standard deviation (gray lines and large circles) and individually (solid and
dashed black lines and small circles). Significant difference from Fasting to 1 h is denoted as * (p< 0.05),
significant difference pre vs. post HFD is denoted as # (p< 0.05).
3.3.3. Extracranial Cerebral Blood Flow
There were no differences in blood flow in CCA, ICA, or VA (all p> 0.05). Accordingly, global CBF
was also unaltered by the diet intervention or acute OGTT (p> 0.05). There was a significant effect of
time for ICA diameter (p= 0.01), VA diameter (p= 0.005), and CCA diameter (p= 0.044), which revealed
that ICA, VA, and CCA diameters were all larger (ICA: 0.017 cm, 95% CI [0.0044, 0.029], Cohen’s
d= 0.52
; VA: 0.015 cm, 95% CI [0.0049, 0.026], Cohen’s d= 0.60; CCA: 0.012 cm, 95% CI [0.00031, 0.024],
Cohen’s d= 0.18) at 60 minutes vs. fasting. There was no effect of HFD on any vessel diameters
(
all p> 0.05
). There were no differences in either CCA or VA velocity, however, there was a main effect
of time for ICA velocity, where velocity was slower at 60 minutes compared to fasting (
3.33 cm/s,
95% CI [5.98, 0.69]; p= 0.015, Cohen’s d=0.08).
Nutrients 2019,11, 489 8 of 13
3.3.4. Arterial Stiffness
There was a significant main effect of diet for peripheral PWV (p= 0.027), with lower PWV
post-HFD (
0.47 m
·
s
1
, 95% CI [
0.89,
0.06], Cohen’s d=
0.48). Central PWV was unaltered by
diet (p= 0.15) and both central and peripheral PWV were unaltered by the OGTT (p> 0.05).
3.4. EMPs
There was a significant effect of time and diet for both CD31+/CD42b- (time: p= 0.03; diet:
p= 0.003
) and CD62E (time:
p= 0.02
; diet: p< 0.001) EMPs. Post-hoc analysis revealed that there was
a tendency for CD31+/CD42b- EMPs to be higher at 60 minutes when compared to fasting (95% CI
[
1.10, 6.71], p= 0.06, Cohen’s d= 0.68) and that CD31+/CD42b- EMPs were significantly higher at
60 minutes when compared to 120 mins post-OGTT (95% CI [1.10, 9.70], p= 0.037, Cohen’s
d= 0.72
) in
the post-HFD condition only (Figure 2A). CD62E EMPs followed the same pattern, with a tendency
towards higher levels at 60 minutes when compared to fasting (95% CI [
1.21, 16.5], p= 0.078, Cohen’s
d= 0.59) and significantly higher levels at 60 minutes compared to 120 minutes (95% CI [2.77, 57.85],
p= 0.005, Cohen’s d= 0.84; Figure 2B). CD62E EMPs were also significantly lower at 120 minutes
compared to fasting in both the pre-HFD (95% CI [
1.21,
5.89], p= 0.02, Cohen’s d=
0.54) and
post-HFD (95% CI [
1.13, 10.37], p= 0.03, Cohen’s d=
0.8) conditions. There were no correlations
between the change in FMD and the changes in either CD31+/CD42b- or CD62E EMPs (data not
shown, all p> 0.05).
Nutrients 2019, 11, x FOR PEER 9 of 14
Figure 2. (A) CD31+/CD42b- endothelial microparticles (EMPs) and (B) CD62E+ EMPs assessed in
the fasting state (Fasting), 1-hour (1 h), and 2-hours (2 h) following consumption of a 75-g glucose
drink pre and post 7-day high-fat diet (HFD). Data are expressed as the mean ± standard deviation
(gray lines and large circles) and individually (solid and dashed black lines and small circles).
Significant difference from 1 h to 2 h post-HFD is denoted as * (p < 0.05), significant difference from
fasting to 2 h post-HFD is denoted as † (p < 0.05).
4. Discussion
The main findings of the present study are that the one-week low-carbohydrate high-fat diet,
which causes relative glucose intolerance (as we reported previously; [13]), coincides with a
reduction in FMD in the fasting state and following ingestion of glucose. Furthermore, the
consumption of a HFD for one week led to increased levels of endothelial damage markers
(CD31+/CD42b- and CD62E+ EMPs) during a physiological excursion into hyperglycemia. These
findings indicate that a short-term HFD in young healthy men (i) can reduce FMD; and (ii) may
render the endothelium susceptible to hyperglycemia-induced damage. We also report findings on
the impact of glucose ingestion on extracranial CBF, with the main findings indicating that an acute
excursion into hyperglycemia induced increases in ICA, VA, and CCA diameter with a
corresponding reduction in velocity in ICA but no statistically significant changes in flow in any of
these vessels.
Our results indicate that FMD is attenuated in healthy young men after both an excursion into
hyperglycemia and following consumption of the HFD for one week. However, despite the
induction of relative glucose intolerance with the HFD, there were no synergistic (i.e., interactive)
Figure 2.
(
A
) CD31+/CD42b- endothelial microparticles (EMPs) and (
B
) CD62E+ EMPs assessed in the
fasting state (Fasting), 1-hour (1 h), and 2-hours (2 h) following consumption of a 75-g glucose drink
pre and post 7-day high-fat diet (HFD). Data are expressed as the mean
±
standard deviation (gray
lines and large circles) and individually (solid and dashed black lines and small circles). Significant
difference from 1 h to 2 h post-HFD is denoted as * (p< 0.05), significant difference from fasting to 2 h
post-HFD is denoted as † (p< 0.05).
Nutrients 2019,11, 489 9 of 13
4. Discussion
The main findings of the present study are that the one-week low-carbohydrate high-fat diet,
which causes relative glucose intolerance (as we reported previously; [
13
]), coincides with a reduction
in FMD in the fasting state and following ingestion of glucose. Furthermore, the consumption of a HFD
for one week led to increased levels of endothelial damage markers (CD31+/CD42b- and CD62E+
EMPs) during a physiological excursion into hyperglycemia. These findings indicate that a short-term
HFD in young healthy men (i) can reduce FMD; and (ii) may render the endothelium susceptible
to hyperglycemia-induced damage. We also report findings on the impact of glucose ingestion on
extracranial CBF, with the main findings indicating that an acute excursion into hyperglycemia induced
increases in ICA, VA, and CCA diameter with a corresponding reduction in velocity in ICA but no
statistically significant changes in flow in any of these vessels.
Our results indicate that FMD is attenuated in healthy young men after both an excursion
into hyperglycemia and following consumption of the HFD for one week. However, despite the
induction of relative glucose intolerance with the HFD, there were no synergistic (i.e., interactive)
effects between the two, as the consumption of 75 g of glucose led to a similar reduction in FMD pre-
and post-HFD. It is well established that FMD is reduced after consumption of an OGTT drink [
7
,
29
]
and a single high-fat meal in humans [
30
]. Furthermore, short-term high-fat diets are often used in
animal studies to induce endothelial dysfunction [
31
]. However, research examining FMD following
short-term low-carbohydrate high-fat diet interventions in young healthy human populations
is lacking. Longer duration low-carbohydrate high-fat diet interventions have demonstrated
increases [
32
], reductions [
33
], and no change [
34
] in FMD, but these studies contain confounding
factors, most importantly co-existing weight loss and caloric restriction. This inconsistency in the
literature makes it difficult to interpret the effect of repeated high-fat feeding on FMD in the absence of
weight loss. Our findings demonstrate that a short-term HFD leads to a reduction in FMD, similar
to the effect on FMD following a single high-fat meal. It has previously been suggested that the
impairment in FMD following the consumption of a high-fat meal could be attributed to heightened
oxidative stress and reduced nitric oxide (NO) bioavailability [35].
It is well established that acute hyperglycemia impairs endothelial function [
7
,
29
], which is also
suggested to be mediated by increased oxidative stress and reduced NO bioavailability [
36
]. A recent
meta-analysis investigating the acute effects of meal consumption on FMD reported an average
reduction of ~2% in postprandial FMD [
37
]. Our findings, although demonstrating a smaller decrease
in postprandial FMD (0.58%), are similar to the literature in that respect. Following the HFD,
glucose levels were higher after the OGTT, but the hyperglycemia-induced reduction in FMD was not
exacerbated (i.e., no interaction effects). This is perhaps suggestive of separate mechanisms leading to
the fasting reduction in FMD following the HFD, and the acute hyperglycemia-induced depression
in FMD. While the clinical relevance of these small reductions in FMD cannot be determined by the
present study in young healthy males, it is possible that the increase in risk would be even greater
for an already at-risk population. It is important to note that baseline brachial artery diameter and
SRAUC were unchanged throughout the study, indicating that the changes observed in FMD were not
due to these variables.
Microparticles (MP) are defined as submicron vesicles that are shed from the plasma membranes
of various cell types in response to activation, injury, and/or apoptosis [
10
]. Although initially regarded
as cellular debris [
38
], MPs are now recognized to play important physiological roles such as signalling
molecules (reviewed in [
39
]). MPs, including EMPs, can contain various biologically active molecules
such as proteins, cytokines, mRNAs, or microRNAs [
40
]. Expressed at the surface of MPs are most of
the membrane-associated proteins of their parent cells, making flow cytometry a viable method for
the detection and differentiation of these particles. It has been suggested that EMPs are markers of
damage, with CD62E+ EMPs being indicative of inflammatory activation and CD31+/CD42b- EMPs
indicative of apoptosis [
10
]. There seems to be a link between hyperglycemia and circulating EMPs,
given the elevated levels reported in T2DM patients [
41
]. Animal models have demonstrated that EMPs
Nutrients 2019,11, 489 10 of 13
generated under high-glucose conditions can induce vascular inflammation and impair endothelial
function, whereas EMPs generated from healthy endothelial cells do not [
42
]. For this reason,
we hypothesized that EMPs would increase following an excursion into hyperglycemia in humans
and that this might be related to endothelial function as measured by FMD. While we did observe
a reduction in FMD and an increase in circulating EMPs following consumption of a glucose load both
pre- and post-HFD, there was no correlation between EMPs and FMD. In addition, high-fat meals
have also been shown to increase circulating EMPs [
43
]; however, we did not observe an increase in
basal EMPs following the HFD, despite the reduction in FMD. This would indicate that the EMPs were
not directly responsible for the impairment in FMD, but rather both are mediated by other, possibly
separate, mechanisms. It also appears that the impact of the HFD, in terms of endothelial damage
markers, was only revealed when combined with hyperglycemia. This suggests that consuming a HFD
over the short-term predisposes the endothelium to hyperglycemia-induced damage.
We observed a significant increase in diameter in the ICA, VA, and CCA following consumption
of a 75-gram glucose drink, with no significant increase in flow in any of these vessels. It has previously
been reported that ICA diameter has been shown to increase with elevations in circulating insulin
concentration [
44
]. Indeed, there was a 10-fold increase in insulin concentration during the OGTT
when the increases in diameter were measured. A reduction in velocity was detected in the ICA,
which explains the consistent ICA flow. However, we did not detect statistically significant reductions
of velocity in the VA or CCA or in their respective blood flow. This is likely due to the relatively small
sample size and resultant insufficient power to detect such changes. Nonetheless, there appeared to be
no direct effects of the short-term HFD on basal CBF in young healthy men. The implications of more
chronic changes in glucose and insulin on cerebrovascular health and remodelling require future study.
We also observed a modest reduction in mean arterial pressure 60 minutes post glucose
consumption and a reduction in the fasting state following the HFD. It is possible that the reduction
following glucose consumption is related to splanchnic blood pooling, which is commonly seen in the
postprandial state [
45
]. The lower mean-arterial pressure seen post-HFD could be due to a reduction in
sympathetic tone. The finding of reduced peripheral PWV after the HFD supports this view, however,
without a direct measure of sympathetic tone in this, this remains speculative.
5. Conclusions
In conclusion, one week of high-fat, low-carbohydrate feeding that leads to a relative impairment
in glucose homeostasis in healthy young adults may predispose them to hyperglycemia-mediated
endothelial damage as well as a reduction in endothelial function. The findings also suggest that
a short-term HFD and acute glucose excursions may reduce FMD via separate and non-synergistic
mechanisms. Increased susceptibility of the endothelium to hyperglycemia-induced damage provides
evidence that the combination of a HFD with glucose ingestion could be detrimental to vascular health.
These findings are especially relevant given the recent increase in popularity of low-carbohydrate,
high-fat diets. These new findings suggest that if young, healthy males are following such diets,
a temporary lapse in adherence with consumption of a food causing a glucose spike might lead to
acute endothelial damage.
Author Contributions:
Conceptualization: J.P.L., C.D., Z.W., and P.N.A.; methodology: C.D., N.L., J.P.L., P.N.A.,
Z.W., and N.J; formal analysis: C.D. and N.L.; investigation: C.D., N.L., Z.W., and J.P.L.; resources: J.P.L. and
P.N.A.; data curation: C.D. and N.L.; writing—original draft preparation: C.D., J.P.L., and N.L.; writing—review
and editing: C.D., J.P.L., N.L., P.N.A., Z.W., and N.T.J.; visualization: C.D.; supervision: J.P.L., P.N.A., and N.T.J.;
project administration: C.D. and J.P.L.; funding acquisition: J.P.L.
Funding:
This research was funded by the Natural Sciences and Engineering Research Council (NSERC) of Canada
Discover Grant (DG-435807) awarded to J.P.L. J.P.L. supported by a Canadian Institutes of Health Research (CIHR)
New Investigator Salary Award (MSH-141980) and a Michael Smith Foundation for Health Research (MSFHR)
Scholar Award (16890).
Acknowledgments:
The authors would like to acknowledge the study participants for their time and efforts in
this investigation.
Nutrients 2019,11, 489 11 of 13
Conflicts of Interest:
J.P.L. is the co-Chief Scientific Officer for the Institute for Personalized Therapeutic Nutrition
(IPTN), a not-for-profit organization that promotes a food-first approach to the treatment and prevention of chronic
disease. J.P.L. is scientific advisor and holds shares in Metabolic Insights Inc., a for-profit company involved in the
development of non-invasive metabolic monitoring devices.
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... Effect of short-term high calorie and/or high-fat diet in inducing insulin resistance The literature consistently reports that short-term HC, HC with high-fat (HCHF) or HFD impair insulin action as measured by glucose tolerance tests, mixed meal challenges or hyperinsulinemic-euglycemic clamp ( Table 2), confirming that high-fat and/or HC diets are a suitable model to study dietinduced insulin resistance. For example, Durrer et al. [39] showed a 17% increase in glucose area under the curve during an oral glucose tolerance test (OGTT) after 7 days on an HFD. Morrison et al. [40] reported a 14% increase in post-prandial glucose area under the curve and a 31% increase in post-prandial insulin area under the curve following a mixed meal challenge after 28 days on an HC diet. ...
... Bui et al. [59] reported that the ingestion of a single high-fat meal (with 50 g of fat), compared to a low-fat meal (with 5.1 g of fat), significantly reduced total forearm blood flow (19.3%) as measured by venous occlusion plethysmography in healthy participants. Flowmediated dilation (FMD) is an indicator of vascular endothelial health and has been investigated in acute high fat meal ingestion studies (single meal) [60, 61] and short-term HFD studies [39,62]. Single high-fat meal studies report no change in FMD with the amount of fat ranging from 50-90g [60,61]. ...
... Single high-fat meal studies report no change in FMD with the amount of fat ranging from 50-90g [60,61]. Durrer et al. [39] showed reduced FMD and impaired glucose tolerance after 7 days of HFD (71% of total energy) in healthy participants. Keogh et al. [62] showed that HFD (with high saturated fat) reduces FMD by 50% within 3 weeks. ...
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There is increasing evidence that skeletal muscle microvascular (capillary) blood flow plays an important role in glucose metabolism by increasing the delivery of glucose and insulin to the myocytes. This process is impaired in insulin-resistant individuals. Studies suggest that in diet-induced insulin-resistant rodents, insulin-mediated skeletal muscle microvascular blood flow is impaired post-short-term high fat feeding, and this occurs before the development of myocyte or whole-body insulin resistance. These data suggest that impaired skeletal muscle microvascular blood flow is an early vascular step before the onset of insulin resistance. However, evidence of this is still lacking in humans. In this review, we summarise what is known about short-term high-calorie and/or high-fat feeding in humans. We also explore selected animal studies to identify potential mechanisms. We discuss future directions aimed at better understanding the ‘early’ vascular mechanisms that lead to insulin resistance as this will provide the opportunity for much earlier screening and timing of intervention to assist in preventing type 2 diabetes.
... Low-carbohydrate, high-protein diets, without consideration of the source of protein, were also associated with increased cardiovascular risk in Swedish women [140]. An interesting perspective is the impact of LCDs on cardiovascular risk factors, such as dyslipidemia, hypertension, obesity, postprandial hypoglycemia, and endothelial dysfunction [111,112,117,118,141,142]. A randomized trial comparing VLCD and calorie-restricted LFD in women with obesity indicated that VLCD was more efficient in short-term weight loss [111]. ...
... Another study proved that, in young adults of normal weight on LCDs for three weeks, LDL-C increased by 44% vs. the control group [141]. Only one week of an LCD leads to a relative impairment in glucose homeostasis in healthy young adults [142]. The authors stated that this process may predispose the endothelium to hyperglycemia-induced damage, but there is a need for further studies on young, healthy men [142]. ...
... Only one week of an LCD leads to a relative impairment in glucose homeostasis in healthy young adults [142]. The authors stated that this process may predispose the endothelium to hyperglycemia-induced damage, but there is a need for further studies on young, healthy men [142]. The most recent meta-analysis that is related to the effects of LCD on CVD risk factors confirmed that this type of diet has a beneficial effect on cardiovascular risk, but long-term studies are needed in order to confirm this [143]. ...
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The incidence of cardiometabolic diseases, such as obesity, diabetes, and cardiovascular diseases, is constantly rising. Successful lifestyle changes may limit their incidence, which is why researchers focus on the role of nutrition in this context. The outcomes of studies carried out in past decades have influenced dietary guidelines, which primarily recommend reducing saturated fat as a therapeutic approach for cardiovascular disease prevention, while limiting the role of sugar due to its harmful effects. On the other hand, a low-carbohydrate diet (LCD) as a method of treatment remains controversial. A number of studies on the effect of LCDs on patients with type 2 diabetes mellitus proved that it is a safe and effective method of dietary management. As for the risk of cardiovascular diseases, the source of carbohydrates and fats corresponds with the mortality rate and protective effect of plant-derived components. Additionally, some recent studies have focused on the gut microbiota in relation to cardiometabolic diseases and diet as one of the leading factors affecting microbiota composition. Unfortunately, there is still no precise answer to the question of which a single nutrient plays the most important role in reducing cardiometabolic risk, and this review article presents the current state of the knowledge in this field.
... Therefore, brachial artery FMD is an important therapeutic target in adults with obesity to prevent cardiovascular disease. Previous studies have examined the effect of LC diet on FMD but their findings are either confounded by the provision of CR [9,10,[12][13][14][15][16][17] or based on a single group design [31]. We found that the 6-week LC diet, regardless of CR, did not change FMD in women with obesity. ...
... Our findings may not be generalizable to men, other age groups, and disease populations, and even healthy individuals with normal body weight. In healthy young men whose BMI less than 30 kg/m 2 , a one-week LC without CR diet (~10% caloric intake from carbohydrate) significantly decreased brachial artery FMD [31]. However, our findings still provide clinically important implications. ...
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Obesity impairs both macro- and microvascular endothelial function due to decreased bioavailability of nitric oxide. Current evidence on the effect of low-carbohydrate (LC) diet on endothelial function is conflicting and confounded by the provision of caloric restriction (CR). We tested the hypothesis that LC without CR diet, but not LC with CR diet, would improve macro- and microvascular endothelial function in women with obesity. Twenty-one healthy women with obesity (age: 33 ± 2 years, body mass index: 33.0 ± 0.6 kg/m2; mean ± SEM) were randomly assigned to receive either a LC diet (~10% carbohydrate calories) with CR (n = 12; 500 calorie/day deficit) or a LC diet without CR (n = 9) and completed the 6-week diet intervention. After the intervention, macrovascular endothelial function, measured as brachial artery flow-mediated dilation did not change (7.3 ± 0.9% to 8.0 ± 1.1%, p = 0.7). On the other hand, following the LC diet intervention, regardless of CR, blocking nitric oxide production decreased microvascular endothelial function, measured by arteriolar flow-induced dilation (p ≤ 0.02 for both diets) and the magnitude was more than baseline (p ≤ 0.04). These data suggest improved NO contributions following the intervention. In conclusion, a 6-week LC diet, regardless of CR, may improve microvascular, but not macrovascular endothelial function, via increasing bioavailability of nitric oxide in women with obesity.
... It has been suggested that postprandial hypertriglyceridemia may contribute, at least in part, to such endothelial dysfunction via increased oxidative stress [13]. Very recently, Durrer C. et al. also observed a reduced FMD after HFD in healthy young men [14]. ...
... As shown recently [14], individual variations might occur. We therefore analyzed each subject's responses to the HFM and, interestingly, the FMD decreased significantly in 10 subjects. ...
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Endothelial dysfunction (ED), often linked to hypertriglyceridemia, is an early step of atherosclerosis. We investigated, in a randomized cross-over study, whether high-fat meal (HFM)-induced ED might be reduced by fruit juice or champagne containing polyphenols. Flow-mediated dilatation (FMD) and biological parameters (lipid profile, glycemia, inflammation, and oxidative stress markers) were determined before and two and three hours after the HFM in 17 healthy young subjects (24.6 ± 0.9 years) drinking water, juice, or champagne. Considering the entire group, despite significant hypertriglyceridemia (from 0.77 ± 0.07 to 1.41 ± 0.18 mmol/L, p < 0.001) and a decrease in Low Density Lipoprotein (LDL), the FMD was not impaired. However, the FMD decreased in 10 subjects (from 10.73 ± 0.95 to 8.1 3± 0.86 and 8.07 ± 1.16%; p < 0.05 and p < 0.01; 2 and 3 hours, respectively, after the HFM), without concomitant change in concentration reactive protein or reactive oxygen species, but with an increase in glycemia. In the same subjects, the FMD did not decrease when drinking juice or champagne. In conclusion, HFM can impair the endothelial function in healthy young subjects. Fruit juice, rich in anthocyanins and procyanidins, or champagne, rich in simple phenolic acids, might reduce such alterations, but further studies are needed to determine the underlying mechanisms, likely involving polyphenols.
... A casecontrol study shows that ketogenic diet can promote arterial stiffening and endothelial damage in children and young adults with epilepsy [105]. In addition, LCHFD shows no improvement of endothelial function (flow-mediated dilation) in normal weight, young, healthy women [106], while LCHFD may lead to a reduction in flow-mediated dilation and predispose the endothelium to hyperglycemia-induced damage in healthy young adults [107]. Indeed, the detrimental effect of ketogenic diet may be attributed to the formation of advanced glycation end (AGE) products, which promote vascular damages [108]. ...
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Healthy lifestyle and diet are associated with significant reduction in risk of obesity, type 2 diabetes, and cardiovascular diseases. Oxidative stress and the imbalance between prooxidants and antioxidants are linked to cardiovascular and metabolic diseases. Changes in antioxidant capacity of the body may lead to oxidative stress and vascular dysfunction. Diet is an important source of antioxidants, while exercise offers many health benefits as well. Recent findings have evidenced that diet and physical factors are correlated to oxidative stress. Diet and physical factors have debatable roles in modulating oxidative stress and effects on the endothelium. Since endothelium and oxidative stress play critical roles in cardiovascular and metabolic diseases, dietary and physical factors could have significant implications on prevention of the diseases. This review is aimed at summarizing the current knowledge on the impact of diet manipulation and physical factors on endothelium and oxidative stress, focusing on cardiovascular and metabolic diseases. We discuss the friend-and-foe role of dietary modification (including different diet styles, calorie restriction, and nutrient supplementation) on endothelium and oxidative stress, as well as the potential benefits and concerns of physical activity and exercise on endothelium and oxidative stress. A fine balance between oxidative stress and antioxidants is important for normal functions in the cells and interfering with this balance may lead to unfavorable effects. Further studies are needed to identify the best diet composition and exercise intensity.
... There have been concerns that LCHF diets may increase the risk of cardiovascular disease (CVD) due to the increased intake of dietary fats (Mansoor et al., 2016b), as saturated fat has been linked to higher levels of low-density lipoprotein (LDL) with increased vascular dysfunction (Vogel et al., 1997;Mensink et al., 2003;Kim et al., 2005;Grasgruber et al., 2016;Chiu et al., 2017;Lambert et al., 2017;Durrer et al., 2019). Diets high in fat have also been linked to disturbance in gut microbiota with increased gut permeability and inflammation (Murphy et al., 2015;Santos-Marcos et al., 2019). ...
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Low-carbohydrate-high-fat (LCHF) diets are efficient for weight loss, and are also used by healthy people to maintain bodyweight. The main aim of this study was to investigate the effect of 3-week energy-balanced LCHF-diet, with >75 percentage energy (E%) from fat, on glucose tolerance and lipid profile in normal weight, young, healthy women. The second aim of the study was to investigate if a bout of exercise would prevent any negative effect of LCHF-diet on glucose tolerance. Seventeen females participated, age 23.5 ± 0.5 years; body mass index 21.0 ± 0.4 kg/m2, with a mean dietary intake of 78 ± 1 E% fat, 19 ± 1 E% protein and 3 ± 0 E% carbohydrates. Measurements were performed at baseline and post-intervention. Fasting glucose decreased from 4.7 ± 0.1 to 4.4 mmol/L (p < 0.001) during the dietary intervention whereas fasting insulin was unaffected. Glucose area under the curve (AUC) and insulin AUC did not change during an OGTT after the intervention. Before the intervention, a bout of aerobic exercise reduced fasting glucose (4.4 ± 0.1 mmol/L, p < 0.001) and glucose AUC (739 ± 41 to 661 ± 25, p = 0.008) during OGTT the following morning. After the intervention, exercise did not reduce fasting glucose the following morning, and glucose AUC during an OGTT increased compared to the day before (789 ± 43 to 889 ± 40 mmol/L∙120min–1, p = 0.001). AUC for insulin was unaffected. The dietary intervention increased total cholesterol (p < 0.001), low-density lipoprotein (p ≤ 0.001), high-density lipoprotein (p = 0.011), triglycerides (p = 0.035), and free fatty acids (p = 0.021). In conclusion, 3-week LCHF-diet reduced fasting glucose, while glucose tolerance was unaffected. A bout of exercise post-intervention did not decrease AUC glucose as it did at baseline. Total cholesterol increased, mainly due to increments in low-density lipoprotein. LCHF-diets should be further evaluated and carefully considered for healthy individuals.
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Extracellular vesicles (EVs) encompassing nanovesicles derived from the endosome system and generated by plasmatic membrane shedding are of increasing interest in view of their ability to sustain cell-to-cell communication and the possibility that they could be used as surrogate biomarkers of healthy and unhealthy trajectories. Nutritional strategies have been developed to preserve health, and the impact of these strategies on circulating EVs is arousing growing interest. Data available from published studies are now sufficient for a first integration to better understand the role of EVs in the relationship between diet and health. Thus, this review focuses on human intervention studies investigating the impact of diet or its components on circulating EVs. Because of analytical bias, only large EVs have been assessed so far. The analysis highlights that poor-quality diets with elevated fat and sugar content increase levels of circulating large EVs, and these can be partly counteracted by healthy food or some food micronutrients and bioactive compounds. However, knowledge of the content and the biological functions of these diet-induced EVs is still missing. It is important to address these aspects in new research in order to state if EVs are mediators of the effects of diet on health.
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Alcohol abuse is positively associated with cardiovascular disease. Dietary low-carbohydrate/high-protein (LCHP) intake confers a greater mortality risk. Here, the impact of ethanol consumption in combination with dietary LCHP intake on left ventricular (LV) systolic function and lethal ventricular arrhythmia susceptibility were investigated in apolipoprotein E/low-density lipoprotein receptor double-knockout (AL) mice. The underlying mechanisms, cardiac sympathovagal balance, beta-adrenergic receptor (ADRB) levels, and gap junction channel protein connexin 43 (Cx43) expression, were examined. Male AL mice fed an LCHP diet with or without ethanol were bred for 16 weeks. Age-matched male AL and wild-type mice received standard chow diet and served as controls. The following were used to assess LV systolic function, lethal ventricular arrhythmia susceptibility, cardiac sympathovagal balance, Cx43 expression, and ADRB levels: •echocardiography •electrocardiography and a ventricular arrhythmia-evoked test •LV tyrosine hydroxylase (TH) expression shown by a fluorescence immunohistochemical examination and the ratio of low-frequency power to high-frequency power (LF/HF) as indicated by the heart rate variability (HRV) •Cx43 expression in both a fluorescence immunohistochemical examination and polymerase chain reaction (PCR); and ADRB1 and ADRB2 expressions in fluorescence immunohistochemical examination The results demonstrated that ethanol consumption in combination with dietary LCHP intake worsened LCHP-induced LV systolic dysfunction in AL mice and enhanced their susceptibility in the ventricular arrhythmia-evoked test. There were concomitant increases in LV weight, LF/HF ratio shown by HRV, TH, ADRB1, ADRB2, and Cx43 expressions by LV fluorescence immunohistochemistry, and LV Cx43 messenger ribonucleic acid expression by PCR. In AL mice, alcohol consumption combined with dietary LCHP intake may thus promote a shift in cardiac sympathovagal balance toward sympathetic predominance, the increases in beta-adrenergic receptors (ADRB1 and ADRB2), and then affect the gap junction channel protein Cx43, which in turn could contribute to increased risks of LV systolic dysfunction and susceptibility to lethal ventricular arrhythmia.
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Microparticles are submicron vesicles shed from a variety of cells. Peter Wolf first identified microparticles in the midst of ongoing blood coagulation research in 1967 as a product of platelets. He termed them platelet dust. Although initially thought to be useless cellular trash, decades of research focused on the tiny vesicles have defined their roles as participators in coagulation, cellular signaling, vascular injury, and homeostasis. The purpose of this review is to highlight the science leading up to the discovery of microparticles, feature discoveries made by key contributors to the field of microparticle research, and discuss their positive and negative impact on the pulmonary circulation.
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The prevalence of obesity is growing and now includes at least one-third of the adult population in the United States. As obesity and dementia rates reach epidemic proportions, an even greater interest in the effects of nutrition on the brain have become evident. This review discusses various mechanisms by which a high fat diet and/or obesity can alter the brain and cognition. It is well known that a poor diet and obesity can lead to certain disorders such as type II diabetes, metabolic syndrome, and heart disease. However, long-term effects of obesity on the brain need to be further examined. The contribution of insulin resistance and oxidative stress is briefly reviewed from studies in the current literature. The role of inflammation and vascular alterations are described in more detail due to our laboratory's experience in evaluating these specific factors. It is very likely that each of these factors plays a role in diet-induced and/or obesity-induced cognitive decline.
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Background: New diagnostic criteria for diabetes based on fasting blood glucose (FBG) level were approved by the American Diabetes Association. The impact of using FBG only has not been evaluated thoroughly. The fasting and the 2-hour glucose (2h-BG) criteria were compared with regard to the prediction of mortality. Methods: Existing baseline data on glucose level at fasting and 2 hours after a 75-g oral glucose tolerance test from 10 prospective European cohort studies including 15 388 men and 7126 women aged 30 to 89 years, with a median follow-up of 8.8 years, were analyzed. Hazards ratios for death from all causes, cardiovascular disease, coronary heart disease, and stroke were estimated. Results: Multivariate Cox regression analyses showed that the inclusion of FBG did not add significant information on the prediction of 2h-BG alone (P>.10 for various causes), whereas the addition of 2h-BG to FBG criteria significantly improved the prediction (P<.001 for all causes and P<.005 for cardiovascular disease). In a model including FBG and 2h-BG simultaneously, hazards ratios (95% confidence intervals) in subjects with diabetes on 2h-BG were 1.73 (1.45-2.06) for all causes, 1.40 (1.02-1.92) for cardiovascular disease, 1.56 (1.03-2.36) for coronary heart disease, and 1.29 (0.66-2.54) for stroke mortality, compared with the normal 2h-BG group. Compared with the normal FBG group, the corresponding hazards ratios in subjects with diabetes on FBG were 1.21 (1.01-1.44), 1.20 (0.88-1.64), 1.09 (0.71-1.67), and 1.64 (0.88-3.07), respectively. The largest number of excess deaths was observed in subjects who had impaired glucose tolerance but normal FBG levels. Conclusion: The 2h-BG is a better predictor of deaths from all causes and cardiovascular disease than is FBG.