The objective of this project is to study the effects of low levels of dietary AGEs in overweight subjects on insulin sensitivity, *-cell function, micro- and macrovascular function, and gut microbiota. The obtained insights can be used to attenuate…
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
- Glucose metabolism disorders (incl diabetes mellitus)
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of this study is to investigate the effect of dietary AGE
restriction on whole-body insulin sensitivity measured by the
hyperinsulinemic-euglycemic clamp.
Secondary outcome
Additionally, we aim to investigate the effects of restriction of dietary AGEs
on cardio-metabolic health, biomarkers of AGEs, inflammation, and the gut
microbiota. We will investigate the following parameters:
- Micro- and macrovascular function by means of skeletal muscle
contrast-enhanced ultrasound (CEUS) measurements, skin capillary
videomicroscopy, skin laser Doppler flowmetry, arterial flow mediated dilation
(FMD), and arterial stiffness (pulse wave velocity and local stiffness).
- AGE measurements in blood plasma and skin. The latter by means of skin
autofluorescence (SAF).
- Glucose metabolism and *-cell function during two consecutive 30-min
hyperglycaemic steps.
- Markers of endothelial function, inflammation, and adipokine markers in blood
plasma
- Gut microbiota using 16s rRNA sequencing
Background summary
Current efforts to arrest the epidemic of type 2 diabetes mellitus (T2DM) have
had limited success. Thus there is an urgent need for effective approaches to
prevent the development of T2DM. It is widely accepted that the current
epidemic is driven by an increase in global food abundance and reduced food
quality, making changes in diet a key determinant of the T2DM epidemic. Dietary
factors can affect cardio-metabolic health; among these factors, advanced
glycation end-products (AGEs) in food are potential risk factors for insulin
resistance and T2DM.
AGEs are a heterogeneous group of unavoidable stable bioactive compounds.
Endogenous formation of AGEs is a continuous naturally occurring process, and
is the result of normal metabolism. However, increased formation of AGEs occurs
during ageing and under hyperglycaemic conditions. AGEs are implicated in the
development of diabetes and vascular complications.
Over the past several decades, methods of food processing have changed and
meals now contain excess fat and sugar and are most susceptible for the
formation of AGEs. In addition, AGEs in food are highly desirable due to their
profound effect on shelf life, sterility, flavour, colour, and thus food
consumption. Hence, a substantial portion of AGEs are derived from exogenous
sources, particularly food. These exogenous AGEs are potential risk factors for
insulin resistance and the development of T2DM. We recently found that dietary
AGEs represent a significant source of circulating AGEs, and have similar
pathogenic properties compared to their endogenous counterparts including the
development of insulin resistance and T2DM. Taken together, dietary AGEs are
proposed to play a pivotal role in the development and progression of T2DM and
its complications. Reduction of dietary intake of AGEs may therefore be an
alternative strategy to reduce the risk of vascular disease and insulin
resistance. We therefore hypothesize that dietary restriction of AGEs in
overweight individuals improves insulin sensitivity, *-cell function, and
vascular function.
Study objective
The objective of this project is to study the effects of low levels of dietary
AGEs in overweight subjects on insulin sensitivity, *-cell function, micro- and
macrovascular function, and gut microbiota. The obtained insights can be used
to attenuate the development of diabetes, and to improve metabolic health in
populations at risk.
Study design
We will conduct a double-blind randomized controlled trial in overweight
subjects in two parallel groups in which the enrolled subjects will follow a
standard diet with either a low AGEcontent or a high AGE content, to determine
whether low dietary AGEs can improve insulin sensitivity, *-cell function, and
vascular function. We will use state-of-the-art UPLC-MS/MS to measure AGEs and
our recently developed dietary AGE database. We will prescribe diets which
differ greatly in AGE content, but which are carefully matched for energy and
macronutrients. Before and after the intervention period of 4 weeks, all
subjects will undergo a hyperinsulinemic-euglycemic clamp to determine insulin
sensitivity. In addition, we will combine these outcomes with macro- and
microvascular function, beta-cel function, gut microbial composition, and
biomarkers of AGEs, endothelial dysfunction and of low-grade inflammation,
Intervention
All subjects will undergo an intervention consisting of a prescribed diet
during 4 continuous weeks. Subjects will follow either a low AGE-diet or a
habitual Dutch diet. Both diets will be similar in energy and macronutrients,
and differ greatly in the amount of AGEs (approximately 75% difference)
Study burden and risks
The number of measurements in this study is quite substantial. Nonetheless, we
expect that the burden for the subjects is limited since all measurements are
performed in a supine, relaxed, and comfortable position and are merely
non-invasive. In addition to the measurements, participants undergo a partial
restricted lifestyle by following a dietary intervention for four weeks. This
could exert some unexpected low levels of strain on the subjects (e.g. stress,
unhappiness). However participants will receive detailed information and are
informed about the procedures of this study. Therefore, we do not expect
substantial discomfort or harm for the participants. Participants will
experience no harm from following the standard diet, because it is a habitual
Dutch diet. Therefore, participants will experience no additional exposure to
dietary AGEs. Additionally, potential benefits of participating in this study
are directly related to the possible beneficiary effects of AGE restriction.
Universiteitssingel 50
Maastricht 6229 ER
NL
Universiteitssingel 50
Maastricht 6229 ER
NL
Listed location countries
Age
Inclusion criteria
- Abdominal obesity: waist circumference for men should be * 102 cm, and for women * 88 cm.
- Caucasian
- Aged 18 years and older
- BMI * 25 kg/m2
Exclusion criteria
- Diabetes (i.e. using anti-diabetic medication, fasting glucose >7.0 mmol/L, HbAc1 > 6.5%).
- Active of history of cardiovascular disease (e.g. stroke, coronary artery disease, peripheral vascular disease, congestive heart failure, cardiac shunts, cardiac surgery, pulmonary hypertension, cardiac arrhythmias, family history of cardiac arrhythmias, or sudden cardiac death).
- Hyperlipidaemia (defined as serum total cholesterol > 8 mmol/L or TG > 4 mmol/L).
- Lipid lowering medication (e.g. statins).
- Use of medication known to influence glucose metabolism, vascular function, and/or lipid metabolism (e.g. statins, glucocorticosteroids, NSAID*s).
- Inability to stop anti-hypertensive medication for 8 weeks. Exclusion of higher grade hypertension (> 179 mmHG SBP and/or > 109 mmHg DBP) in order not to expose subjects to unnecessary risks).
- Pulmonary or inflammatory disease
- Kidney failure or electrolyte disorder
- Pregnancy or lactation
- No change in use of oral anticonceptives or IUD (12 weeks before the intervention).
- Unstable body weight (weight gain or loss > 3 kg in the last 2 months).
- Known allergic reaction to ultrasound contrast-agent
- Smoking (active or cessation <1 year prior to screening date).
- High alcohol usage (>4 U/day) or drug abuse
- Use of dietary supplements or an investigation product within the previous month
- Significant food allergies/intolerance
- Vegetarianism
- Subjects who intend to donate blood during the intervention or subjects who have donated blood less than three months before the start of the intervention.
- Participation in another biomedical trial during the past 30 days.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| CCMO | NL63215.068.17 |
| OMON | NL-OMON20660 |