The effects of timed-restricted eating on insulin sensitivity, de novo lipogenesis and liver fat in subjects with obesity and insulin resistance

Obesity is an alarming pandemic and its prevalence is still rising. The health
concerns they face are alarming. People with obesity and insulin resistance
have a significantly increased risk of developing type 2 diabetes mellitus,
cardiovascular disease, fatty liver disease and various cancers; these diseases
carry a high risk of premature death. In addition, current treatments for
obesity and related diseases are currently inadequate: the long-term results of
dietary interventions are disappointing, pharmacotherapeutic therapies are as
yet of limited effectiveness and bariatric surgery is an invasive, last-resort
therapy. The vastly increased morbidity and mortality, together with the still
growing prevalence and incidence of obesity, makes the intended study
population a large and unfavourable risk group. Recognition of its seriousness
is essential. In addition, the COVID-19 pandemic has further exposed the
underlying obesity pandemic, underscoring the urgency to address it. There is a
great need for cost-effective, minimally invasive interventions to reduce
obesity and associated health risks. An effective dietary intervention, which
does not lead to compensatory feelings of hunger, a strong decrease in resting
metabolism and/or a 'yo-yo effect', is ideally suited for this. Previous
research suggests that time-restricted eating (TRE) may lead to improvements in
multiple metabolic outcomes, such as insulin resistance, fatty liver disease
and hyperglycemia. A possible additional improvement is also seen when food
intake is limited to the morning hours (early TRE), although more research is
needed to determine the optimal times of consuming food (meal timing).
Moreover, insufficient research has been conducted so far into the effects of
time-restricted eating and meal timing in obese women. Therefore, a dietary
intervention study in both obese men and women is needed to investigate the
difference in effect of early versus late TRE on different metabolic outcomes.

Primary objectives: To determine the effects of combined isocaloric TRE and
meal timing on insulin sensitivity.

Secondary objectives: To determine the effects of combined isocaloric
time-restricted eating and meal timing on hepatic fat content, de novo
lipogenesis, resting energy expenditure and substrate oxidation rates, insulin
signalling, gut peptides, brain activity, behaviour, immune system and sleep
pattern and quality.

A randomized controlled cross-over interventional study

Diet intervention in which subjects will adhere to an isocaloric
time-restricted diet (eating period of 10h, followed by a 14h fast) with either
most of the calories in the morning or most of the calories in the evening

Risks assessment
- Stable isotopes are used as tracers, and have no radioactive properties. All
stable isotopes behave like their natural substrates and have been previously
used without adverse effects when infused or ingested in tracer amounts.
Occasionally [aanvullen]
- Venous blood sampling can be painful for a short time. There is a low risk of
local phlebitis, which is unpleasant, but self-limiting. In the study, we will
draw 15 mL of blood for screening and 100 mL on each study day. The total
volume of blood to be drawn during the whole study is 400 mL.
- MRI is a non-invasive imaging modality. All subjects will receive extensive
information about the MRI procedures beforehand. Subjects with contraindication
to MR scanning (e.g. pacemakers, claustrophobia, etc.) will be excluded. During
the study, there is a small chance of incidental findings. Specifically,
abnormalities can be observed in the MRI scan. Although the involved
researchers are not trained to detect any abnormalities, whenever in doubt,
they will consult a radiologist/neurologist. If the abnormality is judged as
(potentially) clinically relevant, a physician will be contacted. By signing
the informed consent form, the subject agrees with this procedure. If subjects
do not agree, they cannot participate in the studu.
- Muscle and subcutaneous adipose tissue biopsies could lead to minor
discomfort from the injection with lidocaine. A possible complication is a
local hematoma within the biopsy area, which will resolve spontaneously in the
following days. Bleeding from the biopsy site might occur, but this risk is
minimized by excluding subjects with coagulation disorders (see exclusion
criteria) and by checking local haemostasis. The day(s) after the biopsies,
participants will experience a sore feeling at the biopsy locations.
- Time-restricted eating entails a fasting period (here 14 hours) which is most
likely longer than the participants are familiar with. Participants might
therefore experience minor discomfort, but since the dietary intervention is
isocaloric and no glucose-lowering drugs are allowed, no symptoms of danger,
i.e. hypoglycemia, are to be expected.
- The COVID-19 pandemic as an ongoing crisis comes with potential restrictions.
With due consideration of our hospital*s advisory guidelines to prevent the
spread of the virus, we believe that the feasibility of the study will not come
into jeopardy. Reasonably, unforeseen restrictions imposed by the government
that would hinder continuance of the research project are not inconceivable but
impossible to take into account and - to the best of our current knowledge -
unlikely to occur before long. Above all, obesity being one of the risk factors
for severe illness from COVID-19, the need for non-invasive, cost-effective
interventions to tackle obesity is even more accentuated. This emphasises the
importance of this study.

We realise that some of the procedures in this study protocol might lead to
minor discomfort. Taking all arguments into account (including our experience,
adverse events reported in literature, possible unknown risks and the study
population), our assessment is that participation is associated with a small
chance of moderate harm, and - compared to standard patient care - the
additional overall risk can be classified as marginal (Kwaliteitsborging
mensgebonden onderzoek 2.0, NFU, oktober 2012). The described procedures are
inevitable in order to achieve our objectives. We believe that the burden and
risks associated with participation will be kept to a minimal, and that the
scientific value of our findings will outweigh the risks described. The
participants could directly benefit from the results of this study and the
results can be extrapolated to the majority of the obese population.