Impact of Circadian Misalignment on Insulin Sensitivity

The prevalence of T2DM has increased rapidly over the last decades, posing a
major burden on the health care system. A major determinant in the development
of T2DM is insulin resistance of metabolic tissues such as skeletal muscle and
liver, which precedes overt T2DM often by several decades. Interestingly,
recent evidence shows that misalignment of the circadian rhythm (e.g. by
rotating shift work) impairs glucose metabolism markedly, possibly by
decreasing insulin sensitivity in peripheral tissues and liver. Nowadays our
society is indispensably connected to a lifestyle that allows wakefulness at
every time of the 24 hours cycle. Social jetlag is a phenomenon that affects a
large part of the general population, thus circadian misalignment extends far
beyond those who are on a shift work schedule. Therefore, decreased insulin
sensitivity in individuals affected by circadian misalignment may help to
explain the increased prevalence of T2DM in night shift workers that has been
found in epidemiological studies. The impact of circadian misalignment on
insulin sensitivity has to date only been assessed by indirect measurements,
such as the intravenous glucose tolerance test (IVGTT), without investigating
the underlying mechanisms. Considering the essential role of insulin resistance
in the aetiology of T2DM, investigating the underlying mechanisms is crucial.
The findings from this study can ultimately lead to novel therapeutic
strategies that will help to attenuate the development of metabolic disease in
populations at risk.

The primary objective is to measure whole body and hepatic insulin sensitivity
in healthy young subjects at baseline and in response to an inverted sleep-wake
cycle (12-hour circadian misalignment). Secondary objectives comprise the
investigation of underlying mechanisms that regulate peripheral insulin
sensitivity (e.g. mitochondrial capacity).

The study is an interventional randomized crossover trial in which each subject
serves as it owns control. For the study, we ask the subjects to participate in
two study periods, one of 3 days length (control condition) and the other of
3.5 days length (misalignment condition). Before each study period, subjects
must adhere to a standardised lifestyle of 7 days.

The study contains a behavioural intervention. During the 3.5 day misalignment
condition, subjects will shift their day-night rhythm by 12 hours, which will
lead to maximal circadian misalignment. During this intervention, subjects will
be awake during the normal night and sleep during the normal day. During both
study periods, subjects must adhere to a standardised behavioural protocol
under dim light conditions.

Subjects will first visit the University once for screening purposes during
which they will fill in 2 questionnaires. If screening was successfully
completed, subjects will visit the University 7 days before each study period
to receive a wrist worn sleep monitoring device (Actiwatch) and a sleep diary,
to assess their sleep duration and quality. During the 7 day monitoring period
at home, subjects will have to adhere to a pre determined lifestyle with
regular sleep-wake cycle which may limit them in their choice of daily
activities. Subject will then visit the University for two study periods, which
last for 3 and 3.5 days respectively, interrupted by 3 weeks. During the two
study periods, subjects will stay inside the MRUM.
For the main outcome measurements, subjects will undergo one hyperinsulinemic
euglycemic 2-step clamp and 3 muscle biopsies during each study period.
Furthermore, subject will undergo several blood draws (in total approximately
362ml per period). Muscle biopsies lead to mild discomfort and there is a risk
of hematoma. During the hyperinsulinemic clamp, a risk of hypoglycaemia exists.
During the misalignment condition, subjects will sleep during the day and be
awake during the habitual sleep time, which may result in mild discomfort
(similar to a jetlag).