The main objective of this study is to investigate if exercise training improves 24h rhythmicity in substrate metabolism in prediabetes subjects. Secondary objectives include linking 24h substrate metabolism to day-night differences in mitochondrial…
ID
Source
Brief title
Condition
- Diabetic complications
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary study endpoint is 24h rhythmicity in substrate metabolism including
whole-body energy metabolism (energy expenditure, respiratory quotient).
Secondary outcome
Secondary study endpoints refer to 24h blood profile of glucose, insulin, free
fatty acids and triglycerides as well as skeletal muscle clock gene expression
and mitochondrial respiration. In addition, 24h rhythmicity in core body
temperature, salivary melatonin and cortisol and the 24h profile of mRNA and
protein levels in peripheral blood mononuclear cells (PBMC*s) involved in the
molecular clock.
Background summary
A disturbed circadian rhythm has recently been suggested to be an important
factor in the development of type 2 diabetes (T2DM). Epidemiologic studies show
that shift work is associated with an increased risk to develop T2DM. Moreover,
we and others have shown that controlled circadian misalignment in healthy
individuals leads to detrimental effects on insulin sensitivity and muscle
metabolism. Next to the central clock in the brain most peripheral tissues also
have their own intrinsic molecular clock. Indeed, it has been previously shown
that healthy human volunteers skeletal muscle displays 24h rhythmicity in
molecular clock gene expression and mitochondrial function. Very intriguingly,
there is evidence to sugegst that this 24h rhythmicity in mitochondrial
function is virtually absent in pre-diabetes volunteers, along with
disturbances in the skeletal muscle molecular clock. This disturbed day-night
rhythm in the skeletal muscle of pre-diabetes subjects was accompanied by
marked alterations in 24h substrate metabolism, indicating metabolic
inflexibility. Together, these findings suggest that circadian rhythmicity of
muscle metabolism may indeed be involved in the aetiology of T2DM.
We here aim to investigate if the disturbed 24h rhythmicity in skeletal muscle
clock gene expression and mitochondrial function in pre-diabetes volunteers can
be restored, and if a potential restoration is accompanied by improvements in
24h substrate metabolism. Whereas exercise has been shown to promote
mitochondrial function and insulin sensitivity, we will investigate the
capability of exercise training to concurrently restore day-night rhythmicity
in pre-diabetes human volunteers.
Study objective
The main objective of this study is to investigate if exercise training
improves 24h rhythmicity in substrate metabolism in prediabetes subjects.
Secondary objectives include linking 24h substrate metabolism to day-night
differences in mitochondrial function and clock gene expression in skeletal
muscle.
Study design
The present study is a single-arm longitudinal study in a pre and post design
with subjects serving as their own control.
Intervention
Subjects will perform a 12-week supervised exercise training program with three
~30 min exercise sessions per week. Pre and post intervention, subjects will
stay at the research unit for 45 hours, where they will receive standardized
meals and undergo a standardized sleep-wake cycle, while staying in the
respiration chambers. During this period, rhythmicity in 24h energy- and
substrate metabolism, circulating blood substrates and muscle gene expression
as well as mitochondrial function will be determined.
Study burden and risks
Before starting the exercise training, subjects will visit the University 3
times for the screening and pre-intervention test days including a 45h stay at
the research unit. During the exercise intervention period, subjects will visit
the University 3 times per week for 12 weeks to receive supervised exercise
training. After finishing the last exercise session, subjects will again stay
at the research unit for 45h and measurements will be repeated.
The main burden of this study is the large time investment for the exercise
training period (12 weeks, 3 times/week). Furthermore, subjects are asked to
adhere to a standardized lifestyle 1 week before the pre- and post-training
test days. Moreover, the pre- and post-training test days comprise several
non-invasive and invasive measurements. The used techniques are safe, but the
muscle biopsies can cause some discomfort and may result in a local bruise or
hematoma. Likewise, blood sampling can cause a local hematoma. The risk of
infection and/or prolonged bleeding is very low due to state of the art
techniques and sterility measures.
Universiteitssingel 50
Maastricht 6229ER
NL
Universiteitssingel 50
Maastricht 6229ER
NL
Listed location countries
Age
Inclusion criteria
• Caucasian
• Healthy (as determined by dependent physician based on medical questionnaire)
• Male
• Age: 40-75
• Overweight: BMI 25 - 35 kg/m2
• Prediabetic based on one or a combination of the following criteria:
o Impaired Glucose Tolerance (IGT): plasma glucose values >= 7.8 mmol/l and <=
11.1 mmol/l 120 minutes after glucose drink consumption during OGTT in
screening.
o Impaired Fasting Glucose (IFG): Fasting plasma glucose >= 6.1 mmol/l and <= 6.9
mmol/l.
o Insulin Resistance: glucose clearance rate <= 360 ml/kg/min, as determined
using OGIS120.
o HbA1c of 5.7-6.4%.
• Regular sleeping time (normally 7 - 9h daily)
• Stable dietary habits: no weight gain or loss > 3kg in the last three months
Exclusion criteria
• Fasting plasma glucose >= 7.0 mmol/l
• Haemoglobin < 7.8 mmol/l
• In case of an abnormal ECG in rest: this will be discussed with the
responsible
medical doctor
• Previously diagnosed with type 2 diabetes
• Any medical condition and/or medication that might interfere with the
investigated parameters as judged by study physician.
• Current alcohol consumption > 20 grams alcohol/day
• Subjects who do not want to be informed about unexpected medical findings
during the screening /study, or do not wish that their physician is informed, 1
month prior to the screening visit
o Claustrophobia
o Epilepsy
• Any contra-indication to the Equivital telemetric pill:
o Known or suspected obstructive disease of the gastrointestinal tract
o History of disorders or impairment of the gag reflex
o Previous gastrointestinal surgery
o Felinization of the esophagus
o Hypomotility disorders of the gastro-intestinal tract
• Implanted electromedical device
• Extreme early bird or extreme night person (score <=30 or >=70 on MEQ-SA
questionnaire, document F1-2)
• Heavily varying sleep-wake rhythm
• Nightshiftwork during last 3 months
• Travel across > 1 time zone in the last 3 months
• Engagement in exercise > 2 hours total per week
• Significant food allergies/intolerance (seriously hampering study meals)
• Participation in another biomedical study within 1 month before the first
study visit
• Using > 400mg caffeine daily (more than 4 coffee or energy drink)
• Smoking
• Any acute condition, exacerbation of chronic condition, or medical history
that would in the investigator*s opinion interfere with the study
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL73834.068.20 |