The relation between sleep characteristics and glycemic control in patients with type 1 diabetes mellitus (with a special focus on role of the skin temperature regulation in relation to sleep)

Type 1 diabetes mellitus (DM1) is caused by destruction of pancreatic β-cells
which results in absolute insulin deficiency. Intensive treatment is essential
to obtain optimal glucoregulation, because diabetic complications depend on the
degree of long term hyperglycemia. However, glucoregulation can not be
normalized in patients with DM1. This is reflected in relatively large
variations in blood glucose levels and relatively high HbA1c levels compared to
healthy subjects.
There is a relation between sleep characteristics and metabolic
regulation. Decreased sleep duration and/or quality can induce glucose
intolerance and a reduction in the acute insulin response to glucose in healthy
volunteers Decreased sleep quality is also a significant predictor of HbA1c
values in patients with DM2. For instance, disruption of slow wave sleep (SWS)
can be responsible for the adverse effects of sleep on glucose metabolism.
There is only limited knowledge of sleep patterns in patients with DM1. A
recent study provided evidence for an altered sleep architecture in patients
with DM1 under non-hypoglycaemic conditions. These patients showed a tendency
toward less deep sleep, with decreased amounts of slow wave sleep (SWS) during
the first half of the night.
In healthy controls, there is a relationship between sleep and the
thermoregulatory system. The circadian rhythms of core body temperature (CBT)
and skin temperature show a day-night rhythm that is linked to the sleep-wake
cycle. The circadian rhythm of the CBT is characterized by a relatively low
temperature throughout the nocturnal sleeping period and a relatively high
temperature during the daytime waking period. The decrease in CBT in the
evening is achieved by allowing heat to be lost. The underlying mechanism is an
increase in skin blood flow caused by reduction of hypothalamically regulated
sympathetic cutaneous vasoconstrictor tone, causing skin warming and
dissipation of body heat. In normal sleeping conditions, skin temperature in
people is therefore higher during the sleep, a rhythm that is the inverse of
that of the CBT.
It has been proposed that autonomic changes in skin temperature modulate the
neuronal activity of thermosensitive neurons in the preoptic area/ anterior
hypothalamus (POAH), which in turn regulate vigilance and sleepiness. A
relatively high temperature of the distal skin (hands and feet) compared to
that of the proximal skin proved to be related to the process of falling
asleep; in other words a higher *distal-to-proximal gradient* (DPG) predicts
sleep onset. Experiments applying controlled skin warming indicate that both
proximal and distal skin temperature variations within the comfortable range
causally affect sleep. Decreased CBT and increased skin temperature is
associated with shortened sleep onset latency, decreased body movement during
sleep and an increase in stage 3 of the non-REM (NREM) sleep. These findings
indicate that the body temperature is a crucial factor affecting SWS. An
impaired ability to lose heat from the periphery is associated with sleep onset
insomnia.
These findings may be of particular relevance for patients with diabetes
because distal thermoregulation is impaired during sleep in patients with DM,
even in patients without clinical evidence of polyneuropathy. Polyneuropathy,
probably the most common complication of longstanding DM [38], is likely to
aggravate this problem. On the one hand sensory nerve damage will impair the
afferent information on skin temperature to hypothalamic areas involved in
thermoregulation and sleep regulation. On the other hand, visceromotor nerve
damage will impair the ability to control both vasomotor and sudomotor tone,
attenuating the ability to control skin temperature.

If patients with DM1 indeed have an altered skin temperature regulation before
and during sleep, this could disturb their sleep characteristics, which in turn
have an impact on glucoregulation. A vicious cycle may well ensue.

To investigate the association between sleep characteristics and
glucoregulation (HbA1c) and sleep in patients with DM1.
- Is there a relation between sleep characteristics and the quality of
glycemic
control in patients with DM1*?

To compare the relation between core and skin temperature and sleep
characteristics in patients with DM1 and healthy controls.
- *Is the relation between core and skin temperature and sleep characteristics
altered in patients with DM1*?

To determine whether diabetic polyneuropathy alters the relation between skin
temperature and sleep characteristics.
- *Are the core and/or skin temperature during sleep altered by diabetic
polyneuropathy in patients with DM1*?

The study consists of 1 study day.
In addition, measurements will be done at home.

•Assessment for polyneuropathy will include quantitative sensory testing using
the "Thermal Sensory Analyzer" (TSA) and the modified Toronto Clinical
Neuropathy score (mTCNs) will be performed.

- Subjective sleep quality/sleepiness by sleep questionnaires and SART

•After the assessment of the absence/presence and severity of the neuropathy
the 9 iButton Temperature monitors will be affixed by the researcher on
standardized places on the body (see Appendix D) to measure the distal and
proximal skin temperatures. The iButtons will be worn for at least 3 days (72
hours). The subjects will be instructed to keep the devices attached throughout
the study period, except during bathing and swimming.

•For the measurement of the CBT the patients and healthy controls will ingest a
JONAH capsule at home. They will be asked to swallow the Jonah-capsule at home
at 4 p.m. After swallowing the capsule they will be asked to eat and drink only
products of ± 37 degrees Celsius. Participants will be allowed to consume the
standard meal and drinks provided by us which only consist of only food and
drinks with fixed temperature, the 37 degrees.

•The patients and healthy controls will be asked to wear an Actiwatch during 7
days, which will be measure the activity and movements during the day and night
and the sleep-wake ratio. The subjects will be requested to maintain a diary
for the period they wear the Actiwatch. They will be asked to record the date,
general activity, start and end time of the activity, whether they were
outside, inside or both during the activity and the exact times the devices
will removed for bathing or other activities. (Appendix G)

•Only the DM1 patients will be asked to wear a subcutaneous glucose sensor at
home during 5 days

•At the end of the study we will select two subgroups of 10 patients with DM,
with extremes in PSQI scores ,who will underwent a polysomnography (PSG) to
assess the relation between glucoregulation and thermoregulation with the
objective sleep parameters.

•Assessment for polyneuropathy will include quantitative sensory testing using
the "Thermal Sensory Analyzer" (TSA) and the modified Toronto Clinical
Neuropathy score (mTCNs) will be performed.

•After the assessment of the absence/presence and severity of the neuropathy
the 9 iButton Temperature monitors will be affixed by the researcher on
standardized places on the body (see Appendix D) to measure the distal and
proximal skin temperatures. The iButtons will be worn for at least 3 days (72
hours). The subjects will be instructed to keep the devices attached throughout
the study period, except during bathing and swimming.

•For the measurement of the CBT the patients and healthy controls will ingest a
JONAH capsule at home. They will be asked to swallow the Jonah-capsule at home
at 4 p.m. After swallowing the capsule they will be asked to eat and drink only
products of ± 37 degrees Celsius. Participants will be allowed to consume the
standard meal and drinks provided by us which only consist of only food and
drinks with fixed temperature, the 37 degrees.

•The patients and healthy controls will be asked to wear an Actiwatch during 7
days, which will be measure the activity and movements during the day and night
and the sleep-wake ratio. The subjects will be requested to maintain a diary
for the period they wear the Actiwatch. They will be asked to record the date,
general activity, start and end time of the activity, whether they were
outside, inside or both during the activity and the exact times the devices
will removed for bathing or other activities. (Appendix G)

• Only the DM1 patients will be asked to wear a subcutaneous glucose sensor at
home during 5 days

• At the end of the study we will select two subgroups of 10 patients with DM,
with extremes in PSQI scores ,who will underwent a polysomnography (PSG) to
assess the relation between glucoregulation and thermoregulation with the
objective sleep parameters.

he subjects will be asked to visit our hospital (duration about 4 hours). In
addition, measurements will be done at home.